Biomaterials 237 (2020) 119827

Contents lists available at ScienceDirect

Biomaterials
journal homepage: www.elsevier.com/locate/biomaterials

Review

Advances in nanomaterials for photodynamic therapy applications: Status T

and challenges
Jianming Chena, Taojian Fana, Zhongjian Xiea, Qiqiao Zengb, Ping Xuec, Tingting Zhengd,
Yun Chend, Xiaoling Luob,∗, Han Zhanga,∗∗
a
Institute of Microscale Optoelectronics, Collaborative Innovation Centre for Optoelectronic Science & Technology, Key Laboratory of Optoelectronic Devices and Systems of
Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen Key Laboratory of Micro-Nano Photonic Information
Technology, Guangdong Laboratory of Artificial Intelligence and Digital Economy (SZ), Shenzhen University, Shenzhen, 518060, PR China
b
Department of Ophthalmology, Shenzhen People's Hospital, Second Clinical Medical College of Jinan University, Shenzhen City, Guangdong Province, 518020, PR China
c
Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, PR China
d
Shenzhen Key Laboratory for Drug Addiction and Medication Safety, Department of Ultrasound, Peking University Shenzhen Hospital, Shenzhen, 518036, PR China

A R T I C LE I N FO A B S T R A C T

Keywords: Photodynamic therapy (PDT), as a non-invasive therapeutic modality that is alternative to radiotherapy and
Photodynamic therapy chemotherapy, is extensively investigated for cancer treatments. Although conventional organic photosensitizers
Nanomaterial (PSs) are still widely used and have achieved great progresses in PDT, the disadvantages such as hydrophobicity,
Photosensitizer poor stability within PDT environment and low cell/tissue specificity largely limit their clinical applications.
Drug delivery
Consequently, nano-agents with promising physicochemical and optical properties have emerged as an attractive
2D nanomaterial
alternative to overcome these drawbacks of traditional PSs. Herein, the up-to-date advances in the fabrication
and fascinating applications of various nanomaterials in PDT have been summarized, including various types of
nanoparticles, carbon-based nanomaterials, and two-dimensional nanomaterials, etc. In addition, the current
challenges for the clinical use of PDT, and the corresponding strategies to address these issues, as well as future
perspectives on further improvement of PDT have also been discussed.

1. Introduction: photodynamic therapy for cancer treatment
In recent years, over 10 million new cancer cases are diagnosed
every year, and around 9.6 million patients died from the disease in
2018 [1,2]. This number is projected to rise by about 70% over the
following two decades [1,3]. In fact, cancer is one of the major causes of
disease-related deaths, which accounts for a large percentage of total
deaths (around 17% in 2018) [1]. Therefore, cancer treatment is a
global task that shows a great impact to the whole society [4,5]. Cur-
rently, different types of clinical treatments for cancer are being
adopted, including surgery, radiotherapy, chemotherapy, and more
recently immunotherapy and molecular targeted therapy. In the past
decade, the treatment programs with a combination of different treat-
ment strategies, such as radiotherapy combined with immunotherapy,
chemotherapy combined with immunotherapy and molecular targeted
therapy combined with immunotherapy, have also gained a lot of
progresses [6–9]. However, these conventional treatment modalities
still show some drawbacks. For instance, surgery needs to work with
radiotherapy or chemotherapy in order to remove the cancer cells
completely [10], and it may suffer from recurrence for certain tumors.
Chemotherapy has an impact on cell division, thus associating with
some side effects like myelosuppression, mucositis, alopecia, etc. [11].
Radiotherapy, on the other hand, needs to be operated precisely to the
tumor site to minimize the damage to the surrounding normal tissues.
In the case of immunotherapy, the therapeutic outcome can be incon-
sistent for different patients [9,12]. In this sense, it becomes essential to
develop alternate treatment modalities that are less invasive, more ef-
fective, and more acceptable.
Photodynamic therapy (PDT) is a potent candidate of such ther-
apeutic method which is rapidly developing for the diagnosis and
treatment of cancer. It is a non-invasive treatment strategy based on the
administration of a photosensitizer (PS), which can accumulate at the
tumor tissues and can be activated by a light source with a specific
wavelength, resulting in the formation of cytotoxic reactive oxygen
species (ROS) in the presence of endogenous molecular oxygen to
eventually cause the death of cancer cells [4,13]. Importantly, the

∗
Corresponding author.
∗∗
Corresponding author.
E-mail addresses: LXL2603@vip.sina.com (X. Luo), hzhang@szu.edu.cn (H. Zhang).

https://doi.org/10.1016/j.biomaterials.2020.119827
Received 25 October 2019; Received in revised form 13 January 2020; Accepted 25 January 2020
Available online 27 January 2020
0142-9612/ © 2020 Elsevier Ltd. All rights reserved.
J. Chen, et al.
individual component of PDT is non-toxic, and the generation of cyto-
toxic ROS, such as singlet oxygen (1O2), superoxide anion (O2•-) and
hydroxyl radicals (%OH), only takes place when the PS is irradiated by
light. In this regard, PDT can destroy the tumor cells in a safe manner,
since the PS drugs themselves are minimally toxic without the presence
of external photo-activating light [14]. Moreover, PDT presents an ef-
fective cancer treatment modality that can significantly reduce the side
effects and improve the target specificity compared to the conventional
cancer treatment options like radiotherapy and chemotherapy, as only
the target cells/tissues under light irradiation are treated [13,15]. A
variety of light sources like monochromatic light from laser sources
(such as metal vapour lasers and argon-pumped dye lasers) or broad-
band light from non-laser sources (such as fluorescent and xenon arc
lamps) can be adopted for PDT [16]. The selection of the light source is
dependent on the PS used, tumor location and light dose. Obviously,
appropriate wavelengths that can excite the PS to produce ROS are
required to induce PDT. The first discovery of PDT can date back to
more than 100 years ago, and the first modern application was reported
by Dougherty and co-workers in 1975 [17]. Since then, tremendous
investigations have emerged in this field and have proven PDT to be an
effective therapeutic modality for a variety of cancers, such as super-
ficial bladder cancer [18], head and neck cancers [19], and skin cancer
[20].
2. Principle of photodynamic therapy and different generations of
photosensitizers
PDT is a combination of the photophysical and photochemical
processes, which eventually leads to biological effect [5]. Fig. 1 illus-
trates the principle of PDT. Initially, the PS in ground state is trans-
formed into an excited singlet state (1PS*) upon absorption of light.
This PS in its excited singlet state has very short lifetime, and may re-
turn to the ground state by means of releasing light energy (fluores-
cence) or heat energy (non-radiative decay). Alternatively, the multi-
plicities of the PS are possibly changed from singlet to triplet state
(3PS*) that has a relatively longer lifetime through intersystem
crossing. Similarly, the triplet state PS may also return back to the
ground state via the emission of phosphorescence or the release of heat
energy. More importantly, this triplet excited PS can react with cellular
substrates directly via electron transfer, which leads to the formation of
free radicals that can generate oxygenated products (e.g., O2%-, %OH and
H2O2) after reaction with O2 (Type I reaction). Alternatively, it can
transfer energy to oxygen (3O2) to produce highly reactive 1O2 (Type II
reaction). The reactive species formed during the photodynamic pro-
cess can eventually result in killing cancer cells directly by means of
apoptosis, necrosis or autophagy, and indirectly by damaging tumor
vasculature that leads to tumor ischemia. Additionally, PDT is able to
elicit immune response against tumor antigens [13,15,21]. PSs can use
either type I or type II reaction, or both of them simultaneously to
destroy cancerous cells. The proportion of these two types of reactions
Fig. 1. Modified Jablonski diagram showing the principle of PDT.
2
Biomaterials 237 (2020) 119827
taking place depends on the specific PS used [22]. Hence, the PS with
high production ability of oxygenated products and singlet oxygen is of
pivotal importance for effective PDT [5].
Many types of PSs have been developed for the treatment of cancer,
which can be classified into different generations. Hemetoporphyrin
was found to be localized in tumor tissues in the early 1950's [23],
which motivated the purification and chemical modifications of he-
matoporphyrin-based PSs for PDT. In the 1970's, Photofrin (structure
shown in Fig. 2) that was isolated from hemetoporphyrin mixture has
been approved by FDA for the use in cancer treatment [17]. The he-
matoporphyrin derivative (HpD) is considered as the first generation
PSs and was widely used in cancer therapy. However, the clinical use of
the first generation PSs also suffers from several dilemmas: (1) they are
generally excited by short wavelengths (such as visible light) that have
poor penetration depth in tissue. Hence, their clinical application in
PDT is limited for superficial tumors [24–27]; (2) synthesizing these PSs
is rather complex and it is very difficult to purify them; (3) Photofrin is
not soluble in water, which also limits its biological use; (4) the molar
extinction coefficient is low, meaning high administration dosage of PS
is required for effective photodynamic activity. Additionally, they have
long half-life and tend to accumulate in the skin, causing skin photo-
sensitization for prolonged period [3,4].
The disadvantages of the first generation PSs triggered further re-
search on the second generation PSs with near IR (NIR) activation and
high production of 1O2. The NIR light is known as the “window of
optical transparency”, which has minimal interaction with surrounding
biological components, hence affording increased tissue penetration
depth and high biomedical imaging resolution [28,29]. Typically, these
are macrocyclic compounds derived from substitutions of the porphyrin
moieties or direct modifications of the porphyrin core, or some new
non-porphyrinoid PS molecules, including phthalocyanines [30–34],
chlorins [35], bacteriochlorins, porphycenes [36,37], hypericin
[38–40], phenothiazines (methylene blue and toluidine blue) [41–43],
cyanines (merocyanine-540) [44,45], xanthenes (rose bengal) [46], and
metalated derivatives of PS (such as metalloporphyrins, AlPcS4, Si(IV)-
naphthalocyanine, and tin ethyl etiopurpurin) [4,47–50], etc. (Fig. 3).
Nevertheless, the main drawback of the second generation PSs is their
non-specific localization at targeted cells/tissues, therefore the atten-
tion was turned to design the targeted third generation PS.
Generally, targeting agents are conjugated to the PS to enhance the
tumor targeting abilities (some examples shown in Fig. 4) [51–53].
Alternatively, tumor specific carriers can be utilized to deliver the PSs
to the target site [4,5]. However, the tumor targeting efficiency is still
not high enough for clinical uses [54], and organic PSs mostly suffer
from stability issues, resulting in reduced reaction rates [55].
Despite some of early generation PSs have been approved for clin-
ical use (Table 1), the shortcomings, like hydrophobicity and low pe-
netration depth of the first generation PSs, and low cell/tissue specifi-
city associated with the second generation PSs, still hinder their clinical
therapeutics. Over the past few years, extensive attention has been paid
to the investigation of nanomaterial-based PDT, which presents a new
therapeutic modality that uses nanomaterial as a carrier or PS. Com-
pared to the organic PSs, nanomaterials represent some unique prop-
erties that make them more potent for PDT. First of all, nanomaterials
are stable under irradiation. Next, nanomaterials have very promising
optical properties which lead to improved penetration and efficacy of
PDT [22]. Moreover, molecule-modified nanocarriers are capable of
delivering PS to the target cells more precisely than traditional PSs,
transferring into improved curative effect and reduced side effects
[56,57]. Some nanomaterials, such as semiconducting nanoparticles,
are able to produce ROS intrinsically via an energy transfer or electron
transfer process, owing to their particular light absorption properties
[58]. Nanomaterials are more widely utilized as a carrier for PS, which
allows for targeting delivery of PS toward the tumor site with increased
drug loading efficiency and enhanced uptake by the cancer cells, due to
the large surface area and versatile surface modifications [4]. In this
J. Chen, et al.
NaO2C(H2C)2 Me
N Me
NaO2C(H2C)2 Me
NH
N
Me H O OC(CH2)2
N N
Me
R Me NaO2C(H2C)2
Me
R= or
OH
Fig. 2. Structure of Photofrin®.
review, some of recent progresses on the use of nanomaterials in PDT,
including various types of nanoparticles, carbon-based nanomaterials,
and two-dimensional nanomaterials, etc., will be reviewed. Further-
more, special interest is devoted to the current challenges of PDT and
the corresponding actions to deal with these issues. In the last section,
future perspectives for the viable application of PDT will be discussed
by exemplifying the multimodal treatment modality and several ad-
vanced techniques.
3. Application of nanomaterials in photodynamic therapy
3.1. Gold nanoparticles
Gold nanoparticles have been investigated for many years to induce
PDT due to some of their promising properties, such as high surface
areas, good biocompatibility and facile surface modification via gold-
thiol chemistry [59]. Additionally, gold nanoparticles are also ex-
tensively studied in diagnostic applications, due to their tunable optical
scattering and absorption [14,60,61]. The first use of gold nanorods (Au
NRs) alone (without employing an organic PS) for PDT was reported by
the Hwang group in 2014 [62]. Under the excitation of NIR light
(915 nm, λ1), gold nanorods were found to be able to produce singlet
oxygen leading to the destruction of B16F0 melanoma tumors in mice
(Fig. 5). Next to the generation of 1O2, the excitation of gold nanorods
with 780 nm (λ2) can also increase the temperature around tumor
tissues by converting the photon energy to heat, as confirmed by the
formation of heat shock protein (HSP 70). In this process, gold nanorods
mostly exerted the so-called photothermal therapy (PTT) effect, leading
to the apoptosis of cancer cells (Fig. 5b). By changing the activation
wavelengths (λ1 or λ2), the dominating phototherapeutic effects can be
switched between PDT and PTT. In particular, further experiments
showed that gold nanorods usually provided much higher PDT effect (at
least 10 folds) than the PTT effect in killing tumor cells. Additionally, it
was able to track the distribution of gold nanorods in vivo through the
single photon‐induced fluorescence emitted by themselves.
In the same year, the same group reported the production of singlet
oxygen by gold nanoechinus (Au NEs), a different morphology of gold
nanoparticles, under excitation with wavelengths covering both the
biological windows NIR I (650–950 nm) and NIR II (1000–1350 nm)
(Fig. 6) [63]. The extinction coefficients of gold nanoechinus observed
at 915 nm (NIR I) and 1064 nm (NIR II) are both greater than that
previously observed from conventional organic PSs and gold nano-
particles. Owing to the extraordinarily high extinction coefficients of
these gold nanoechinus, it was able to significantly decrease the amount
of nanoparticles used, the light intensities, as well as the irradiation
time for deep tissue cancer treatments.
The Hwang group also demonstrated that gold nanoshells, including
nanocages, nanorod-in-shell and nanoparticle-in-shell, can produce
singlet oxygen and induce PDT as well for the complete removal of solid
tumors in mice [64]. Similar to the phototherapeutic effects induced by
gold nanorods, it was possible to control and switch the dominant role
of PDT and PTT by changing the activation wavelength. Gold nanocages
Biomaterials 237 (2020) 119827
R Me Me R
N Me Me N
Me
O H
NH N N HN
H Me Me (CH2)2CO2Na
N
Me Me (CH2)2CO2Na
n
n = 0-6
mostly exhibited PDT effect when excited by a 980 nm light, whereas
808 nm irradiation led to effective PTT effect. Upon 940 nm excitation,
in vivo studies demonstrated that the gold nanoshells can trigger bi-
modal PDT/PTT for more efficient treatment of B16F0 melanoma tumor
than the clinically used drug doxorubicin. Of note is that, no photo-
sensitizing drugs have been approved by FDA for melanoma cancer yet.
By using gold bipyramids, He et al. found that singlet oxygen can be
generated upon irradiation with a wide range of wavelengths
(660–975 nm) [65]. Particularly, the highest formation of 1O2 was
obtained when the gold bipyramids were excited at the wavelength
overlapping with the localized surface plasmon resonance (LSPR) peak.
This observation was very different from that of other gold nano-
particles. In addition, it was demonstrated that efficient formation of
singlet oxygen can be achieved under low-intensity light irradiation
(200 mW/cm2).
Generally, current PDT uses one-photon absorption to excite PS to
produce ROS. In earlier studies, metal nanoparticles have shown the
abilities to generate singlet oxygen via the one-photon excitation me-
chanism [66,67]. However, one-photon excitation may cause potential
photodamage to the adjacent tissues around tumor site. Therefore, two-
photon excitation with precise manipulation of treatment dose is more
preferable in this sense. In two-photon PDT, femtosecond laser beam is
utilized to obtain high fluxes of light. In the work of Jiang and co-
workers, aggregates of gold nanospheres and gold nanorods have been
assessed as PSs for two-photon PDT [68]. Upon irradiation with fem-
tosecond laser pulses at 800 nm, two-photon induced generation of
singlet oxygen was observed using either unaggregated or aggregated
gold nanoparticles. However, the 1O2 generation capability was gen-
erally enhanced by aggregated gold nanoparticles. That is, the 1O2
generation capability by aggregated gold nanospheres was 8.3-fold
higher than that by the unaggregated ones. A similar trend was ob-
served when aggregated gold nanorods were used, in which the effi-
ciency of singlet oxygen generation was improved for 1.8 times with
respect to the case of unaggregated gold nanorods.
Along with the fast development of nanotechnology, there are
various synthetic methods available for the researcher to obtain the
gold nanoparticles with satisfactory architecture and features for PDT
application [69]. Next to the multiple physicochemical properties, the
possibility of further chemical modifications enables the improvements
in bioavailability and usability, making the gold nanoparticles a potent
candidate for clinical cancer treatment.
3.2. Silver nanoparticles
Silver is known as one of the strongest natural antibiotics and has
been used by humans to kill a variety of microorganisms for a long time.
Nowadays, silver nanoparticles are also widely used in antibacterial
treatment. One of the intriguing properties of the silver nanoparticles is
that they typically have an exceptionally high specific surface area,
which means the contact surface area of silver with bacteria can be very
large. Consequently, using silver nanoparticles would significantly re-
duce the amount of silver (up to hundreds of times) without a drop in
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J. Chen, et al. Biomaterials 237 (2020) 119827

N
NH N
NH N NH N NH N
N N
N HN N HN N HN N HN
N

Phthalocyanine Chlorin Bacteriochlorin Porphycene

OH O OH

Cl
Me OH Cl Me2 N S NH2
Me2 N S NMe2
Me OH
N Me
N

OH O OH
Hypericin Methylene blue Toluidine blue

SO3Na Cl
Cl Cl
N N N
O Bu KO2C Cl H
M H
O N I I N N
S
N
KO O O
O Bu M = metal
I I
Merocyanine-540 Rose bengal Metalloporphyrin

HO3S SO3H CO2Et

Me Me
N N Me
Me
N N N N H
N Cl N
N Al Cl N N Si N Sn
N N N N
N Cl N
N N Me
Me
HO3S SO3H Me
Me
Aluminum phthalocyanine tetrasulfonate Tin ethyl etiopurpurin
(AlPcS4) Si(IV)-naphthalocyanine (SnET2)
Fig. 3. Structures of some second generation PSs.

bactericidal effects [70]. Silver nanoparticles are also found to show the
ability to generate the singlet oxygen, thus attracting many efforts on
their use in PDT. Same as the cases of gold nanoparticles, silver nano-
particle-mediated sensitization and generation of singlet oxygen are
highly related to their morphology, as reported by Hwang et al. [71].
For instance, while either a very small or no 1O2 phosphorescence
signal was observed when silver nanocubes or gold decahedrons were
utilized, excitation of silver decahedrons and silver triangular nano-
plates can lead to the production of singlet oxygen. In general, it was
found that the radiation wavelength should be different from the LSPR
band of the silver and gold nanoparticles, in order to sensitize the
formation of singlet oxygen. For example, photo-excitation of silver
decahedrons (ca. 520 nm LSPR band) at the NIR wavelength of 885 nm
resulted in a significant formation of singlet oxygen, in sharp contrast,
activating gold decahedrons that have a LSPR band in this wavenumber
range with the same laser light did not give any 1O2 phosphorescence
signal. Similarly, silver triangular plates (ca. 590 nm LSPR band) gave a
strong 1O2 phosphorescence signal under 544 nm excitation, whereas
irradiating silver nanocubes (ca. 500 nm LSPR band) at 525 nm only
resulted in weak generation of singlet oxygen.

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J. Chen, et al. Biomaterials 237 (2020) 119827

N OR N O O
O Si R=
H N N O
N OMe O O
HNAc N OR N
O O N

Ac-L-Phe-ALA-OMe
Galactose substituted Si(IV)-phthalocyanine

R
F F OH
HO
F O S
F
HO OH
F F F F
NH N
or
R R R=
N HN OH
F F F F
O S
F F HO
HO OH

F F
R
R
F F
OH OH

F F N HO
OH OH
O OH
F F F F
NH N S HO
R R or OH O O OH
HN R=
N
F F F F HO
OH O O OH
F F
HO
O OH
F F
R S
Suger conjugated chlorins
Fig. 4. Some examples of third generation PSs (conjugated with targeting agents) [51–53].

The diverse morphologies and compositions of silver nanoparticles
can translate into highly tunable optical features, endowing them with
attractive applications in PDT [72]. Moreover, silver nanoparticles have
the ability to cause oxidative stress to tumors, leading to the apoptosis
of tumor cells [73].
3.3. Silica and silicon nanoparticles
Although silica is not active for PDT itself, silica nanoparticles can
be used for encapsulating PSs in PDT, due to the nontoxicity, chemical
inertness and optical transparency of silica [22]. Additionally, it is
feasible to make chemical functionalization for silica, owing to the
hydroxyl groups on the silica surface. In this regard, silica nanoparticles
are normally used for drug delivery in the studies [22]. In 2007, Yan
and co-authors embedded the PS meta‐tetra(hydroxyphenyl)‐chlorin
(m‐THPC) into sol–gel silica matrix-based nanoparticles via a modified
Stöber sol–gel process [74]. It was shown that this Si/m‐THPC nano-
system produced singlet oxygen more efficiently than the free THPC
molecules, i.e., the exact reaction rate constants with anthracene‐9,
10‐dipropionic acid for free m‐THPC and m‐THPC embedded in silica
nanoparticles were 2.7 × 108 M−1 s−1 and 4.8 × 108 M−1 s−1,
respectively. Organically modified silica (ORMOSIL) nanoparticles can
be conjugated with both hydrophilic and hydrophobic molecules effi-
ciently, which makes them promising to transport PS drugs [75]. In
2007, Ohulchanskyy and co-authors incorporated PS molecules into
ORMOSIL nanoparticles covalently, finding that the covalently bound
PS molecules could generate singlet oxygen robustly upon excitation
while retaining their spectroscopic and functional properties [76]. In
this study, an ORMOSIL precursor was incorporated with a PS iodo-
benzylpyropheophorbide (IP), forming iodobenzyl-pyro-silane (IPS).
Subsequently, IPS was coprecipitated with the ORMOSIL precursor vi-
nyltriethoxysilane (VTES) to provide the ORMOSIL nanoparticles.
These as-prepared nanoparticles have a size of ca. 20 nm and show high
monodispersity and good stability in aqueous solution. It was demon-
strated in vitro that the ORMOSIL nanoparticles can be uptaken by
tumor cells effectively and were capable of killing colon carcinoma cells
upon irradiation at 514 nm.
Mesoporous silica nanoparticles (MSNs) have also been extensively
utilized for delivering PS due to the intriguing features like large sur-
face area and pore volume, and high chemical stability [77,78]. MSNs
can be used as a nanocarrier for hydrophobic PSs, such as ZnPc that
tends to self-aggregation in aqueous medium. In 2012, Tu et al.

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J. Chen, et al. Biomaterials 237 (2020) 119827

Table 1
Some first and second generation PSs approved for clinical use.
PS Tradename Chemical structure Indication uses Maximum Extinction
absorption coefficient (M−1
wavelength cm−1)

HpD Photofrin See Fig. 2 Lung, esophageal, bladder, 630 3000

gastric cancer
5-Aminolevulinic acid (5-ALA) Levulan O Actinic keratoses, basal cell 635 < 1000
carcinoma, head and neck
H 2N OH
cancer
O
5-ALA-hexylester Hexvix O Diagnosis of bladder cancer 400 < 1000
H 2N O

O
Methyl aminolevulinate (MLA) Metvix O Actinic keratoses, basal cell 635 < 1000
H 2N O carcinoma

O
Meta-tetrahydroxy phenyl Foscan OH Prostate and pancreatic tumors, 652 30,000
chlorine (m-THPC) head and neck cancer

OH
N
H
N N
H
N
HO

HO
Sulfonated Aluminium Photosens See Age-related macular 675 110,000
phthalocyanine (AlPcS4) Fig. 3 degeneration, prostate cancer
Benzoporphyrin derivative mono- Visudyne Age related macular 693 35,000
acid (BPD-MA) degeneration, non-melanoma
skin cancer

Mono-L-aspartyl chlorine e6 Aptocine/ Lung cancer, recurrent 664 45,000

(NPe6) Laserphyrin subcutaneous tumors

incorporated polyethyleneglycol (PEG)- and polyethylenimine (PEI)-
modified zinc phthalocyanine (ZnPc) to MSNs, forming a PEG-PEI-
MSNs/ZnPc nanosystem that was developed for PDT [79]. In this study,
PEI was used to facilitate the endosomal escape of MSNs from the ly-
sosome to the cytosol via a “proton sponge” mechanism. However, the
incorporation of PEI also introduced the side effect of high cytotoxicity
aroused by its cationic property. Therefore, PEG was used to further
modify PEI-MSNs to reduce the toxicity and enhance the biocompat-
ibility. By doing so, the phototoxicity of the PEG and PEI modified
MSNs/ZnPc was largely improved in vitro, in comparison with the solely
ZnPc-loaded MSNs. As shown in Fig. 7a, all of the nanoparticles showed
highest biodistribution at tumor site, and the PEGylated MSNs/ZnPc
exhibited enhanced uptake in tumor over unmodified ones.
Importantly, injection of PEG-PEI-MSNs/ZnPc resulted in efficient
passive tumor targeting and successful destruction of tumor upon ex-
posure to 680 nm light (Fig. 7b–c). MSNs functionalized with galactose
on the surface were reported in the same year for the use as delivery
vehicle and PDT agent [80]. Confocal microscopy experiments revealed
that galactose functionalization can contribute to the enhanced uptake
by the cancer cells through galactose receptor–mediated endocytosis,
resulting in the accumulation of the nanoparticles in the endosomal and
lysosomal compartments. The MSNs equipped with a PS (porphyrin)
and an anti-cancer drug (camptothecin) were tested for synergistic
anticancer effects, which showed a dramatically increased death of
cancer cell under light at 650 nm compared to separate treatments.
In 2017, folic acid (FA)-modified silica nanoparticles were prepared

6
J. Chen, et al.
Fig. 5. Schematic working mechanisms of gold nanorod‐induced PDT/PTT ef-
fects under NIR laser light. (a) Destruction of melanoma tumors in mice in vivo
by Au NRs. (b) Various cellular events involved in cellular deaths induced by
gold nanorod‐mediated PDT/PTT effects upon photoexcitation. Reproduced
with permission [62]. Copyright 2014, Wiley-VCH Verlag GmbH & Co. KGaA.
by Bharathiraja et al. for site-specific delivery of PS chlorin e6 (Ce6)
[81]. Efficient generation of singlet oxygen was obtained with 670 nm
irradiation, leading to improved killing efficacy of MDA-MB-231 cells
than free Ce6. Very recently, a multifunctional nanoplatform based on
perfluorohexane (PFH)-encapsulated MSNs was fabricated by Huang
et al., with PS indocyanine green (ICG) loaded within polydopamine
7
Biomaterials 237 (2020) 119827
(PDA) layer and PEG-FA decoration [82]. Under 808 nm excitation, the
PDA layer and ICG were able to exert PTT effect, and ICG was capable
of producing ROS as well. Additionally, the light irradiation can also
mediate the vaporization of PFH to generate bubbles for tumor ultra-
sonic (US) imaging and ICG can provide NIR fluorescence emission
upon release. Consequently, combined PTT/PDT mediated effective
inhabitation of MCF-7 tumors in mice guided by UC/fluorescence
imaging has been achieved in vivo by this MSNs nanosystem. Very re-
cently, a tumor-targeting PDT based on zinc(II) phthalocyanine deri-
vative (PcC4)-incorporated MSNs and a wrapping DNA has been re-
ported by Li et al. [83]. The selectivity was realized by the self-
quenching photoactivity of PcC4 and the subsequent recover of pho-
toactivity driven by the reaction between the nanocomposites and
proteins (telomerase and albumin). In the study of Lin et al., ZnPc was
conjugated to MSNs via an acid-responsive hydrazone bond [84]. The
as-obtained ZnPc-MSNs nanoplatform showed no photodynamic ac-
tivity due to the aggregation of PS ZnPc. Nevertheless, the generation of
singlet oxygen can be selectively turned on through the release of PS
upon acidic solution treatment.
Porous silicon nanoparticles were found to be able to generate
singlet oxygen under light covering entire visible range, due to broad
absorption band of porous silicon [85]. Xiao et al. etched single crystal
silicon wafers electrochemically to prepare porous silicon nano-
particles, which can produce singlet oxygen with a quantum yield of
~0.1 or ~0.17 in ethanol or H2O2, respectively. Under white light il-
lumination, these Si nanoparticles were proven to cause significant cell
death in vitro [86]. More recently, porous silicon nanovectors with gold
nanoparticle decoration and mannose tumor targeting agent functio-
nalization were reported by Chaix et al. [87]. The as-prepared silicon
nanostructures showed phototoxicity toward human breast cancer cells
under NIR light excitation. Porous silicon nanorods have also been
demonstrated to be capable of inducing photodynamic effects with a
quantum yield of singlet oxygen at 0.24 [88]. Accordingly, decreased
viabilities of HeLa cells cultured with these silicon nanorods were ob-
served from in vitro assays with 635 nm laser exposure.
Using different synthetic methods, a variety of silica and silicon
nanoparticles with preferable size and porosity can be prepared for
PDT. Besides, it is possible to incorporate cancer-specific agents to the
silicon-based nanoparticles via surface functionalization, hence
Fig. 6. Au NEs-induced PDT effects illustrated by the
changes of tumor volume after treatment with dif-
ferent conditions for 14 days, and photos of tumor-
bearing mice at the 14th day in different groups
under irradiation with NIR I (808 and 915 nm) and
NIR II (1064 nm) Reproduced with permission [63].
Copyright 2014, Wiley-VCH Verlag GmbH & Co.
KGaA.
J. Chen, et al.
Fig. 7. (a) Biodistribution of different MSNs/ZnPc nanoparticles in H22 tumor
bearing mice. (b) Changes of tumor size in different groups as a function of
time. (c) Images of mice bearing H22 tumor after treatment with different
conditions for different experiment time. Reproduced with permission [79].
Copyright 2012, Elsevier.
improving the tumor-targeting ability [78]. Moreover, recent studies
have revealed their promising uses in NIR and two-photon PDT for deep
cancer therapy.
3.4. Quantum dots (QDs)
Another type of nanomaterials, QDs, have also been extensively
studied for the application in PDT. QDs possess some unique optical
properties, including high emission quantum yield, size- and composi-
tion-tunable emission, as well as facile surface modification, that are
important for being promising nanocarriers [89–91]. Moreover, QDs
are also utilized as donors in fluorescence resonance energy transfer
(FRET), which is used extensively for studying the dynamics of biolo-
gical macromolecules [91–93].
In 2010, biocompatible CdSe QDs conjugated with water-soluble
porphyrin were prepared by Qi et al. for PDT through two-photon ex-
citation [94]. It was concluded that porphyrin-conjugated QDs under
two-photon excitation provided 2-fold higher 1O2 quantum yield than
the solely porphyrin solution. By employing the FRET mechanism, en-
ergy was transferred efficiently between the QDs and the porphyrin.
Moreover, the energy transfer efficiency was enhanced by the larger
Fig. 8. Illustration of the fabrication of the hybrid nanocomposite contain the TMPyP-Zn-QD nanocomplex, the PS R6G, NIR fluorophore NIR775 and phospholipids,
and their use in tumor selective imaging and PDT. Reproduced with permission [98]. Copyright 2017, Elsevier.
8
Biomaterials 237 (2020) 119827
amount of porphyrin, which was attributed to the increased effective
overlap integral due to the interaction between multiple porphyrin
acceptors and a central QD donor [95]. A water-soluble QD-organic dye
nanosystem has been used by Shi et al. as a PS for PDT, which was
synthesized from CdTe QDs, the stabilizer 2-aminoethanethiol and the
organic dye meso-tetra(4-sulfonatophenyl)porphine dihydrochloride
(TSPP) [96]. The surface of the CdTe QDs was modified with TSPP via
electrostatic interaction, as a result, slight shift in the luminescence
maximum to the blue region was observed, as compared to the case
with free TSPP. Production of singlet oxygen was obtained when irra-
diating the CdTe QD-TSPP with near-UV or visible light. A significant
amount of singlet oxygen (0.43 quantum yield) was detected using a
355 nm Nd:YAG laser where the absorption of TSPP is minimal
(~10%). In addition, no phosphorescence signal from singlet oxygen
was detected when the CdTe QDs were irradiated without the presence
of TSPP. Therefore, it indicated that singlet oxygen was produced from
the irradiation of the QDs followed by a FRET-type mechanism. In
2015, water-soluble nanocomposites containing ZnSe/ZnS QDs and Ce6
were synthesized by Martynenko et at. For PDT in cancer cells [97].
Approximately 50% intracomplex FRET between ZnSe/ZnS QDs and
Ce6 was detected, indicating these nanocomposites were an effective
photosensitizing agent. PDT test was done by employing the nano-
composites against the Erlich acsite carcinoma cells, and it was revealed
that the cancer cell photodynamic destruction was enhanced for two
times in comparison with that of free PS Ce6. This significant en-
hancement was attributed to the efficient photoexcitation energy
transfer from QDs to Ce6, and the enhanced cellular uptake of the PS
Ce6 incorporated to ZnSe/ZnS QDs.
More recently, Shen and co-authors reported a QD-based tumor-
targeting hybrid nanocomposite, in which a QD-Zn-porphyrin (TMPyP-
Zn-QD) nanocomplex, a highly fluorescent PS rhodamine 6G (R6G) and
a NIR fluorophore NIR775 were encapsulated in FA decorated phos-
pholipid polymers (Fig. 8) [98]. Porphyrin can be largely loaded on
these nanoparticles, and the light absorption capability was found to be
strong. As a consequence, a very high singlet oxygen quantum yield of
ca. 0.91 was achieved through an effective dual energy transfer process.
Additionally, the folate receptor can contribute to the highly selective
delivery of as-prepared nanoparticles to cancerous tissues, thus al-
lowing non-invasive fluorescence imaging and successful photodynamic
destruction of tumors in vivo without scathing the surrounding healthy
cells. Zhang and co-workers revealed that Ag2S QDs can be utilized as a
potent fluorescent probe that have bright photoluminescence, good
biocompatibility, and emission in the NIR biological window II [99].
These Ag2S QDs showed strong targeting abilities and imaging of dif-
ferent cell lines in vitro, such as human breast cancer cell line and
human glioblastoma cell line. Additionally, it was illustrated from cy-
totoxicity study that the Ag2S quantum dots exhibited negligible toxi-
city in the aspects of cell proliferation, apoptosis and necrosis, ROS
generation, as well as DNA damage. It is important to use external
J. Chen, et al.
Fig. 9. (a–b) Injection of FA-PEG-UCNPs into the mice bearing melanoma tumors and time-dependent changes of tumor volume under different conditions. The
group with the treatment of FA-PEG-UCNPs showed greatest tumor growth suppression. (c) Images of the mice under different conditions (FA-PEG-UCNPs, UCNPs
alone or PBS) showing the changes of tumor volume before and after PDT treatment (at the 7th day). Reproduced with permission [110]. Copyright 2012, Nature
Publishing Group.
excitation light source with proper tissue-penetrating properties to ac-
tivate PS drugs, in order to achieve successful clinical application of
PDT. In 2012, Hsu and co-authors developed a new type of QD con-
jugate immobilized with light-emitting Renilla luciferase 8 (QD-RLuc8),
which can produce bioluminescence as the external light source [100].
The addition of coelenterazine triggered the bioluminescence resonance
energy transfer (BRET) from the substrate to the QD conjugates,
thereby inducing self-illumination at 655 nm to activate the PS m-THPC
(Foscan®) to exert PDT effects. It was shown that QD-RLuc8 with coe-
lenterazine could sensitize efficient production of ROS by using BRET-
mediated PDT, resulting in killing half amount of A549 cells with
Foscan® in vitro and remarkably suppressed tumor growth in vivo. These
results demonstrated that it is able to realize deep tumor therapy by
using BRET-mediated PDT.
To date, a wide range of different QDs have been exploited for PDT
owing to their promising characteristics, providing many achievements
in cancer treatment. Nevertheless, the major drawback of using QDs is
their potential toxic effects, which is mainly due to the absorbed or-
ganic species on the surface from the synthesis stage [101], and the
release of heavy metals from the QD cores (such as CdSe and CdS)
caused by surface oxidation upon oxygen/UV exposure [102–104]. In
this regard, continuous efforts should be paid on developing QDs with
less toxicity, in order to achieved clinical PDT applications.
3.5. Upconversion nanoparticles
The upconversion nanoparticles (UCNPs) are able to convert low
energy NIR light into higher energy visible/UV light using a non-linear
anti-stokes mechanism [105,106]. During PDT within the biological
environment, this emitted photon can activate the PS to sensitize the
formation of ROS. Generally, the photon upconversion process involves
a real metastable electronic state of lanthanide ions embedded into a
host lattice with a lifetime scale of microsecond. Whereas two-photon
PDT requires simultaneous absorption of two NIR photons involving a
virtual state with an ultra-short lifetime (femtoseconds). Therefore, the
conversion efficiency of upconversion process is orders of magnitude
higher than that of a two-photon excitation mechanism. Hence, a much
lower power density is required for achieving photon upconversion
(typically 0.1–100 W/cm2) [107]. Additionally, the emission band of
the UCNPs is similar to the absorption band of PS, resulting in improved
ROS production efficiency [22]. In this regard, the UCNPs can also act
as a promising carrier for anti-cancer drugs or PS in PDT.
In 2007, Zhang and co-authors reported the use of the UCNPs in
PDT for the first time [108]. The UCNPs used in this study,
NaYF4:Yb3+/Er3+, showed strong emission bands in the visible region
around 537 and 635 nm when excited by an IR source (974 nm). The PS
molecule, Merocyanine 540 (MC-540) was attached to the UCNPs
during the silica coating process. Together with rose bengal, Mc-540
has been used for generating ROS in the 1980's [109]. However, the
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Biomaterials 237 (2020) 119827
activation wavelengths of these PSs are within the range (< 700 nm)
where endogenous molecules (like hemoglobin) have strong absorp-
tion, which largely limited their use in PDT. In this study, the genera-
tion of singlet oxygen mediated by the MC-540-coated UCNPs was
successfully detected with NIR excitation by measuring the decrease in
the fluorescence bands of the 1O2 sensor 9,10-anthracenedipropionic
acid (ADPA). In vitro PDT tests showed that the as-obtained MC-540-
coated UCNPs exhibited photodynamic cytotoxicity to MCF-7/AZ
breast cancer cells. UCNP-mediated PDT can also be used for in vivo
tumor therapy, as first demonstrated by Idris and co-authors [110], who
used NaYF4:Yb/Er nanoparticles coated with mesoporous silica as a
nanotransducer and a carrier of two different PSs (i.e., ZnPc and MC-
540). Improved ROS production ability and reduced cell viability were
obtained, showing that the synthesized UCNPs with the dual-PS gave
higher PDT efficacy compared to that using a single PS. Both direct
injection of the UCNPs into melanoma tumors and intravenous injection
of FA and PEG modified UCNPs (FA-PEG-UCNPs) into tumor-bearing
mice have led to tumor growth inhibition in vivo upon 980 nm excita-
tion. In the latter case, the tumor targeting capabilities and the circu-
latory lifetime of the UCNPs were improved by FA and PEG, respec-
tively, which resulted in more significant PDT effects, as shown in
Fig. 9.
NaYF4:Yb/Er nanoparticles coated with polymer have also been
used as a delivery vehicle for the PS Ce6, which formed a UCNP–Ce6
supermolecule complex [111]. This UCNP–Ce6 nanosystem showed two
emission bands at 550 and 660 nm upon 980 nm irradiation. Of note is
that the 660 nm emission wavelength overlaps with the absorption
band of Ce6. Singlet oxygen production and good PDT performance
were achieved with 4T1 murine breast cancer cells upon intratumoral
injection of UCNP–Ce6 under NIR light irradiation. Notably, there was
nearly no observation of the administrated UCNPs in the mouse body
after 1–2 months, which demonstrated their nontoxicity to the treated
animals. Chen et al. doped gadolinium (Gd)‐ion to the NaYF4:Yb/Er
UCNPs to fabricate the NaYF4:Er/Yb/Gd upconversion nanocrystals
[112]. By using a water‐in‐oil reverse microemulsion strategy, the hy-
drophilic PS drug methylene blue (MB) was efficiently conjugated to
the UCNPs in a silica matrix, providing the UCNPs/MB nanocomplex
having a particle size smaller than 50 nm. The as-obtained UCNPs/
MB‐based PDT drug successfully generated singlet oxygen under
980 nm excitation. In contrast, no signal was observed in the case of
either using NaYF4:Er/Yb/Gd alone, or free MB solutions under the
same conditions.
The reason for typically using NaYF4 crystal as host co-doped with
Yb3+/Er3+ in UCNP-based PDT, as discussed above, is that the emis-
sion bands of both Er3+ overlaps with the activation wavelengths of
several organic and inorganic PSs [113]. Similar phenomenon was also
observed when NaYF4 was doped with Yb3+/Tm3+. In 2017,
Nd3+‐sensitized NaYF4:Yb/Tm was synthesized by Chan et al. for in vivo
PDT [114]. In combination with an inorganic PS, graphitic carbon
J. Chen, et al.
nitride quantum dots (CNQDs), this nano-pharmaceutical platform al-
lowed the absorption of 808 nm NIR light to produce UV light emission,
which in turn produced ROS to achieve PDT effect. Consequently, high
energy light generated by UCNPs without overheating the tissue can be
achieved due to the 808 nm excitation bands. Moreover, the conjuga-
tion of polymer poly(L‐lysine) (PLL) can improve the binding between
the UCNPs and the CNQDs, as the surface of the nanoparticles was
converted to full positive. Dou et al. coated the NaYF4: Yb/Tm UCNPs
with a nanometric layer of silica, which were further modified with (3-
aminopropyl) triethoxysilane (APTES) using Stöber method [115].
Subsequently, the UCNPs were covalently incorporated to the PS Ce6
through the amino groups on the silica layer. The PDT effect was as-
sessed with the MCF-7 human breast adenocarcinoma cell line in vitro.
By using a low concentration (50 μg/mL) of this UCNP–Ce6 nano-
composite, 50% of the cells were killed under mild dosage (7 mW/cm2)
of 980 nm light for 10 min. In addition, more than 90% of cell viability
was achieved under the same conditions, indicating that the toxicity of
this UCNP–Ce6 nanosystem was low in the effective concentration
range. Alternatively, the UCNPs LiYF4: Tm3+/Yb3+ have also been used
for singlet oxygen generation, which exhibited stronger blue emission
upon NIR irradiation, as compared to the NaYF4 UCNPs [116]. By using
m-THPC as PS, which was modified with 4-(bromomethyl)benzoic acid
(BMBA), the LiYF4: Tm3+/Yb3+- UCNPs produced singlet oxygen when
activated at 980 nm. In vitro studies demonstrated that this nanocon-
struct was able to kill HeLa cell from 20% to 70% under 980 nm irra-
diation for 1 h.
More recently, research attentions have been turned to focus on
investigating multifunctional UCNP-based nanocomposites that are
combined with image-guided PDT and multimodal therapy [117–119].
Very recently, the UCNPs coated with the PS TiO2 have been adopted
for image-guided in vivo PDT, which realized a complete photo-
switching in UV–blue region [120]. The emission band of these UCNPs
depended on the wavelength of the excitation light, i.e., the prominent
UV–blue emission from Tm3+ was turned on or completely turned off
with 980 nm or 800 nm excitation light, respectively. Consequently, in
vivo tumor imaging prior to the actual treatment can be achieved.
Under 980 nm excitation, the Tm3+ emission band at 350 nm well
matched the absorption of TiO2, thus generating ROS to induce PDT. On
the other hand, only the Er3+ emission band at 660 nm appeared under
excitation at 800 nm, which allowed tracing the therapeutic process by
monitoring the emission around 650 nm in vivo.
In recent years, the UCNPs have also been utilized in combination
with other nanoparticles to realize multimodal tumor therapy, which
combines two or more therapeutic strategies of cancer (e.g. PTT, PDT,
radiotherapy, chemotherapy) [121]. It has been shown that different
therapeutic modalities can take effect synergistically, which leads to
improved anticancer outcomes, thereby attracting the interest in de-
veloping nanomaterials that are able to induce multimodal therapy
[117,122]. In 2015, gold nanorod dimer-UCNP-Ce6 assembly was fab-
ricated by Sun et al. to achieve combine PTT/PDT, which allowed
successful tumor therapy in vivo (Fig. 10) [123]. The gold nanorod
dimer (core) and the UCNPs NaGdF4 (satellite) loaded with the PS Ce6
were hierarchically assembled via complementary base pairing,
Fig. 10. Illustration of the fabrication of gold nanorod dimer-UCNP-Ce6 as-
sembly for imaging-guided combinational phototherapy. Reproduced with
permission [123]. Copyright 2015, Wiley-VCH Verlag GmbH & Co. KGaA.
10
Biomaterials 237 (2020) 119827
forming the core–satellite structures. In this system, the gold nanorod
dimer core can generate heat upon irradiation at 808 nm, thus acting as
photothermal agent, whereas the UCNPs excited Ce6 to trigger PDT
under excitation with 980 nm light. Furthermore, successful tumor
elimination was achieved without regrowth after combined photo-
therapeutic treatment with a low power dosage (2 mW/cm2 for 980 nm
and 0.2 W/cm2 for 808 nm, respectively).
Next to the outstanding optical characteristics and rich surface
functionalities, the energy transfer ability of UCNPs offers the oppor-
tunity to achieve NIR-triggered deep tissue PDT while using appropriate
energy to sensitize efficient formation of ROS. Hence, UCNPs present as
a powerful nanoplatform for PDT. Yet, the generally low upconversion
quantum yield (< 3%) and the relatively poor compatibility in phy-
siological environment still hinder their biological application
[107,124]. Besides, the potential side effects of emitted UV light, like
photocarcinogenesis, should be carefully assessed before they can be
applied in clinical use.
3.6. Carbon-based nanomaterials
Carbon-based nanomaterials have aroused considerable research
interests in the field of PDT for their inimitable optical and mechanical
features, versatile chemical functionalization, good biocompatibility
and low toxicity [125–128]. Numerous carbon-based nanomaterials are
existing due to many allotropic forms of carbon. Amongst them, carbon
nanotubes (CNTs), fullerenes and graphene-based nanomaterials are
most widely applied in PDT.
3.6.1. Carbon nanotubes
Carbon nanotubes (CNTs) can be considered as the one-dimensional
form of rolled-up single or multilayered graphene, with a typical inner
diameter between 1 and 10 diameters. Depending on the number of
wrapped sheets, two types of CNTs, namely, single-walled carbon na-
notubes (SWCNTs) and multiwalled carbon nanotubes (MWCNTs), are
usually studied. In addition to their exceptional physical properties, the
versatile surface modifications of CNTs can turn them into outstanding
PDT agents. Murakami et al. revealed that semiconducting and metallic
SWCNTs were capable of producing ROS (singlet oxygen and O2%-)
under NIR light irradiation (808 nm) [129]. It was found that SWCNTs
exhibited stronger photodynamic effects than MWCNTs in this study.
More importantly, the death of cancer cells was achieved using
SWCNTs after stabilization with high-density lipoprotein. However, no
in vivo experimental results on the destruction of solid tumors in animal
model have been reported in this study. Through functionalization of
SWNTs with PEI covalently or polyvinylpyrrolidone (PVPk30) non-
covalently, two modified SWCNTs were prepared by Wang and co-
workers [130]. It was concluded that the functionalization method had
an impact on the photodynamic ability, and the PEI functionalization
showed higher photodynamic efficiency than the PVPk30 modification
both in vitro and in vivo. The SWCNTs have also been used for delivering
PS drugs to induce photodynamic activity. In the work of Staicu et al.,
PS verteporfin was loaded on the SWCNTs functionalized with amino
covalently for PDT [131]. In order to obtain higher quantum yield of
1
O2, verteporfin needed to be conjugated to the amino-SWCNTs rather
than mixed physically (51% vs. 23%). This was a result of the smaller
quenching of 1O2 due to the conjunction between verteporfin and the
amino-SWCNTs. Very recently, a multifunctional nanoplatform was
reported by Zhang et al., in which Fe3O4@CQDs were coated on PE-
Gylated SWCNTs [132]. By loading the chemotherapy drug doxorubicin
(DOX) and conjugating with sgc8c aptamer, this nanoplatform can be
used simultaneously for combined photodynamic/photothermal
therapy, drug release, as well as magnetic resonance imaging (MRI).
3.6.2. Fullerenes
Fullerenes are three-dimensional spherical, ellipsoidal or tubular
structure of all-carbon materials, with C60 as the mostly studied
J. Chen, et al.
example. Although fullerenes alone are poorly soluble in water and they
exhibit intrinsic toxicity, a variety of modifications on the surface of
fullerenes have been developed to overcome these issues [133]. In
addition, fullerenes have been proven to possess higher biocompat-
ibility than other carbon-based materials like graphene and CNTs
[134–137]. In 2015, Li et al. reported a fullerene-based multifunctional
nanocomposite, in which C60 was modified with phenylalanine and was
attached with polylactic acid (PLA) [138]. This as-prepared nanoplat-
form can highly selectively transport anticancer drug mitoxantrone to
the tumors in C57BL mice, therefore mediating combined che-
motherapy/PDT effects upon visible light irradiation with negligible
toxicity to the normal healthy organs. Later on, the same group re-
ported a drug delivery system adopting PEGylated C60 with a tunable
“off-on” property for controllable release of drug [139]. It was realized
by utilizing a ROS-sensitive thioketal linker to bind DOX and C60, which
can be selectively broken by ROS. DOX was encapsulated efficiently by
C60 at “off” state. Upon irradiation with a 532 nm laser, this nanosystem
was switched to “on” and C60 was excited to produce ROS to break the
thioketal linker, leading to the precise release of DOX. This study re-
vealed the potential application of C60-based nanoplatform in light-
controlled drug delivery system to achieve tumor-targeting combined
PDT/chemotherapy. In the work of Wang et al., C60 was doped with
mesoporous silica, forming a C60-silica nanoparticle system, which was
coated with hyaluronan for targeted therapy of cancer stem-like cells
(CSCs) [140]. By loading the chemotherapy drug DOX and photo-
thermal agent indocyanine green (ICG), this C60-silica nanosystem was
found to be effective for the destruction of the breast CSCs through
synergistic photodynamic/photothermal/chemo therapy under excita-
tion at 800 nm. Li et al. reported the conjugation of graphene oxide
(GO) to C60 to obtain a GO-C60 hybrid, which exhibited good stability
under physiological conditions [141]. The introduction of GO can not
only mediate the photothermal effects but also transmit the absorbed
light energy to C60 to trigger the ROS production of C60 under NIR
irradiation. As a consequence, the as-prepared GO-C60 hybrid can in-
duce synergistic PDT/PTT effects on Hela cells in vitro. Very recently,
Iohara and co-workers used an anionic γ-cyclodextrin derivative, su-
gammadex, to largely improve the stability of C60 in physiological en-
vironment [142]. This was attributed to an electric layer generated by
the strong host-guest interactions between sugammadex and the surface
of C60. Moreover, the as-obtained sugammadex-C60 complex was tested
by in vitro and in vivo experiments to show high antitumor ability
through PDT effects.
3.6.3. Graphene-based nanomaterials
Due to the large surface area, outstanding thermal and optical
properties, as well as good biocompatibility [143–145], graphene-base
nanomaterials, including graphene quantum dots (GQDs), graphene
oxide (GO), and reduced GO (rGO), have been extensively exploited for
cancer therapy, such as anticancer drug delivery and PDT [146–148].
GQDs have been demonstrated by Ge et al. to be a good PDT agent,
which were able to give an excellent quantum yield of singlet oxygen
(up to 1.3) [149]. By employing the hydrothermal method, the GQDs
were synthesized using polythiophenes as the carbon precursor. The
PDT effects of the GQDs were tested both in intro and in vivo, where the
death of HeLa cells and the tumor decomposition in BALB/nu mice with
breast cancer were observed. Unfortunately, the GQDs reported in this
study showed photodynamic activity only when excited by the visible
light. In 2018, Kuo et al. doped and functionalized the GQDs with ni-
trogen and an amino group, demonstrating that the corresponding
amino-N-GQDs showed outstanding singlet oxygen production ability
in the NIR region (800 nm) [150]. Importantly, compared to the un-
modified GQDs, the as-prepared amino-N-GQDs turned out to be a more
efficient PDT agent with enhanced two-photon excitation.
In comparison with graphene, GO exhibits more favorable proper-
ties in terms of being a vehicle for delivering PSs, due to its improved
water solubility and diverse functionalization chemistry. In addition,
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Biomaterials 237 (2020) 119827
GO nanomaterials possess abundant oxygen-containing moieties on the
surface. These characteristics allow further modifications by many
functional molecules, such as hydrophilic macromolecules, targeting
agents and active agents, thus extending their biological applications
and reducing the toxicity [144,151]. Notably, the fluorescence
quenching ability of GO nanomaterials is extremely high, which further
expands the applications in PDT [152]. In 2016, Ding and co-workers
loaded the PS hypocrellin A (HA), and TiO2 nanoparticles onto the
surface of GO, forming a light-sensitive drug delivery system [153].
Increased ability of generating ROS was realized through mutual sen-
sitization mechanism, in which the sensitization effect was formed from
the HA–TiO2 stable complex. Simultaneously, modifying TiO2 with GO
could also generate ROS upon exposure to visible light. Improved ef-
ficacy of PDT was confirmed by in vitro assays, in which the as-obtained
HA-TiO2-GO nanoplatform showed largely improved ability to kill
cancer cells than the HA-TiO2 or TiO2-GO complex. Furthermore, the
generated ROS can destroy GO, indicating the potential use this drug
delivery system in clinical PDT in terms of the metabolism. In another
example, Cho and Choi conjugated the PS Ce6 to GO via a redox-re-
sponsive cleavable disulfide linker (GO-SS-Ce6), in which the fluores-
cence and the ROS generation were activated in the presence of in-
tracellular redox agents (such as glutathione) [154]. Without
glutathione, the fluorescence of Ce6 bound to GO was largely quenched
due to the FRET process, avoiding non-specific excitation and poor
targeting abilities of PS. Compared to the free Ce6, GO-based Ce6
conjugate showed more efficient cellular internalization and pre-
ferential accumulation of the PSs, and on-demand release of Ce6 inside
A549 cancer cells. Additionally, the as-prepared GO-SS-Ce6 complex
was demonstrated to be an effective drug delivery vehicle, given the
high surface area and enhanced chemical tethering properties of GO.
In the study of Rong et al., GO was functionalized by PEG and was
loaded with the PS 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-
alpha (HPPH) via supramolecular π-π stacking [155]. The radiolabeling
of HPPH with 64Cu allowed for in vivo fluorescence imaging and posi-
tron emission tomography (PET) imaging, revealing that GO-PEG-
HPPH exhibited improved cellular uptake of the HPPH in comparison
with free HPPH via a more active endocytosis strategy. As a result, GO-
PEG-HPPH exhibited enhanced killing ability to 4T1 murine breast
cancer cells upon activation at 671 nm. Importantly, mice injected with
GO-PEG-HPPH showed remarkably longer life time (~40 days) than the
ones under treatment with free HPPH (~24 days), indicating increased
long-term survival of tumor-bearing mice after GO-PEG-HPPH treat-
ment. Similarly, Yan et al. loaded the PS sinoporphyrin sodium
(DVDMS) onto PEGylated GO, forming a novel phototheranostic na-
noplatform GO-PEG-DVDMS [156]. The fluorescence intensity of
DVDMS can be dramatically improved after loading of GO-PEG through
intramolecular charge transfer, leading to enhanced fluorescence ima-
ging. Furthermore, the GO-PEG nanoplatform can more effectively ac-
cumulate DVDMS in tumors through enhanced permeability and re-
tention (EPR) effect in comparison with free PS. As a consequence, PDT
studies revealed that complete destruction of the U87MG tumor in vivo
was achieved after treatment with GO-PEG-DVDMS (Fig. 11). By in-
corporating with PEG-folate, GO has also been reported to be capable of
producing singlet oxygen intrinsically without the use of an organic PS
[157]. The combined PDT/PTT effects mediated by the as-prepared GO-
PEG-folate was demonstrated both in vitro and in vivo on the destruction
of B16F0 melanoma tumor with 980 nm light irradiation.
In addition to GO, rGO was also investigated for the theranostic use
in cancer. A nanosystem was reported by Zhang et al. for a combination
of lysosome-targeted phosphorescent imaging and photothermal/pho-
todynamic therapy, which was composed of rGO nanosheet and a PEG
functionalized Ru(II) complex (Ru-PEG) [158]. The Ru-PEG complex,
acting as PS and imaging agent, was decorated onto rGO via π-π
stacking and hydrophobic interactions. Under irradiation at 450 nm,
poorer quantum yield of ROS produced by rGO-Ru-PEG was found than
that by Ru-PEG (0.31 and 0.06, respectively), which was likely caused
J. Chen, et al.
Fig. 11. (a) Images of mice bearing U87MG tumor after treatment with different conditions. (b) Time-dependent changes of tumor volume in different groups.
Reproduced with permission [156]. Copyright 2015, Elsevier.
by the quenching effect of rGO. It was demonstrated that rGO was able
to improve the cellular uptake of Ru-PEG by human lung cancer
A549 cells with specific localization to lysosome. Dual-modal PTT and
PDT treatment by rGO-Ru-PEG exhibited higher anticancer efficacy as
compared with either treatment alone. Next to the generation of ROS,
cathepsin-initiated lysosomal damage by combined photothermal/
photodynamic effect was also found to contribute to the apoptosis of
cancer cells. Moreover, rGO-Ru-PEG exhibited photothermal imaging
under illumination at 808 nm, which revealed the high antitumor ef-
ficacy in vivo by the prepared nanosystem.
In short conclusion, numerous carbon-based nanomaterials have
been designed through surface modifications to increase the bio-
compatibility and tumor-targeting efficiency, exhibiting great potential
for PDT application. Also, it is feasible to control the structural and
surface properties of carbon-based nanomaterials to get intended tox-
icokinetics and pharmacokinetics [159]. Nevertheless, the biomedical
use of carbon-based nanomaterials still faces a few problems, such as
the lack of standardized synthetic protocols for large-scale production
with fixed properties, and dose-related toxicity in vivo [125,127]. For
instance, it has been documented that the lattice defects and oxygen-
containing agents of CNTs may cause peroxidation damage, resulting in
the toxicity [160].
3.7. Two-dimensional (2D) nanomaterials
Since the first mechanical exfoliation of graphene was discovered in
2004, the development of 2D nanomaterials has achieved un-
precedented scientific and technological advances [161–163]. 2D na-
nomaterials exhibit some unique physical and chemical features on
account of their large surface area, ultrathin thickness, tunable com-
position and facile surface modifications [164–167]. These properties
are highly desirable for diverse potential applications such as catalysis,
device fabrication [168–170], optoelectronics [171–174], energy sto-
rage [175], sensing [176,177], as well as disease diagnosis [178–181]
and therapeutics [182–185]. Therefore, 2D nanomaterials acting as PSs
not only share the same advantages as the other types of nanomaterials,
Fig. 12. Schematic illustration of the decomposition of MnO2 nanosheets from the UCSMs-H2O2 redox reaction, resulting in improved UCL imaging and oxygen
generation for enhancing the PDT effect. Reproduced with permission [192]. Copyright 2015, Wiley-VCH Verlag GmbH & Co. KGaA.
12
Biomaterials 237 (2020) 119827
but also offered some new benefits to further improve the therapeutic
efficacy at the same time [161].
3.7.1. Manganese dioxide (MnO2) nanosheets
One of the issues for PDT-based tumor treatment is the consumption
of generated ROS by the solid tumors that are mostly in a constant
hypoxic state. Moreover, the excessive expression of glutathione (GSH)
in the tumor cells can consume the ROS produced by PDT agents as well
[186]. Therefore, the PDT efficacy and the clinical therapeutics of
current PDT agents could be largely limited [187,188]. MnO2 na-
nosheets have been proven to be able to regenerate oxygen by reacting
with H2O2 within the tumor microenvironment, and decrease the
amount of GSH from the reaction between them, thus rapidly increase
the oxygen level in the tumor tissues [161,189]. Besides, MnO2 na-
nosheets also show some attractive features for use as a carrier for PSs.
For instance, they have strong PS adsorption ability due to electrostatic
interaction and Mn–N coordinate bonds, which can promote their en-
docytosis in intracellular PDT [190]. Additionally, MnO2 nanosheets
show good biocompatibility owing to the important role of nontoxic
manganese in physiological metabolism [191]. From these perspec-
tives, extensive attentions have been attracted to investigate the use of
MnO2 nanosheets in PDT.
In 2015, Shi group reported a MnO2 nanosheet-based theranostic
nanosystem, where MnO2 nanosheets were used for immobilizing up-
conversion nanoprobes (UCSMs) loaded with PS silicon phthalocyanine
dihydroxide (SPCD) [192]. In the acidic tumor microenvironment,
significantly increased signal intensity of oxygen was detected attrib-
uted to the redox reaction between MnO2 and endogenous H2O2, en-
hancing tumor saturated O2 by about 7%. Simultaneously, the
MnO2–H2O2 redox reaction also enhanced the upconversion lumines-
cence (UCL) emitted by UCSMs, which can be used for high-resolution
tumor imaging (Fig. 12). In addition, singlet oxygen generated by the
PS-loaded UCSMs upon NIR irradiation was also improved by the O2
generation due to the UCSMs-H2O2 redox reaction, leading to increased
PDT efficacy in killing 4T1 murine breast cancer cells. MnO2 nanosheets
have also been used as a nanocarrier for PS Ce6, in which the MnO2
J. Chen, et al.
nanosheets also acted as an oxidant to consume the intracellular GSH in
order to achieve enhanced photodynamic efficiency [189]. In this na-
nosystem, Ce6 was efficiently loaded on the MnO2 nanosheets and was
protected by MnO2 from self‐destruction under light exposure, so that
the PS can be effectively transported to cytoplasm. Remarkably, the as-
prepared Ce6–MnO2 nanocomplex outperformed the other nanoma-
terial-based platforms (such as Ce6‐GO and Ce6‐MSN) in killing
MCF‐7 cells under the conditions the authors used. The Ce6–MnO2-
mediated PDT led to over 95% cell death, while these numbers for
Ce6‐GO and Ce6‐MSN nanosystems were 36% and 21%, respectively.
These results demonstrated high potential of MnO2 nanosheets for im-
proving the PDT efficacy under a clinically relevant setting.
Zhang et al. deposited MnO2 nanosheets with TiO2-coated UCNPs,
which was further modified by amino-polyethylene glycol (PEG-NH2)
[193]. In addition to the oxygen generating from MnO2-catalyzed de-
composition of H2O2 for overcoming tumor hypoxia, the TiO2 nano-
shells can be activated by the UCL of UCNPs under NIR illumination to
produced cytotoxic 1O2 and hydroxyl radicals (%OH) via water splitting,
which are highly damaging to the tumor cells. Meanwhile, intracellular
superoxide dismutase (SOD) can catalyze the water-splitting process to
produce by-product superoxide anion radicals (O2%-), thereby re-
plenishing more H2O2 and O2. In this sense, ROS generation was am-
plified from reactive oxygen circulation, providing a significantly en-
hanced PDT outcome. Very recently, in another study by Zeng and co-
authors, MnO2 nanosheets were modified with PEG-cyclic arginine-
glycineaspartic acid tripeptide (PEG-cRGD), which was subsequently
conjugated with PS Ce6 with a high loading efficiency [194]. The
prepared MnO2-PEG-cRGD/Ce6 nanocomplex can significantly elevate
the oxygen concentration and was specifically uptaken by PC3 cells,
due to the cRGD-mediated tumor-targeted ability. As a result, favorable
therapeutic outcomes were realized in vitro upon irradiation at 660 nm.
3.7.2. 2D transition metal dichalcogenide (TMD) nanosheets
TMD nanosheets are a powerful tool for drug delivery and tumor
therapy, as they possess high specific surface area, good biocompat-
ibility, facile modification, and ultrahigh light and heat conversion ef-
ficiencies [195,196]. MoS2 nanosheets are one of the most re-
presentative and explored 2D TMDs that attract a lot of research
interests in the development and applications in biomedicine due to
several favorable features. First, the precursor for MoS2 nanosheets,
molybdenite, is very abundant in nature [197]. Second, similar to other
2D nanomaterials, MoS2 nanosheets also represent many unique phy-
sical and chemical properties like large surface area and strong absor-
bance in NIR region [198,199]. Additionally, it is feasible to modify the
surface of MoS2 nanosheets, making them more promising for biome-
dical uses [200].
In 2014, Liu et al. used lipoic acid-terminated PEG (LA-PEG) to
modify MoS2 nanosheets, obtaining the PEGylated MoS2 (MoS2-PEG)
nanosystem that was highly stable in physiological solutions [201].
MoS2-PEG showed remarkably enhanced delivery efficacy of the PS Ce6
to cells, as much stronger intracellular Ce6 fluorescence was detected in
the cells incubated with MoS2-PEG/Ce6 in comparison with those in-
cubated with free Ce6. In vitro experiments further demonstrated that
MoS2-PEG/Ce6 exhibited dramatically enhanced photodynamic ther-
apeutic efficacy in killing 4T1 cancer cells under 660 nm light exposure
compared to free Ce6, which was possibly caused by the promoted
cellular uptake of the PS that led to more singlet oxygen produced in-
side cells. In the work by Ji and co-workers [202], MoS2 nanosheets and
fluorophore-labeled glycoligands could undergo self-assembly to form
the MoS2 glycosheets. The glycoligands can effectively and selectively
interact with the highly expressed galactose receptors on Hep-G2 cells,
leading to the high tumor-specific efficiency of the as-obtained MoS2
glycosheets. Importantly, the MoS2 glycosheets have been proven to
show good singlet oxygen generation capability under light activation,
which eventually led to the death of Hep-G2 human liver cancer cells
(Fig. 13). More recently, Kapri and co-workers integrated p-type MoS2
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Biomaterials 237 (2020) 119827
glycosheets onto n-type nitrogen doped reduced GO (n-rGO) through
p–n heterojunction, which was subsequently decorated with PEGylated-
modified MnO2 nanoparticles, forming a p-MoS2/n-rGO–MnO2–PEG
nanocomposite [203]. In this nanosystem, the p–n heterojunction pro-
motes the migration of electrons and holes to enhance the separation of
electron–hole pairs when exposed to NIR light [204], thus increasing
the ROS production through photocatalysis. In addition, MnO2 trig-
gered the disproportionation of intracellular H2O2 to generate more O2,
which in turn further improved the production of ROS. In vitro studies
revealed that this nanocomposite showed effective PDT effect in killing
HeLa cells. In 2019, a mesoporous silica nanorods (MSNR)/MoS2 na-
nocomposite was constructed by Yang et al. [205], which was further
modified by human serum albumin (HSA) to improve the tumor tar-
geting ability and reduce the toxicity. Under excitation at 808 nm, MoS2
was able to exert photothermal effect that can lead to both the direct
tumor destruction and the release of loaded PS Ce6 to generate ROS
upon 660 nm light illumination, thereby achieving the synergetic
photothermal/photodynamic therapy. The anti-tumor effect has been
proven in both the in vitro experiments with breast cancer cells and in
vivo experiments with mice bearing 4T1 tumor.
The nanomaterial-based combinational PTT/PDT treatment, which
takes advantage of biomechanics and phototherapy, as well as the high
specific surface area of nanomaterials, has gained increasing popularity
in the field of multimodal therapy of cancer cells [195,206]. 2D TMDs,
like WS2 nanosheets, have also been utilized in the combinational PTT/
PDT strategy. In 2014, Yong and co-authors fabricated WS2-based na-
nocomposites, in which PS MB was loaded on bovine serum albumin
(BSA)-modified WS2 nanosheets [207]. The WS2 nanosheets were pre-
pared through liquid exfoliation during which H2SO4 intercalation and
ultrasonication was adopted in order to improve the water and air
stability. BSA was utilized to further functionalize the as-synthesized
WS2 nanosheets via physical adsorption to improve the biocompat-
ibility and dispersibility in physiological solutions, as well as the ad-
sorption capability of loading the PS molecule thanks to BSA's amphi-
philic molecular structure (Fig. 14). The as-obtained BSA–WS2@MB
nanocomplex exhibited photothermal effects under 808 nm irradiation,
leading to the release of MB molecules. Although the BSA–WS2@MB
nanocomposites generated only little amount of singlet oxygen with
665 nm LED lamp, the production of ROS was greatly improved under
NIR irradiation at 808 nm. The PTT and PDT dual synergistic therapy
confirmed better therapeutic performance of the BSA–WS2@MB na-
nocomposites to kill the HeLa cancer cells, compared to the treatment
using PTT or PDT alone. It was argued that the reason for enhanced
PTT/PDT effects is that the NIR irradiation can promote both the
photothermal effects of WS2 that resulted in accelerated release of PS
and the formation of singlet oxygen.
3.7.3. Graphitic-phase carbon nitride (g-C3N4) nanosheets
As one of the newly emerging 2D nanomaterials, g-C3N4 nanosheets
have been used in various biomedical applications, owing to their low
toxicity, high stability, good biocompatibility, and high photo-
luminescence quantum yields. The first example of their use in PDT was
reported by Lin et al. in 2014, in which the g-C3N4 nanosheets were
utilized as PS to generate singlet oxygen, achieving effective HeLa cells
death upon light exposure with low power density (20 mW/cm2) at
440–450 nm [208]. Furthermore, by loading anticancer drug DOX, the
g-C3N4 nanosheets can act as a carrier with high loading capacity of
18,200 mg/g, owing to the high surface-to-volume ratio. The release of
DOX was accelerated under acidic pH environment due to the promoted
protonation and solubility of DOX in the acidic condition. Additionally,
thanks to the high photoluminescence quantum yield of the g-C3N4
nanosheets, it was possible to use them for imaging to track the delivery
process.
In the work by Ma and co-workers, FeIII-modified g-C3N4 nanosheets
have been demonstrated to show outstanding catalytic ability of de-
composing H2O2 to produce O2 in cancer cells, thereby reducing tumor
J. Chen, et al. Biomaterials 237 (2020) 119827

Fig. 13. a) Structures of the glycoligands DK1, DK2,

and DK3 (Gal = galactose; GalNAc = N-acetyl ga-
lactosamine; Lac = lactose). b) Illustration of the
supramolecular self-assembly between MoS2 and DK,
and the targeted intracellular 1O2 generation via two
steps (I) receptor endocytosis and (II) light illumi-
nation. Reproduced with permission [202]. Copy-
right 2016, Wiley-VCH Verlag GmbH & Co. KGaA.

Fig. 14. Illustration of the preparation of BSA–WS2@MB nanocomposites and

their use as a PS delivery system for combinational PTT and PDT treatment.
Reproduced with permission [207]. Copyright 2014, The Royal Society of
Chemistry.

Fig. 15. Structure of PCCN and illustration of the enhancement of PDT by light-
hypoxia and enhancing the PDT outcome [209]. A mitochondria-tar- driven water splitting. Reproduced with permission [210]. Copyright 2016,
geting moiety, (4-carboxybutyl)triphenylphosphonium bromide (TPP), American Chemical Society.
was conjugated to deliver the C3N4–Fe nanosheets loaded with PS MB
to the mitochondria. Furthermore, the conjugation of TPP could also
photoexcitation of the g-C3N4 suspensions containing spherical gold
facilitate the sensitivity of cancer cells to produce singlet oxygen by
nanoparticles (Fig. 16) [211]. The incorporation of gold nanoparticles
improved mitochondria dysfunction, which further triggered the death
could improve the absorption efficiency of 670 nm light, hence sig-
of cells. As a result, nearly complete removal of mouse cervical tumor
nificantly improving the efficiency of 1O2 production through photo-
was achieved in vivo. Similarly, by doping with carbon dots, C3N4 na-
catalytic water-splitting process due to the enhanced electron/hole se-
nosheets have also shown the ability to generate O2 in tumor tissues
paration. Good PDT effects of the g-C3N4-AuNPs nanocomposites have
[210]. In this strategy, carbon dots have been utilized to enhance the
been demonstrated in the apoptosis and/or necrosis of three tested
red light absorption of the C3N4 nanosheets, which could induce in vivo
cancer cell lines (i.e., A549, MCF-7, and HeLa) upon 670 nm laser il-
water splitting under 630 nm light, thus increasing the intracellular O2
lumination. In addition, effective suppression of tumor growth has also
concentration. The PS protoporphyrin IX (PpIX) was linked with tumor-
been achieved in MCF-7 tumor-bearing mice.
targeting sequence RGD (Arg-Gly-Asp) via PEG, forming an amphi-
pathic polymer, which was subsequently assembled with carbon-dot-
doped C3N4 (CCN) via π-π stacking between PpIX and C3N4 to obtain 3.7.4. Black phosphorus (BP)
the PCCN nanoparticles (Fig. 15). Both in vitro and in vivo assays showed BP, as a new type of 2D semiconductor, has attracted extensive
that this as-obtained PCCN nanosystem showed superior ability over- scientific efforts in the field of PDT since the first successful exfoliation
come tumor hypoxia and enhanced PDT effects. Very recently, Dai et al. of bulk BP into single- or few-layer BP in 2014, owing to its exceptional
decorated the g-C3N4 nanosheets with gold nanoparticles via structural, optical and chemical properties [212–221]. First, the
bandgap of BP is tunable and is correlated to the number of layers, and

14
J. Chen, et al.
Fig. 16. Schematic illustration of the g-C3N4-AuNP-mediated PDT and the production of ROS under 670 nm irradiation. Reproduced with permission [211].
Copyright 2019, American Chemical Society.
it is feasible to obtain monolayer or few-layer BP nanosheets via ex-
foliation [222]. This unique optical property, in combination with its
impressive carrier mobility, allows broad optical absorption of BP,
which determines that it can be used effectively in many biomedical
uses, including PDT, PTT and drug delivery [107,196,223–227].
Second, BP has ultrahigh surface-area-to-volume ratio owing to its
single-atomic thickness, providing large amounts of anchoring points
for anticancer drugs, which makes it an ideal candidate for nanocarrier
in drug delivery systems [228–230]. Most importantly, BP generally
exhibits better biocompatibility and biodegradability inside the human
body with respect to other nanomaterials. Phosphorus (P) is an essential
element of the human body which accounts for about 1% of body
weight [228], indicating its high potential in biomedical applications.
Additionally, BP can be readily biodegraded to nontoxic phosphate,
phosphite or other PxOy in the human body, thus exhibiting its safety
for in vivo cancer therapy [231–233].
The first use of BP nanosheets in PDT was documented by Wang and
co-workers [234] in 2015. In this work, ultrathin BP nanosheets were
obtained from the exfoliation of bulk BP in water (Fig. 17a), with a
thickness showing a height of about 2.0 nm (Fig. 17b). The as-obtained
BP nanosheets provided a high quantum yield of singlet oxygen (up to
0.91) upon irradiation with xenon lamp or 660 nm laser, demonstrating
their attractive applications in PDT. In vitro cell viability tests revealed
significant death of human MDA-MB-231 breast cancer cells by the BP
nanosheets under 660 nm light illumination (Fig. 17c). Cell apoptosis
test showed remarkable cell apoptosis of the cancer cells after treatment
of the BP nanosheets under irradiation (Fig. 17d). In vivo PDT studies
demonstrated high tumor-suppression effect of the BP nanosheets by
intratumor injection of them in MDA-MB-231 breast tumor-bearing
mice combined with light irradiation (Fig. 17e). Typically, BP na-
nosheets alone can only be activated by visible light to cause PDT ef-
fects [228]. However, the use of irradiation wavelength within the
visible light region suffers the issue of low tissue penetration, which
limits its clinical therapeutics. To this end, a multifunctional composite
in which BP nanosheets were integrated with UCNPs was reported by
Lv et al. to achieve NIR-mediated PDT at 808 nm [235]. In this study,
the energy donor, NaGd-F4:Yb,Er@Yb@Nd@Yb UCNPs were first
15
Biomaterials 237 (2020) 119827
decorated with polyacrylic acid (PAA), which were subsequently in-
corporated to the surface of BP nanosheets functionalized with PEG-
NH2 by electrostatic interaction, giving the UCNPs-BPS nanosystem
(Fig. 18a). Importantly, both in vitro and in vivo assays confirmed that
the UCNPs-BPS composite with 808 nm light irradiation showed greater
ROS generation capability and improved effect of tumor inhibition in
comparison with other groups under 650 nm and 980 nm light acti-
vation (Fig. 18b–d), indicating the great potential of UCNPs-BPS as a
PDT agent. Yet, the relatively low quantum yield (< 3%) caused by the
upconverted process for the energy donor still remained a problem for
its clinical application and industrialization [167]. To address this
issue, a novel BPs@Au@Fe3O4 nanocomposite was developed by as-
sembling iron oxide (Fe3O4) nanoparticles and gold nanoparticles on BP
nanosheets through an ordinary electrostatic attraction method [236].
With a combination of the PTT effect of gold nanoparticles, the tumor-
targeting and MRI guiding abilities of Fe3O4 nanoparticles, as well as
the PDT effect of BP nanosheets, this nanosystem showed enhanced
therapeutic effect with improved targeting abilities. Furthermore, the
mice bearing U14 tumor treated with BPs@Au@Fe3O4 upon 650 nm
illumination showed significant suppression of tumor growth. This
work revealed the new horizons of BP nanosheets for biomedicine.
Very recently, in the work from Yang et al., polydopamine (PDA)
functionalized BP nanosheets were covalently bound to PS Ce6 and
TPP, giving the BP@PDA–Ce6&TPP nanosystem [237]. In this nano-
platform, PDA coated BP showed strong absorption in the NIR region
and Ce6 provided effective ROS formation. Furthermore, the TPP
moiety offered the mitochondria-targeting capacity. As a result, sig-
nificantly enhanced killing ability of cancer cells and outstanding per-
formance in tumor growth inhibition have been achieved in the vi-
sualized synergistic therapy. In another study by Liu and co-workers
[238], Rhodamine B (RhB)-encapsulated MnO2 (R–MnO2) and fluor-
escein isothiocyanate (FITC)-decorated BP with peptide modification
(FBP) were electrostatically assembled, forming a BP/MnO2 nanoplat-
form (Fig. 19). In this R–MnO2-FBP nanocomposite, R–MnO2 acts as the
O2 supplier and indicator, which could induce the generation of O2
under the acidic and H2O2-rich condition upon targeted FA receptor
(FR)-mediated endocytosis. Besides, the oxygen generation process can
J. Chen, et al. Biomaterials 237 (2020) 119827

Fig. 17. (a) Schematic illustration of the fabrication of ultrathin BP nanosheets

through water exfoliation of bulk BP. (b) Atomic force microscopy (AFM) image
of the prepared BP nanosheets and the corresponding height image. (c) Cell
Fig. 18. (a) Synthetic scheme of the preparation of the UCNPs-BPS composite.
viability with different concentrations of BP nanosheets. (d) Cell apoptosis
(b) Cancer cells with UCNPs-BPS upon irradiation with different wavelengths.
following transfection with PBS, BP nanosheets and BP nanosheets under light
(c) Photographs of tumor-bearing mice and tumors after different treatments for
irradiation. (e) Time-dependent tumor growth under different formulations,
14 days. (d) Changes of tumor volume and body weight in different groups.
and the corresponding photographs of tumors after the treatment. Reproduced
Reproduced with permission [235]. Copyright 2016, American Chemical So-
with permission [234]. Copyright 2015, American Chemical Society.
ciety.

be monitored by fluorescence and magnetic resonance (MR) imaging

attributed to the released dye RhB and Mn2+. The FBP moiety, acting as
the theranostic agent, could mediate highly efficient PDT both in vitro
and in vivo. Futhurmore, a self-feedback system can be built for the
therapeutic response by utilizing the activated caspase in the cell
apoptosis caused by oxygen-evolving PDT (Fig. 19).
In short summary, the past decade has witnessed unprecedented
advancements of 2D nanomaterials for the use as next-generation
technologies in PDT application, attributed to their unique structural
architecture, noteworthy physical and chemical characteristics, and
flexible surface chemistry. Still, several concerns need to be addressed
before practical biomedical use: (1) how to get appropriate lateral size
with large-scale production [239]; (2) how to improve the tumor-tar-
geting efficiency [239]; (3) how to enhance the biocompatibility and
reduce the toxicity of some 2D nanomaterials [240].

3.8. Other nanomaterials

3.8.1. Nanoscale metal-organic frameworks (MOFs)

Nanoscale MOFs (NMOFs) have emerged as a promising delivery
platform for PDT due to versatile functionalities of their chemical
Fig. 19. Schematic illustration of the fabrication of the R–MnO2-FBP nano-
compositions, the well-defined crystalline structures, high porosity, and platform and the uses for monitoring oxygen self-supply, enhancing PDT and
tunable framework stability [48,241–243]. In 2014, the Lin group de- evaluating the therapeutic effects. Reproduced with permission [238]. Copy-
signed an Hf−porphyrin NMOF consisting of a porous UiO NMOF right 2019, Elsevier.
structure and a H2DBP (5,15-di(p-benzoato)porphyrin) bridging ligand
[244]. The PS is well-isolated from the framework, therefore avoiding

16
J. Chen, et al.
the aggregation and self-quenching of PS. Furthermore, the promoted
intersystem crossing attributed to the coordination between the ligands
and heavy Hf centers, as well as the unique porous NMOF structure,
enhanced the production efficiency and the diffusion ability of singlet
oxygen. Consequently, strong photodynamic effects have been achieved
both in vitro cancer cell examination and in vivo tumor-bearing mice
assays. Subsequently, the same group reduced to ligand H2DBP to
H2DBC (5,15-di(p-benzoato)-chlorin), thereby preparing the chlorin-
based incorporated NMOF [245]. This DBC-UiO nanoplatform ex-
hibited a red (13 nm) shift and an increased extinction coefficient (11-
fold) of the lowest-energy Q band compared to the previous DBP-UiO
structure. As a consequence, DBC-UiO outperformed DBP-UiO in the
terms of singlet oxygen generation efficiency and PDT performance on
in vitro and in vivo tests. More recently, they incorporated the TBP
(5,10,15,20-tetra(p-benzoato)porphyrin) ligand to Fe3O clusters, fabri-
cating the Fe-TBP nanoconstruct [246]. Particularly, the Fe3O clusters
were able to catalyze the decomposition of intracellular H2O2 to form
O2 via a Fenton-like reaction to overcome tumor hypoxia. Therefore, a
significantly enhanced PDT performance has been achieved for effec-
tive inhibition of tumors. Similarly, He and co-authors have reported a
Mn-porphyrin based MOF consisting of the Mn-porphyrin ligands and
biocompatible Zr4+ ions, where Mn-porphyrin exhibited good cata-
lytic ability to decompose H2O2 to O2, realizing the oxygen self-sup-
plementing PDT [247]. Besides, the unique porous MOF frameworks
can prevent the self-aggregation of Mn–porphyrin and accelerate the
diffusion of H2O2 and generated O2.
3.8.2. Organic nano-agents
Some recently developed nano-agents, such as nanostructured
phthalocyanine self-assemblies [248] and porphysome [249], have also
been utilized for PDT application. In 2017, Li et al. reported the na-
nostructured phthalocyanine self-assemblies prepared from zinc(II)
phthalocyanine building blocks decorated with triethylene glycol (TEG)
linkers as targeting agents [250]. The as-prepared nanoassemblies show
targeted protein-induced partial disassembly, due to the unique non-
covalent interactions between the targeting agents and phthalocya-
nines. Hence, the nano-phthalocyanine assemblies possess switchable
photoactivity, which triggered the generation of ROS and enables
tumor-specific PDT. Subsequently, they have fabricated a nanos-
tructured assembly from a phthalocyanine derivative and chemother-
apeutic drug mitoxantrone (MA) [251]. The molecular recognition in-
teractions of these two building blocks are ideal for spontaneous
assembly, therefore generating uniform nano-assemblies. This nano-
composite underwent nucleic-acid-responsive ROS production and
showed tumor targeting PDT in vivo. In addition, the pure phthalo-
cyanine molecule can also undergo self-assembly, which was able to
produce ROS through type I reaction [252]. The as-obtained nanos-
tructured phthalocyanine assemblies exhibited good PDT performance
on bacterial cells. By using albumin to trap the phthalocyanine mole-
cule, the nanostructured phthalocyanine self-assemblies with hydro-
philic groups can exhibit disassembly [253]. As a result, time-modu-
lated PDT has been achieved via the albumin-driven production of ROS.
Very recently, Li and co-authors developed the size-controllable na-
nostructured self-assemblies based on a silicon(IV) phthalocyanine-
biotin conjugate by using different amounts of surfactant Cremophor EL
[254]. The ROS generation ability was dependent on the particle size,
and decreased along with the increase of particle size. The nanoscale
self-assemblies could undergo disassembly driven by a tumor-specific
biotin-binding protein, i.e., avidin, resulting in the PDT-based photo-
cytotoxicity on HepG2 cells. Porphysomes present as a stable and effi-
cient carrier for porphyrin. However, they were reported to covert the
photodynamic activities to photothermal activities completely [255].
By conjugating with a folate-receptor, the nanostructure of the folate-
porphysomes was disrupted in cancer cells rapidly, hence reversing the
PTT effects back to PDT effects aroused by the densely loaded por-
phyrins [249]. Effective inhibition of tumor growth has been observed
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Biomaterials 237 (2020) 119827
in KB-tumorbearing mice attributed to the folate-driven PDT.
3.8.3. Transition metal carbides (TMCs)
Recently, TMCs, including Ti3C2 and W2C, have also been in-
vestigated considerably in the biomedical application, because of their
flexible surface functionalization, strong NIR light absorption ability
and good biocompatibility [48,256]. Several studies have also reported
their use in PDT. In 2017, Ti3C2 nanosheets have been prepared by Liu
et al. for the use in synergistic PTT/PDT/chemotherapy by using a
surface modification method during the synthesis, resulting in a thin
thickness of ca. 100 nm and high surface stability [257]. Generation of
singlet oxygen has been observed under 808 nm excitation, presumably
owing to the energy transfer of photoexcited electrons from Ti3C2 to
oxygen. Additionally, by loading with the anti-cancer drug DOX and
modifying with tumor-targeting agent hyaluronic acid (HA), this as-
prepared multifunctional nanosystem exhibited tumor-specific accu-
mulation and effective ablation of human colon carcinoma tumor in
vivo. In another work by Li and co-workers, W2C nanoparticles have
been prepared from the generation of organic–inorganic nanostructures
triggered by ionic self-assembly [258]. By further functionalizing with
HA, the W2C nanoparticles showed enhanced biocompatibility and
tumor-targeting efficiency. Upon irradiation with NIR II light
(1064 nm), the as-obtained nanocomposite was able to produce both
hydroxyl radicals and singlet oxygen via type I and type II reaction
mechanisms, respectively. In addition, the W2C nanoparticles also ex-
hibited photothermal activity upon 1064 excitation, thus allowing sy-
nergetic photodynamic/photothermal therapy for efficient eradication
of tumors.
To sum up, thanks to the rapidly developed nanoscience in the field
of biomedicine over the last few decades, it is believed that an in-
creasing number of new nanomaterials are expected to be emerged,
bringing hope for offering promising alternative treatment modalities of
cancer.
4. Current challenges of photodynamic therapy
4.1. Tumor targeting efficiency
The lack of good tumor targeting efficiency associated with most of
traditional organic PSs has largely limited their clinical use. On one
hand, the reason for the higher concentration of some PSs in the tumor
tissue than the neighboring healthy tissues is still not clear, and this
tumor targeting ability is attributed to the unnormal physiological
features of the tumors [4,13]. On the other hand, the inherent prop-
erties of PSs, such as the morphology, particle size, and surface mod-
ulation can dramatically influent the tumor targeting ability [48]. In
this sense, improving the tumor targeting efficiency of the PSs could be
complicated and challengeable. To overcome this issue, targeting li-
gands conjugated to PSs and surface modification of the PDT agents
with targeting moieties could be adopted to deliver the photosensitizing
drugs specifically to the tumors (Table 2) [51,259–270]. The use of
nanomaterials in PDT will provide great potentials for surface func-
tionalization that can enhance the tumor targeting efficiency.
4.2. Deep tissue PDT
During the PDT with traditional earlier generation PSs, visible light
is normally required for photoexcitation. However, the penetration
depth of visible light is rather low (< 3 mm) because of strong light
absorption in visible region by most tissue chromophores [271].
Therefore, the photodynamic outcome is significantly hampered by the
weakening light intensity along with the increase of tissue depth. One
strategy to deal with this issue is to employ PSs that can be excited by
NIR light, which is within the “optical window” of biological tissue. The
use of NIR light in PDT could not only offer deeper tumor therapy, but
also decrease the phototoxicity to healthy tissues as compared to the
J. Chen, et al. Biomaterials 237 (2020) 119827

Table 2 independent modalities (such as PTT and chemotherapy) can also be

Some commonly used targeting conjugates for PDT. adopted to deal with tumor hypoxia [48,280].
Conjugate Targeted tumor/cancer cells Reference
4.4. More efficient and more reliable nanomaterial-based photosensitizers
Folic acid Brain, lungs and ovary tumors [259–262]
Low-density lipoprotein Colon, hepatoblastoma (HepG2) and [263,264]
Undoubtedly, the PS represents a pivotal role in PDT. Hence, the
(LDL) retinoblastoma tumors
Epidermal growth factor Breast carcinoma cells, epidermal [265,266]
PDT treatment results are largely related to its physical, chemical and
(EGF) carcinoma and ovarian cancer pharmacokinetic properties. The PSs with high ROS generation effi-
Retinoic acid Neuroblastoma SK-N-DZ cells [267] ciency, good biocompatibility and good stability under physiological
Monoclonal antibodies Ovarian and breast cancer cells [268] conditions, as well as high tumor targeting ability are still highly de-
(MAbs)
manded. This review highlights some of the recent studies on the ap-
Magnetoliposomes Melanoma [269]
Glucose and galactose K562 cells [270] plication of nanomaterials in PDT (Table 3). Each nanoconstruct pos-
Phenylalanine Transformed PAM212 keratinocyte [51] sesses certain fascinating features and clear advantages that can be
cells exploited for PDT. Yet, it should be realized that the defects of the
nanomaterials still exist, which limit their practical clinical use. For
instance, the toxicity associated with (heavy) metal-based nanomater-
ials, long multi-step preparation associated with UCNPs, and instability
associated with BP nanosheets, and many others as discussed above.
Therefore, extending the potentials of nanomaterials in PDT by devel-
oping more efficient and more reliable nanomaterials still needs ex-
tensive and unremitting efforts.

5. Conclusions and future perspectives

Throughout the over 100-year history of PDT, more than 1000

Fig. 20. Illustration of the use of UCNPs to convert low-energy NIR irradiation
to high-energy UV/visible emission for activating the PS to produce ROS (ex-
emplified by Type II reaction).
PDT with UV or visible light [48,272]. However, the shortcoming ac-
companied by the use of NIR light is the low energy that may not ef-
fectively trigger the PSs to produce sufficient ROS. Therefore, there are
increasing interests in using UCNPs for PDT. UCNPs could convert low-
energy NIR light, which has deep tissue penetration, to high-energy
UV/visible light that could excite the accompanying PS to generate ROS
(Fig. 20) [273]. The other strategy is to use the light source that are not
restricted by tissue thickness, such as X-ray and internal lights. Never-
theless, the low ROS generation efficiency and side effects to healthy
tissue associated with X-ray and poor energy transfer to the PS asso-
ciated with internal lights indicate that more efforts are needed in these
fields [48]. In general, to realize deep tissue PDT with high efficiency is
still a challenging task.
4.3. Tumor hypoxia
Apparently, the photodynamic effect is highly dependent on the
concentration of surrounding oxygen. Hence, the antitumor effects
elicited by PDT are significantly hampered in hypoxic tumors, in which
oxygen is largely consumed by vastly growing tumor cells. Besides, PDT
is an oxygen consuming process that would aggravate the tumor hy-
poxia, thereby leading to decreased PDT efficiency. In order to deal
with tumor hypoxia, nanoplatforms consisting of PS and nanomaterial
that can catalyze the decomposition of H2O2 to produce O2, such as the
MnO2 nanosheets discussed above, were developed. Besides, some
techniques that can contribute to the reperfusion of O2, such as light
fractionation for controlled “on” and “off” periods of light exposure
[274,275] and low fluence rate PDT [276–278], have also been used to
overcome tumor hypoxia. Unfortunately, these methods do not take
effect in the cases where tumor hypoxia is caused by rapid growth of
tumor cells [279]. Alternatively, the PSs that are independent of
oxygen, like TiO2 and g-C3N4, and PSs that can mediate the O2-in-
dependent type I reaction and combinational therapy with O2-
known PSs that are both natural and synthetic have been discovered
[70]. Yet, only a few of them have gained access into the clinical ap-
plications in the management of cancers, mainly because of the lim-
itations of conventional PSs [5]. It is still imperative to develop the
“ideal” PSs that can be excited efficiently by longer activation wave-
lengths with higher yield of ROS [281–285], and that can be highly
selectively distributed to the targeted site [286–288]. Undoubtedly, the
road to reach this target and eventually to make PDT as a first-line
treatment strategy in treating cancers is still long and challengeable.
Nevertheless, the utilization of nanomaterial-based agents in PDT pre-
sents a great stride forward towards this goal, which could greatly
tackle some of the shortcomings associated with conventional PSs. Next
to the exceptional physicochemical and optical properties of nanoma-
terials that make them more favorable to be used in PDT than the
conventional PSs, the facile modifications and functionalization of the
surface can offer additional versatility, such as the targeting moieties
leading to improved specificity in the accumulation of PS-conjugated
nanomaterials at the target site [4]. In this review, the development of
various nano-agents that were reported for the application in PDT is
summarized.
In recent years, PDT-based multimodal treatment of cancer has
become a popular trend, in which PDT is carried out synergistically
with other therapeutic methods, including PTT, MRI, drug delivery,
fluorescence imaging, chemotherapy and immunotherapy, etc. The
combinational treatment can make use of the advantages of each
modality and compensate each's shortcomings, therefore representing a
more promising way to achieve safe and effective therapeutic results as
compared to the single treatment strategy. Based on this principle, it is
worth mentioning the combination of the smart NIR-responsive drug
delivery system and UCNP-based PDT, which shows some appealing
superiorities as a treatment modality of cancer. This multimodal system
utilizes the spatiotemporally controllable feature of NIR for on-demand
drug release, as well as the photon upconversion property of UCNPs to
generate high energy light for promoted drug release and effective ROS
production (Fig. 21) [289,290].
Many other advanced techniques, such as X-ray light irradiation,
microwave-induced PDT, bacteriophage nanowire- or stem cell-based
PS delivery system, have also been used to improve the PDT effects
[291]. As mentioned earlier, X-ray possesses deep tissue penetration
capability [292,293], but also has weak PS activation ability and can
lead to side effects to normal tissues. However, using heavy element-

18
 J. Chen, et al.

Table 3
Summary of representative nanoplatforms for PDT.
Nanomaterial PS drug Modification agents Remarks Light source Applications Ref.

Au NRs - - Length: 37.3 ± 2.4 nm; 915 & 780 nm PDT/PTT for B16F0 melanoma tumor [62]
Diameters: 11 ± 1.2 nm
Au NEs – - Extinction coefficient: NIR I and NIR II PDT/PTT for B16F0 melanoma tumor [63]
~0.69 × 1012 M−1 cm−1 at 915 nm, 0.74 × 1012 M−1 cm−1 at
1064 nm
Silver nanoparticles - - Ag decahedrons (50 nm diameter) NIR PDT for HeLa cells [71]
Ag nanocubes (58 nm edge length)
Ag triangular plates (33 nm edge length, 7.5 nm thickness)
ORMOSIL nanoparticles IP - Size: ~20 nm; Highly monodispersed and stable in aqueous 514 nm PDT for RIF-1 tumor cells [76]
suspension
MSNs ZnPc PEG & PEI Diameter: 50 nm 680 nm PDT for H22 tumors [79]
Silica nanoparticles Ce6 FA Up to 100 μg/mL in MDA-MB-231 cells for 24 h 670 nm PDT for MDA-MB-231 cells [81]
Porous silicon nanoparticles – Gold nanoparticles & mannose 80 μg/mL in MCF‐7 breast cancer cells for 5h 800 nm Fluorescence imaging/PDT for MCF‐7 breast [87]
moieties cancer cells
1
CdTe QDs – TSPP O2 quantum yield: 0.43 355 nm Imaging and PDT [96]
1

19
NAC-CdTe/ZnS QDs R6G TMPyP & NIR775 O2 quantum yield: 0.91 400 nm Fluorescence imaging/PDT for KB tumors [98]
NaYF4:Yb/Er UCNPs ZnPc & MC-540 FA and PEG Size: ~80 nm 980 nm PDT for melanoma tumors [110]
NaGdF4 UCNPs Ce6 Gold nanorod dimer Size: 20 ± 2 nm PTT: 808 nm; PDT: PTT/PDT for HeLa tumors [123]
980 nm
SWCNTs DOX Fe3O4@CQDs & PEG Width: 35 nm 808 nm MRI/PTT/PDT for HeLa tumors [132]
C60 and mesoporous silica DOX Hyaluronan & ICG Diameter: ~60 nm 800 nm PTT/PDT/chemo therapy for breast CSCs [140]
N-GQDs – Amino group Lateral size: 7.24 ± 0.70 nm 800 nm Two-photon PDT for KB-50 cancer cells [150]
GO DVDMS PEG Size: < 50 nm; 630 nm Fluorescence imaging/PDT for U87MG tumors [156]
Thickness: ~2 nm
MnO2 nanosheets and UCSMs SPCD – 200 μg/mL in cells for 24 h NIR UCL imaging/PDT/RT for 4T1 tumors [192]
MoS2 nanosheets Ce6 LA-PEG Ce6 loading ratio: ~30% 660 nm PTT/PDT for 4T1 tumors [201]
WS2 nanosheets MB BSA Extinction coefficient: 21.8 L g−1 cm−1 808 nm PTT/PDT for HeLa tumors [207]
Diameter: 20–100 nm;
Thickness: 4–5 nm
Carbon-dot-doped C3N4 PpIX RGD & PEG Hydrodynamic size: 180 nm 630 nm O-elevated PDT for EGFP-4T1 tumors [210]
BP nanosheets – – Hight: 2.0 nm; 1O2 quantum yield: up to 0.91 660 nm PDT for MDA-MB-231 breast tumors [234]
BP nanosheets Ce6 PDA & TPP Thickness: 24.3 nm; Heigh: 49.1 nm; Biocompatibility: 25 μg/mL 660 nm PTT/PDT for tumors [237]
UiO NMOF – DBP Diameter: 76.3 nm; Biocompatibility: 30 μg/mL for 12 h 640 nm PDT for SQ20B tumors [244]
Nano-phthalocyanine assemblies – TEG Size: 100 nm 655 nm PDT for A549 tumors [250]
Ti3C2 nanosheets – Al(OH)4– Thickness: ~100 nm; 808 nm PTT/PDT/chemotherapy for HCT-116 tumors [257]
Extinction coefficient 28.6 Lg–1 cm−1
Biomaterials 237 (2020) 119827
J. Chen, et al. Biomaterials 237 (2020) 119827

Fig. 21. Illustration of multimodal cancer treatment with smart NIR-responsive drug delivery system and UCNP-based PDT. Reproduced with permission [289].
Copyright 2019, Elsevier.

Fig. 22. Some advanced techniques used for PDT. (a)

Schematic illustration of X-ray-induced PDT.
Reproduced with permission [296]. Copyright 2018,
The Royal Society of Chemistry. (b) Schematic illus-
tration of microwave-induced PDT. Reproduced with
permission [291]. Copyright 2019, Wiley-VCH Verlag
GmbH & Co. KGaA. (c) Schematic illustration of the
use of phages in PDT for delivering PS pyr-
opheophorbide a (PPa). Reproduced with permission
[305]. Copyright 2013, Wiley-VCH Verlag GmbH &
Co. KGaA. (d) Schematic illustration of the use of
mesenchymal stem cells (MSC) in PDT for delivering
PS-loaded nanoparticles. Pp-18 = purpurin-18. Re-
produced with permission [306]. Copyright 2014,
Wiley-VCH Verlag GmbH & Co. KGaA.

containing and X-ray sensitive nanoparticles, the photoelectric cross- developing new nanomaterial-based platforms for enhanced PDT and
sections can be largely increased, therefore reducing the radiation to the emerging new techniques for future enhancement of PDT, it is be-
healthy tissues [291]. In addition, these nanoparticles are able to lieved that PDT will gain acceptance as a potent therapeutic modality in
transfer the X-ray irradiation to light emission that can activate the PS clinical therapeutics of cancer.
to produce ROS (Fig. 22a) [292,294–299]. Microwave, on the other
hand, can not only induce local hyperthermia that makes tumors more
sensitive to chemotherapeutic drugs and ionizing radiation [300,301], Declaration of competing interest
but also trigger some nanoparticles to produce ROS [302]. Additionally,
the heat induced by microwave could increase the blood supply The authors declare that they have no conflict of interest.
through dilation of blood vessels, which in turn enhances the photo-
dynamic activity (Fig. 22b) [291]. In another advanced technique,
Acknowledgements
bacteriophage nanowires (phages) that show outstanding stability and
biocompatibility [303,304], are exploited for carrying photosensitizing
This work was partially supported by the Financial supports from
drugs (for instance, pyropheophorbide a) with high loading efficiency
the Science and Technology Development Fund (Nos. 007/2017/A1
via chemical conjugation [305]. Furthermore, the cancer-targeting
and 132/2017/A3), Macao Special Administration Region (SAR),
peptides attached to the phages can lead to selective destruction of
China, the State Key Research Development Program of China (Grant
SKBR-3 cancer cells (Fig. 22c) [305]. These results provided new stra-
No. 2019YFB2203503), National Natural Science Fund (Grant Nos.
tegies for PDT by developing various phage-based PS delivery systems.
61875138, U1801254, and 61961136001), and Science and
Lastly, stem cells that are naturally tumor-homing, are able to enhance
Technology Innovation Commission of Shenzhen
the accumulation of PSs in tumors when encapsulating PS-loaded na-
(KQTD2015032416270385, JCYJ20150625103619275, and
noparticles (Fig. 22d) [306,307]. The use of stem cells opens new in-
JCYJ20170811093453105). Authors also acknowledge the support
sights for further development of potent nanoplatforms for photo-
from Instrumental Analysis Center of Shenzhen University (Xili
dynamic cancer treatments. All in all, given the great achievements in
Campus).

20
J. Chen, et al.
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