Expert Opinion on Drug Delivery

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Pharmaceutical strategies in improving anti-

tumour efficacy and safety of intraperitoneal
therapy for peritoneal metastasis

Puxiu Wang, Xiujuan Qu, Xiaofang Che, Qiuhua Luo, Xing Tang & Yunpeng
Liu

To cite this article: Puxiu Wang, Xiujuan Qu, Xiaofang Che, Qiuhua Luo, Xing Tang &
Yunpeng Liu (2021): Pharmaceutical strategies in improving anti-tumour efficacy and safety
of intraperitoneal therapy for peritoneal metastasis, Expert Opinion on Drug Delivery, DOI:
10.1080/17425247.2021.1896493

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Published online: 10 Mar 2021.

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EXPERT OPINION ON DRUG DELIVERY
https://doi.org/10.1080/17425247.2021.1896493

REVIEW

Pharmaceutical strategies in improving anti-tumour efficacy and safety of

intraperitoneal therapy for peritoneal metastasis
Puxiu Wanga, Xiujuan Qub,c,d, Xiaofang Che b,c,d
, Qiuhua Luoa, Xing Tange and Yunpeng Liub,c,d
a
Department of Pharmacy, The First Affiliated Hospital of China Medical University, Shenyang, China; bDepartment of Medical Oncology, The First
Hospital of China Medical University, China; cKey Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China
Medical University, China; dLiaoning Province Clinical Research Center for Cancer, China; eDepartment of Pharmaceutics, College of Pharmacy,
Shenyang Pharmaceutical University, Shenyang, China.

ABSTRACT ARTICLE HISTORY

Introduction: In selected patients with limited peritoneal metastasis (PM), favorable tumor biology, and Received 15 August 2020
a good clinical condition, there is an indication for combination of cytoreductive surgery (CRS) and Accepted 24 February 2021
subsequent intravenous (IV) or intraperitoneal (IP) chemotherapy. Compared with IV injection, IP
KEYWORDS
therapy can achieve a high drug concentration within the peritoneal cavity with low systemic toxicity,
Intraperitoneal therapy; anti-
however, the clinical application of IP chemotherapy is limited by the related abdominal pain, infection, tumor efficacy; peritoneal
and intolerance. metastasis; pharmaceutical
Areas covered:To improve the anti-tumor efficacy and safety of IP therapy, various pharmaceutical strategies; safety
strategies have been developed and show promising potential. This review discusses the specialized
modification of traditional drug delivery systems and demonstrates the preparation of customized drug
carriers for IP therapy, including chemotherapy and gene therapy. IP therapy has important clinical
significance in the treatment of PM using novel anti-tumor agents as well as conventional drugs in new
applications.
Expert opinion: Although IP therapy exhibits good performance both in mouse models and in patients
with PM in clinical trials, its clinical application remains limited due to the serious side effects and low
acceptability. Further investigations, including pharmaceutical strategies, are needed to develop poten­
tial IP therapy, focusing on the efficacy and safety thereof.

1. Introduction resistance (MDR). Also, standardized treatment protocols of

IP chemotherapy have not been approved.
Peritoneal metastasis (PM) is caused by the dissemination of
Various novel drug delivery systems have been developed to
cancer cells within the peritoneal cavity [1]. Cancer cells are
increase the anti-cancer efficacy and safety of IP therapy for PM.
also exfoliated and shed during the cytoreductive surgery
Each system has its own advantages and inevitably their own
(CRS) in the peritoneal cavity. Intraperitoneal (IP) administra­
shortcomings as well. For instance, implants provide continuous
tion can obviate the need for complicated delivery barriers
drug release in the peritoneal cavity, but require surgical exper­
and deliver drugs directly into the disseminated tumor cells
tise and cause tissue damage. Nanoparticles and liposomes can
[2]. Thus, this technique provides an effective drug level sur­
increase tumor penetration and tumor targeting, but the rate of
rounding the tumors, improves anti-tumor efficacy, and
clearance is rapid [6]. Many researchers have attempted to
decreases adverse systemic effects [3]. IP chemotherapy has
modify and optimize conventional drug delivery systems for
been recommended for treatment of peritoneal tumors by the
good performance in PM therapy. In this paper, rather than
National Cancer Institute (NCI), and several clinical trials have
providing an overview of the different types of drug delivery
shown that IP chemotherapy could prolong the survival of
systems and their advantages, we focus on the pharmaceutical
advanced ovarian cancer patients [4].
modifications and optimizations which can lead to enhanced
Nowadays, the most common application of IP chemother­
anti-cancer efficacy and safety (Figure 1).
apy is repeated instillation of therapeutic agents using a port
catheter [5]. These catheters cannot be removed until the IP
chemotherapy is finished, which sometimes lasts for several 2. Current clinical application of PM
weeks. Thus, serious infection, pain, and other catheter-related
The peritoneal membrane is composed of several connective
problems are likely to occur, which limits the clinical applica­
tissue layers, including mesothelial layers, basement mem­
tion of IP chemotherapy. In addition, IP chemotherapy also
brane, interstitial space, and endothelial cells [5]. The patho­
faces several challenges, such as a lack of tumor selectivity,
physiology of PM formation is complicated and unclear,
poor drug penetration and development of multidrug
however it may be explained with reference to several

CONTACT Yunpeng Liu ypliu@cmu.edu.cn Department of Medical Oncology, The First Hospital of China Medical University, China.
© 2021 Informa UK Limited, trading as Taylor & Francis Group
2 P. WANG ET AL.
Article highlights
● Following IP chemotherapy, a high drug concentration can be
achieved within the peritoneal cavity, with low systemic toxicity
and enhanced therapeutic effect.
● In order to improve the antitumor activity and safety of commonly
used drugs in IP therapy, many pharmaceutical strategies have been
developed, including synthesising drug complexes, preparing novel
nano/microscale drug delivery systems, and modifying and repurpos­
ing traditional drug carriers with new functions. In this review,
pharmaceutical strategies were classified by their functions in IP
chemotherapy.
● For PM, therapeutic genes can be delivered directly to tumours by IP
injection, with high therapeutic efficiency and tumour specificity, but
without inducing toxic side effects to healthy organs or cells.
● Some novel antitumor agents and conventional drugs in new appli­
cation provide good performance in preclinical studies, but do not
produce positive results in clinical trials owing to an ineffective
concentration or serious systemic toxicity. For these drugs, the IP
route may be a potential approach to prove their antitumor activity.
● Although IP therapy has exhibited good performance both in mouse
models and in patients with PM in clinical trials, clinical application
remains limited due to the serious side effects and its low accept­
ability. Further investigations are needed to develop potential IP
therapy, focusing on the efficacy and safety.
● This box summarizes key points contained in the article.
theories [7]: (1) ‘tumor rupture’ theory, the exfoliated cancer
cells adhere to the peritoneal membrane or are delivered by
the lymphatic system; (2) ‘secretion’ theory, where some
growth factors and angiogenic factors are secreted in the
peritoneal cavity to create a fertile area for tumor growth.
In selected patients with limited tumor extension, favor­
able tumor biology, and otherwise good clinical condition,
there is an indication for combination of CRS and subsequent
intravenous (IV) or IP chemotherapy. IP chemotherapy is
a superior strategy for delivering anti-cancer drugs to the
abdominal cavity compared with IV chemotherapy.
Following IP chemotherapy, a high drug concentration can
be achieved within the peritoneal cavity, with low systemic
toxicity and enhanced therapeutic effect [8]. The pharmaco­
kinetics and tissue distribution of docetaxel (dextrose solu­
tion) after IP versus IV administration in the Sprague Dawley
rat models was evaluated [9]. The ratio of AUCperitoneal fluid
/AUCplasma (docetaxel) in the IP administration group was
significantly higher compared with that in the IV administra­
tion group. In addition, the IP administration group had a low
drug concentration in the heart and liver, and in contrast was
higher in the abdominal wall and colon. The same conclusions
were drawn using cancer-bearing mice models [10]. In fact,
low-molecular weight chemotherapeutics injected intraperi­
toneally are quickly absorbed into systemic circulation
through peritoneal capillaries or lymphatics. Also, the tumor
penetration of drugs in cancer-bearing mice is lower than in
healthy mice, which may be because the penetration is lim­
ited by the hard, adhesive, disseminated peritoneum.
Nanotax are naked, rod-shaped particles with a size in
the range of 600–700 nm [11], and were fabricated by
use of supercritical fluid technology. In a phase I study,
IP administration of Nanotax exhibited higher/prolonged
peritoneal paclitaxel levels and reduced side effects in
patients with solid tumors, compared with IV paclitaxel
injection. In clinical practice, IP chemoperfusion is often
performed under hyperthermic conditions, called
hyperthermic intraperitoneal chemotherapy (HIPEC). In
a phase I trial, HIPEC with doxorubicin-loaded
PEGylated liposome showed good tolerance and pro­
longed survival [12]. It was speculated that HIPEC could
enhance the penetration of chemotherapeutic agents
into tumor nodules and improve their distribution
throughout the peritoneal cavity. Hyperthermia might
also enhance the anti-tumor effects of several cytotoxic
drugs, however this remains controversial [5]. It should
be noted that the performance of CRS-HIPEC requires
specialized equipment, an operating room, and
a perfusionist: there remains a paucity of level 1 evi­
dence in support of this aggressive therapeutic
approach within each disease site [13]. As an improved
method of IP instillation, pressurized intraperitoneal
aerosol chemotherapy (PIPAC) is performed by injecting
the drug solution under a high pressure, which leads to
an aerosol dispersion on the tumor surface in the peri­
toneal cavity. PIPAC with cisplatin showed a high local
drug level, low systemic exposure and efficient activity
in chemo-resistant tumors in three end-stage patients
with PM [14]. PIPAC was found to be efficient in tumor
treatment with homogeneous drug distribution in the
peritoneal cavity, enhanced tissue penetration, low sys­
temic toxicity, and decreased discomfort [15,16]. In addi­
tion, electrostatic precipitation pressurized
intraperitoneal aerosol chemotherapy (ePIPAC) entails
a combination of aerosolisation of the drug, an applied
pressure, and an electrostatic gradient. ePIPAC exhibits
more efficient drug uptake, lower dose, and shortened
time compared with PIPAC application [17].
Despite the theoretical and clinical advantages, the appli­
cation of IP chemotherapy has not been widely used. The
primary problems include abdominal pain, toxicity caused by
the high local drug level, and catheter-related complications.
In the GOG trial 172, only 42% of patients completed the
assigned cycle [18]. Termination of IP therapy was mainly
caused by catheter-related complications (such as infection
and obstruction), gastrointestinal toxicities, and patient refu­
sal [19]. Moreover, the clinical application of IP chemotherapy
is also limited by high costs and technical difficulty.
3. Pharmaceutical strategies for improving
anti-tumor efficacy and safety of IP therapy for PM
In order to improve the anti-tumor activity and safety of
commonly used drugs in IP therapy, many pharmaceutical
strategies have been developed, including synthesizing drug
complexes, preparing novel nano/microscale drug delivery
systems, and modifying and repurposing traditional drug car­
riers with new functions. In this section, pharmaceutical stra­
tegies were classified by their functions in IP chemotherapy.

Figure 1. Schematic diagram of pharmaceutical strategies in improving antitumor efficacy and safety of IP therapy for PC.a: Sustained released drug delivery system;
b: Active targeting drug delivery system; c: Physical and chemical targeting drug delivery system; d: Improvement of tumor penetration; e: overcomethe MDR; f:
vectors of therapeutic gene for PC.
3.1. Providing effective drug levels in the peritoneal
cavity for a prolonged residence time
The persistent major challenge in IP chemotherapy is to
decrease the rate of drug clearance and expose tumors to
a high drug concentration for a prolonged time in the perito­
neal cavity. The high drug level can lead to an efficient con­
centration gradient to force drug diffusion into the tumor.
Many pharmaceutical investigations have been performed,
including preparation of complexes, micro/nanoparticles and
hydrogel-based systems (Table 1).
3.1.1. Microsphere-based drug delivery system
Microspheres are widely used as a sustained release drug
delivery system in IP therapy. Microspheres exhibited the
highest drug level in the peritoneal cavity and the lowest
absorption into system circulation after IP injection. The
survival time of mice was prolonged compared with the
control group [4]. Drug release rate is determined by parti­
EXPERT OPINION ON DRUG DELIVERY 3
cle properties, including type of material, molecular weight/
viscosity of polymers, particle size, and surface modification
of microspheres. Gelatin is widely used for preparing micro­
spheres, with a sustained drug release profile, decreasing
the nephrotoxicity and haematotoxicity, offering better
tumor targeting, and increasing survival in a mouse model
of PM [3]. Biodegradable copolymers, such as poly(dl-lactic
acid, PLA) and poly(lactide-co-glycolide; PLG) are commonly
used materials for preparation of an IP sustained release
drug delivery system [20,21]. In addition, amphiphilic tri­
block copolymer poly (e-caprolactone) poly (ethyleneglycol)
poly (e-caprolactone) (PCL-PEG-PCL)- based microspheres
(camptothecin loading) exhibited sustained drug release
and improved anti-tumor activity [22]. Paclitaxel release
from poly(ethylene glycol)-co-poly(sebacic acid) micro­
spheres remained in the peritoneal cavity for at least
13 days in vivo. Moreover, the median survival times of
mice were prolonged to more than 75 days [23].
4 P. WANG ET AL.

Table 1. Pharmaceutical strategies in enhancing drug retention in the peritoneal cavity (high concentration and long time).
Modification or
Formulation material preparation method Retention time/Improvements
1 Nanosuspension Paclitaxel [9] Pluronic More than 90 h.
(400 nm) Wet milling Exhibited faster recovery.
technique
2 Nanoparticles Paclitaxel [10] Spraying More than 28 days. 16/21 patients made positive
(600–800 nm) assessments, and 5/21 patients with advanced
cancers survived longer than 400 days.
3 Nanosized Paclitaxel and HA [8] - More than 14 days. Showed higher cytotoxicity and
precipitates- improved anti-tumor effects than Micron-sized
HA gel precipitates-HA gel.
4 Nanosized Irinotecan [11] HA The ratio of AUC (plasma, 100 mg/kg, IP administration)/AUC
complexes (plasma, 40 mg/kg, IV administration) was less than 2%.
5 Micelle Cremophor EL [12] - The bioavailability and systemic exposure decreased
significantly.
6 Liposomes DMPC/CHOL/DMPG/DOX [13] PEGylation Remained in the abdominal cavity increased from 3.1%
(doxorubicin solution) to 54.3% by loading drug in
PEGylated liposomes.
7 Nanoparticles PLGA [6] Polydopamine More than 3 days. Drug release was controlled by
and PEG dual- polydopamine coating and PLGA degradation.
layer surface Adhesion of polydopamine to the tumor cell further
coating increased retention time.
8 Nanoparticles PLA [14] Hyperbranched The adhesive nanoparticles interacted and adhered
Polyglycerol strongly with mesothelial cells in peritoneal cavity,
which prolonged the retention time up to 5–10 days
and improved the antitumor efficacy.
9 Microspheres Gelatin/PLA/PLG/PCL-PEG-PCL [15–18] - ~21 days. Exhibited enhanced antitumor efficacy,
reduced systemic toxicity and prolonged survival of
mice model.
10 Nanogels HA [19] Cisplatin More than 7 days. Showed a size-dependency
conjugate antitumor efficacy: number of small nodules (<
1.0 mm) were significantly decreased.
11 Hybrid gel chitosan gel [24] Cisplatin alginate More than 2 weeks. Showed a significant effect in
inhibiting tumor cells growth and prolonging survival
of tumor-bearing mice.
12 Thermosensitive Poly(ethylene glycol)-poly(ɛ-caprolactone)-poly(ethylene Thermosensitive ~6 weeks.
hydrogels glycol) (PECE), Poly(ε-caprolactone-co-1,4,8-trioxa [4.6] Exhibited improved antitumor effect compared with
spiro-9-undecanone)-poly(ethylene glycol)-poly (ε- free drug, due to the sustained release of
caprolactone-co-1,4,8-trioxa [4.6]spiro-9-undecanone) encapsulated drug.
(PECT), Pluronic F-127, poly(organophosphazenes)
[25,32,102,103]
13 Nanoparticles/ PLGA/PLA, chitosan and phosphatidylcholine [20] Nanoparticles Showed increased tolerability and therapeutic efficacy
hybrid film were dispersed in a peritoneal ovarian cancer xenograft model.
in the hybrid
film
14 Hybrid film chitosan derivative, phospholipid and lauric aldehyde [21] - 2 weeks. Significant tumor inhibition in SKOV3
(PoLigel-LA) xenograft model without toxicity or inflammation.
15 Woven Polydioxanone [22] Electrospinning Over 8 weeks. Exhibited enhanced antitumor efficacy
nanotextile technique and and safety in peritoneal ovarian cancer xenograft
woven model.
16 Microdevices poly-L-lactic acid (PLLA) [23] - 42 days. Exhibited similar antitumor efficacy in mouse
model to weekly bolus injection of cisplatin solution,
and less toxicity, no bowel obstruction or
inflammation.

3.1.2. Nanoparticle-based drug delivery system
With the development of pharmaceutical technology, some
novel nanoscale particles have been used in IP chemotherapy
to expose tumors to high concentrations of agents for an
extended time. A paclitaxel nano-suspension (wet milling
technique with a pluronic (a poloxamer) as stabilizer) and
the NanoTax (nanoparticles prepared by spraying acetone
solution into the anti-solvent of paclitaxel-compressed CO2)
provided an improved drug level in the peritoneal cavity
(28 days) and reduced systemic toxicity [11,24].
IP administration of nanoscale liposomes has become
a valuable modality in the treatment of PM, because it can
decrease drug absorption into systemic circulation and side
effects, prolong drug retention in the peritoneum, passively
target tumor sites, and increase anti-cancer activity [25,26].
Particle size is a major factor that affects the peritoneal reten­
tion and organ distribution of liposomes. Generally, the peri­
toneal retention increases with liposome size. Positively
charged liposomes show the highest peritoneal drug level,
compared with neutral and negatively charged liposomes.

This can be attributed to the electrostatic interactions
between positive liposomes and the negative surface charge
of the peritoneal mesothelium. Another reason for this is the
low uptake of positively charged liposomes by the peritoneal
macrophages. Large cationic liposomes (1000 nm) showed
the highest peritoneal concentration of 99mTc, compared
with anionic and small liposomes. Cationic liposomes
(100 nm) also had a high peritoneal level, however
AUCperitoneal cavity was 24.33% lower than in the larger ones
(1000 nm) [27].
The surface modification of liposomes with PEGylation can
increase their peritoneal retention. This is because the pre­
sence of PEG on the liposomal surface protects them against
peritoneal macrophages. Following IP administration of dox­
orubicin/vinorelbine loaded PEGylated liposomes, more drug
could be accumulated in ascites and tumors [25,28]. Peritoneal
retention of neutral, negative, and positively charged lipo­
somes (100 nm) could all be increased by PEGylation [27];
however, for large liposomes (1000 nm), PEGylation can have
the opposite effect. Within liposomes, the partition of phos­
pholipid molecules is asymmetric, with most of these and the
PEG-phospholipids distributed in the outer monolayer [29].
Due to the increase of PEG-phospholipid molar ratio on the
outer monolayer, the bilayer structures of liposomes become
heterogeneous, with lipid packing defects, lipid domains, and
phospholipid interfacial regions [30]. Other pharmaceutical
modifications to liposomes also were investigated to increase
the peritoneal retention of IP administrated drugs. 188Re was
conjugated to a N,N-bis(2-mercaptoethyl)-N9,N9-diethyle thy­
lenediamine (BMEDA) chelator and encapsulated in liposomes.
IP administration of 188Re liposomes could prolong the peri­
toneal retention and inhibit tumor growth in a mouse model,
compared with free 188Re [31].
Epothilone B loaded bioadhesive nanoparticles, composed
of polylactic acid block hyperbranched polyglycerol (PLA-HPG)
copolymers, were developed by oxidation of the vicinal diols
on the surface into aldehydes [32]. Polydopamine (sustained
release) and a PEG dual-layer surface coating of PLGA nano­
particles (adhesive to the tumor cell) exhibited a prolonged
peritoneal retention after IP administration, because a tight
PEG loop was formed on the nanoparticle surface, which
prevented macrophage phagocytosis [6].
Preparing hydrogel-nanoparticles hybrids may delay nano­
particle clearance. Hybrid gels that were obtained by disper­
sing PLGA nanoparticles in composite HAX gels could
successfully prevent postsurgical adhesions and prolong the
residence time in the peritoneum [33].
3.1.3. Multifunctional hydrogels
Most microparticles with a diameter exceeding 4 μm escape
the lymphatic drainage and remain in the peritoneal cavity for
a long time, however, large particles incur the risk of hetero­
geneous drug distribution, inflammation, and peritoneal adhe­
sion. As hydrogels exhibit sustained drug release and
inhibition of adhesion without serious side effects, they have
been widely investigated as carriers for IP chemotherapy.
Cisplatin-loaded cross-linkable hyaluronic acid (HA) hydrogels
EXPERT OPINION ON DRUG DELIVERY 5
were used as a sustained delivery system to inhibit the peri­
toneal dissemination of gastric cancer [34]. Moreover, some
intelligent multifunctional hydrogels have been developed for
IP therapy.
pH-responsive cisplatin-incorporating HA nanogels were
fabricated by coordination of cisplatin to a chelating ligand,
and exhibited a specific localization in peritoneal nodules
and a high penetration into tumor tissue after IP injection
[35]. The hybrid system (cisplatin-incorporating HA nanogels
with HA hydrogels via Schiff base formation) showed a size-
dependency on anti-tumor efficacy; the number of small
peritoneal nodules (< 1.0 mm) was significantly decreased
[36,37]. After IP injection of the mucoadhesive chitosan-
alginate-cisplatin hybrid gels, the hybrid gels localized at
the peritoneal sidewall for more than three days, and chit­
osan specifically accumulated in the genomic DNA of perito­
neal tissues [38].
Thermosensitive hydrogels are smart drug delivery systems,
which can be transformed from a sol state to gel state after IP
injection. Poly(ethylene glycol)-poly(ɛ-caprolactone)-poly
(ethylene glycol) (PECE) hydrogels [39], poly(ε-caprolactone-
co-1,4,8-trioxa [4.6] spiro-9-undecanone)-poly(ethylene gly­
col)-poly(ε-caprolactone-co-1,4,8-trioxa [4.6] spiro-9-undeca­
none) (PECT) hydrogels [40] and poly(organophosphazenes)
and conjugated linoleic acid-incorporated Pluronic F-127 (Plu-
CLA) hydrogels [41] were investigated in IP treatment of PM,
with enhanced anti-cancer efficacy and lower side effects.
3.1.4. Implantable drug delivery system
Implantable drug delivery systems are different to particle
systems. Due to the particular material, large size, and high
viscosity, most implants provide a continuous drug release at
a constant rate: however, their disadvantages cannot be
ignored: (1) production of fibrous encapsulation around the
implant site, which results in inconsistent drug release; (2)
degradation of implantable materials may cause an acidic
environment, local irritation, and drug degradation; (3) devel­
opment of necrosis of normal tissue and enhanced host
immune response; (4) any implant must be implanted using
a large syringe needle or surgery. To overcome these pro­
blems, some novel/modified biodegradable/injectable materi­
als have been developed.
An implantable hybrid film (chitosan-ePC film) composed
of chitosan and phosphatidylcholine (PC) lipids was found to
be a potential local carrier for IP treatment [42–44]. The chit­
osan-ePC film provided a sustained, zero-order drug release
for 2 weeks in vivo, consequently increasing the anti-cancer
efficacy by diminishing tumor repopulation and increasing cell
apoptosis. Furthermore, the development of MDR may be
attenuated by IP administration of chitosan-ePC film [45].
An implantable woven nanotextile was used as a sustained
drug delivery system in IP metronomic chemotherapy [46].
Paclitaxel molecules were trapped in the nanofiber interfaces,
and the drug release rate could be modulated by change of
packing density and the architecture of the woven nanotextile.
Other micro-devices composed of an injection-molded reser­
voir (biodegradable poly-L-lactic acid) and cap have been used
6 P. WANG ET AL.
as the carrier of cisplatin powder for the treatment of ovarian
cancer mouse models [47]. Following IP administration, the
micro-devices were found to have similar anti-tumor efficacy
in a mouse model to weekly bolus injection of cisplatin solu­
tion, but with less toxicity, no bowel obstruction, and no
inflammation; however, it is necessary to implant multiple
micro-devices at different sites or fix micro-devices to the
planned site to achieve a uniform drug distribution.
The hybrid film must be implanted and removed surgically,
due to their fixed shape and slow biodegradation. Thus, an
injectable implant system is more desirable, which can provide
minimal invasiveness and increased patient compliance.
A hybrid film (PoLigel-LA) (composed of chitosan derivative,
phospholipid, and lauric aldehyde) could be injected through
a 22-gauge needle [48]. Constant release of docetaxel from
PoLigel-LA lasted for two weeks in the peritoneal cavity after IP
administration. Furthermore, IP injection of docetaxel-loading
PoLigel-LA exhibited significant tumor inhibition in a SKOV3
xenograft model without toxicity or inflammation.
3.2. Improvement of the tumor targeting of the drug
delivery system
Increasing drug peritoneal exposure is seen as a promising
measure to improve the anti-tumor efficacy and safety in PM
treatment. In addition to simply increasing the peritoneal
retention, it is also advantageous to target the drug specifi­
cally to tumor cells in the peritoneal cavity. Despite most
traditional chemotherapeutics being effective against tumor
cells in vitro, the nonspecific distribution in vivo causes
reduced anti-tumor efficacy and serious adverse side effects.
Thus, it is necessary to develop potential tumor targeting
formulations to increase the drug level at the tumor tissue
(Figure 2). Generally, modification of particles with different
particle sizes, shapes, and surfaces can result in passive or
active tumor targeting (Table 2).
3.2.1. Passive targeting
IP injection of liposomes showed increased drug accumula­
tion in tumor cells, improved anti-tumor activity, and
decreased side effects, as they could escape from the reti­
culoendothelial system (RES) to achieve a prolonged
Figure 2. Schematic of active targeting(A) and physical/chemical targeting(B) drug delivery system fortreatment of PM.
residence time and showed passive tumor-targeting by the
EPR effect. An IP injection of radio-labeled PEGylated lipo­
somes exhibited significant accumulation and prolonged
residence time within the ascites and tumor in the perito­
neal cavity [31,49]. In addition, the IP administration of
inorganic nanoparticles is widely used for tumor therapy,
due to their unique physical properties and multifunctional
engineering abilities. For instance, mesoporous silica nano­
particles (MSNs) containing paclitaxel exhibited a 6.5-fold
specific accumulation in tumors after IP injection, compared
with free paclitaxel [50]. MSNs also could be used as carriers
of radio-nanomedicines for internal radiation therapy, due
to their high loading capacity, high stability, tuneable par­
ticle/pore size, and modified functional surfaces [51].
Amphiphilic PEG-coated lanthanide-loaded up-conversion
nanoparticles (P-PEG-UCNPs) was another type of passively
targeting inorganic nanoformulation in PM models [52],
however, IP injection of P-PEG-UCNPs may cause renal func­
tion injury over a long period.
3.2.2. Active targeting
Compared with passive targeting, active targeting formula­
tions provide more efficient tumor-targeting and enhanced
drug accumulation in tumor tissue. Drugs are selectively deliv­
ered to tumor sites, due to the interaction of ligands modified
on the formulations and particular receptors on the surface of
cancer cells.
HA, a natural ligand for CD44, has been utilized as
a targeted drug carrier for IP tumor treatment, and is recog­
nized as a marker for cancer stem cells [53]. In addition, the
chelating ligands (iminodiacetic acid and malonic acid) were
used to fabricate cisplatin-encapsulated HA nanogels, by form­
ing stable coordinate bonds with cisplatin [35]. Accumulation
of HA nanogels in peritoneal nodules was increased by the
CD44 targeting property and pH sensitivity.
The surface of nanoscale drug delivery systems can be
modified with special targeting moieties (ligand or chemical
compounds) to fabricate tumor-selective formulations.
Liposomes coated with biotin and avidin were utilized for
developing a tumor targeting liposome system in IP therapy
[54]. In addition, Tf receptor-mediated endocytosis has been
utilized for an intracellular targeting system. Following IP
 EXPERT OPINION ON DRUG DELIVERY 7

Table 2. Tumor targeting drug delivery system used in IP therapy for PC.
Successful research
Type Mechanism Tumor targeting formulation Target site-ligand / Mechanism
Passive targeting Passive targeting is caused by EPR effect, due to the Nanoparticles (spherical and Nanosized particles-EPR effect
leaky vasculature and poor lymphatic clearance cylindrical), nanosized
surrounding the tumors. liposomes, etc. [30,31,33–35]
Active targeting (1)Drug delivery system modified by ligand is Hyaluronan (HA) microparticles HA-CD44
actively accumulated in the target region with [38] HA is a natural ligand for CD44
the receptor. Liposomes coated with biotin Avidin-biotin
(2)Adipose-derived stem cells/neural stem cells - and avidin [45] Avidin is composed of 4 sub-units, and each sub-
mediated drug delivery system. unit has one binding site for biotin, leading to
a high binding affinity between avidin and biotin.
Tf-PEG liposome [46] Tf/Tf receptor
LBA-PDA-PEG-DSF nanoparticles Lactobionic acid-D-galactose receptor
[48]
RGD functionlized POEGMA-PDPA iRGD-neuropilin-1
polymersomes [52] Interaction between iRGD and neuropilin-1 triggers
the increase of transcytosis, subsequently leads
to the accumulation of iRGD-polymersomes in
tumor cells.
TT1 peptide functionalized TT1/p32
PEGylated iron oxide TT1, a type of CendR peptides, is tumor targeting
nanoworm [50] peptide.
Gold clusters composed one type Peptide-EGFR
of peptide, which holds the
specific target sequence for
EGFR [51]
CE2-ASCs/irinotecan system [104] Adipose-derived stem cells (ASCs)-tumors
NSC SiNPs [105] Neural stem cells (NSCs)-tumors
Physical and Respond to physical and chemical stimulation, such Ferrimagnetic iron oxide Ferrimagnetic iron oxide-magnetic field
chemical as pH, temperature, light, magnetic field and nanoparticles encapsulated Ferrimagnetic iron oxide nanoparticles concentrated
targeting ultrasound, drug delivery system reaches the liposomes [53] in tumor tissue where an external magnetic field
target site. are added.
pH-responsive expansile Cholesteryl hemisuccinate(CHEMS)-pH
nanoparticles [54] Structure of CHEMS nanoparticles was broken down
in the tumoral site (acidic) to release the
encapsulated drug.
Multifunctional photosensitive Photosensitizer-visible light
nanoparticles [55] The surface of hydrophobic upconversion
nanoparticles was modified with the conjugates
of poly-L-lysine (PLL) and photosensitizer
Combination of (1)Respond to physical and chemical stimulation Folate-targeted microbubbles/ Folate-folate receptor
physical/ drug delivery system reach the target site. Ultrasound-mediated (1) folate receptor is over-expressed in both cancer
chemical and (2)Drug delivery system modified by ligand is microbubble destruction [56] cells and tumor-associated macrophages(TAM).
active actively accumulated in the target region with (2)Ultrasound induces the disruption of the cell
targeting the receptor. membrane and improves the intracellular uptake
at the selective site.
Tumor-targeting photosensitizer/ Mannose-mannose receptors
photodynamic therapy [58] (1) The mannose-conjugated chlorin was
synthesized as the TAM-targeting
photosensitizer.
(2) Photodynamic therapy

administration of cisplatin-loaded Tf-PEG liposomes, the con­
centration of cisplatin was higher in the peritoneal cavity and
tumor cells, and the survival rate of mice bearing PM were
significantly increased, compared with mice treated with PEG-
liposome [55]. This was the result of Tf leading to active
accumulation in cancer cells and PEG modification achieving
passive tumor targeting by the EPR effect. Tumor-targeted
nanoparticles (LDNP) were fabricated by the self-assembly of
lactobionic acid (LBA)-PDA-PEG-DSF (diethyldithiocarbamate)
[56]. Following IP injection of LDNP/Cu, both tumor weight
and number reduced by more than 80% in a peritoneal ovar­
ian tumor mouse model.
Compared with the long circulation times in the body of
antibody-mediated cell targeting systems (one week), peptide-
mediated systems show rapid renal excretion within hours,
which is safer when delivering toxic compounds with a long
half-life. If radioactively labeled antibodies are bound to untar­
geted cells, their long-term retention may increase the toxicity
to normal tissue. The diblock copolymer poly(oligoethylene
glycol methacrylate) (POEGMA)- poly(2-(diisopropylamino)
ethyl methacrylate) (PDPA) was synthesized and assembled
to form flexible and pH-sensitive polymersomes [57]. The
POEGMA block is hydrophilic, which prevents clearance by
the immune system and prolongs the residence time in the
body; the PDPA block makes the polymersomes pH-sensitive.
These polymersomes could selectively deliver encapsulated
paclitaxel to peritoneal tumors and showed high anti-tumor
activity after IP administration. On this basis, Irgd-
8 P. WANG ET AL.
functionalized POEGMA-PDPA polymersomes showed higher
drug accumulation in tumors and improved therapeutic effi­
cacy for peritoneal tumors [58]. The TT1 peptide (another type
of CendR peptide)-functionalized PEGylated iron oxide nano­
worms (TT1-NWs) were prepared and showed increased tumor
selectivity [59,60]. Except for the tumor targeting property, the
elongated nanoworms had a longer residence time in vivo and
larger surface area for functionalizing with more targeting
ligands, compared with the spherical particles. It may be
meaningful to combine iRGD and TT1, with different and
complementary target sites, to develop a more effective
tumor targeting system for PM.
Stem-progenitor cell-mediated drug delivery has been
extensively studied to enhance the therapeutic effect and
reduce the toxicity of chemotherapy, due to their inherent
tumor-tropic and well-tolerated properties. Commonly-used
stem-progenitor cells are from neural, adipose and mesench­
ymal tissues. The migration and extravasation of mesenchymal
stem cells into tumors are driven by tumor-secreted cytokines.
Adipose-derived stem cells (ASCs) could actively target
tumors. A CE2-ASCs/irinotecan system was demonstrated to
be an effective enzyme/prodrug for killing of ovarian cancer
cells [61]. Meanwhile, it has been demonstrated that neural
stem cells (NSCs) are tumor-tropic and can migrate to various
tumors, including glioma, neuroblastoma, and breast carci­
noma [62]. NSCs have been exploited for the targeted delivery
of many anti-cancer agents, including prodrug-activating
enzymes, therapeutic genes, antibodies and apoptosis-
inducing agents. In addition, NSCs also can be used as carriers
for nanoparticles (silica nanoparticles were externally conju­
gated to the NSC surface or internalized by NSC) targeting
tumors via IP injection. Due to the increased efficacy and
reduced toxicity of stem cell-mediated tumor-selective ther­
apy, this appears to be an effective therapy for PM.
3.2.3. Physical and chemical targeting
Many physical and chemical targeted preparations that can
respond to pH, temperature, light, magnetic field, and ultra­
sound have been developed and used for PM treatment.
Magnetic drug delivery systems that have been widely
used for cancer treatment via IV and IP administration
become concentrated in tumor tissue when an external
magnetic field is added. To improve their colloidal stability,
prevent local dilution and reduce the therapeutic dose and
Figure 3. The improvement of tumor penetration of antitumor agents
toxicity, magnetic nanoparticles can be encapsulated within
liposomes to form magnetic nanocarriers [63]. Ferrimagnetic
iron oxide nanoparticles-encapsulated liposomes were
further modified with a PEG coating to prepare ferri-
liposomes, which exhibited significant targeting to both
tumor and stromal components.
pH-sensitive liposomes, prepared by cholesteryl hemisucci­
nate (CHEMS) as the acid-sensitive material, were designed to
increase the peritoneal retention and reduce the toxicity of
cisplatin [64]. Furthermore, other pH-responsive expansile
nanoparticles were prepared by free radical photopolymeriza­
tion of an acrylate monomer and an emulsification methodol­
ogy [65]. The expansile nanoparticles could increase in volume
to release their encapsulated drug at pH 5 (cellular endo­
some). Photodynamic therapy has been widely used as tar­
geted therapy for many years. Multifunctional photosensitive
nanoparticles have been developed by modifying the surface
of hydrophobic up-conversion nanoparticles with the conju­
gates of poly-L-lysine (PLL) and a photosensitizer [66].
3.2.4. Combination of physical and chemical targeting
and active targeting
The combination of two targeting techniques is an effective
and simple method with which to provide enhanced anti-
tumor efficacy and safety in PM therapy. For example, the
ultrasound-mediated microbubble destruction (UTMD) tech­
nique has been used for targeted delivery of various ther­
apeutic compounds, as it induces disruption of the cell
membrane to improve intracellular uptake at the selective
site. The UTMD technique has been combined with micro­
bubbles modified by ligands, such as folate, luteinizing
hormone-releasing hormone (LHRH) and breast tumor hom­
ing peptide (LyP-1), to improve the tumor selectivity and
safety [67]. Dual-targeting microbubbles were developed by
the combination of the UTMD technique and folate-targeted
microbubbles [68]. Following IP administration, folate-
targeted OPLMB (TOPLMBs) significantly accumulated in
cancer cells and tumor-associated macrophages (TAMs) in
ascites fluid. The combination of tumor-targeting photosen­
sitizer and photodynamic therapy (PDT) also showed
improved anti-cancer efficacy [69]. Mannose-conjugated
chlorin (M-chlorin) was synthesized as the TAM-targeting
photosensitizer, as the M-chlorin can specifically bind to
mannose receptors, which are highly expressed on TAM.

PDT with M-chlorin (IP injection) inhibited the tumor growth
to a significant extent in the mouse model, without affect­
ing immune responses elsewhere.
3.3. Enhancement of tumor penetration of anti-tumor
agents
Larger tumors (> 1 mm) in PM can be removed by surgery, but
the elimination of small and numerous tumor nodules is
dependent on the IP therapy, however, in tumor tissues high
interstitial pressure, the extracellular matrix and severe fibrosis
around the tumor restrict the penetration of drugs and drug
delivery systems. For instance, the tissue penetration of most
drugs is less than 1.0 mm in depth, and drug-encapsulated
microbubbles cannot penetrate into the hypoxic tumor central
area [68]. Tissue penetration of drugs is closely related to their
characteristics, such as molecular weight, lipophilicity, concen­
tration, and exposure time. To increase the tissue penetration
of chemotherapeutic agents administrated intraperitoneally,
various methods including synergism with physico-chemical
techniques, combination with penetration enhancers and
other modulation of the drug delivery system have been
explored (Figure 3).
The combination of IP chemotherapy and hyperthermia has
attracted a lot of attention for the treatment of PM. Tumor
penetration in HIPEC is improved because tumor barriers are
broken, drug diffusion is increased, and vasodilation is caused
due to the hyperthermia [70]. The further to enhance the
tumor penetration, penetration enhancers have been used in
HIPEC, because of their effects in reducing the barrier resis­
tance of cells and tight junctions. Citral is a widely used
penetration enhancer for delivery of drugs through the skin
Figure 4. Inactivation of the efflux pump.
EXPERT OPINION ON DRUG DELIVERY 9
[71]. According to their lipophilicity and low molecular
weights, citral can increase the fluidity of cell membranes
and cause their leakage. Thus, a combination of citral and
HIPEC with pirarubicin showed significant anti-tumor efficacy
in mice bearing PM of colorectal cancer [72]; however more
studies are necessary to ascertain the safety and long-term
outcome of this combination.
Recently, novel drug delivery systems have been developed
to enhance the tumor penetration of the encapsulated drugs.
Au’s group developed the tumor penetrating microparticles
(TPM) for the treatments of PM [19]. TPM comprises two types
of paclitaxel-loaded microparticles: (1) Priming TPM (prepared
by PLG at a 50:50 L:G ratio), a rapid release component, which
induces apoptosis and promotes interstitial transport of other
particles into the tumor nodules; (2) Sustaining TPM (prepared
by PLG at a 75:25 L:G ratio), a slow-release component, which
provides sustained paclitaxel release.
Tumor penetration can also be improved by the assistance
of tumor-penetrating peptides (such as iRGD), which can
home into tumors and be actively transported through
tumor parenchyma. iRGD initially binds to a tumor-specific
receptor and activates the CendR pathway, which is the key
point to trigger extravasation transport of iRGD [73]. IP injec­
tion of iRGD improved tumor selectivity and penetration of its
conjugated cargo (fluorescein) and co-injected agents (dex­
tran and doxorubicin, reaching a penetration depth up to
10 mm in mouse peritoneal tumors in vivo) [70]. Tumor-
penetrating peptides also can be utilized to functionalize
drug delivery systems: paclitaxel-loaded pH-sensitive polymer­
somes modified by RPARPAR (CendR peptide) or iRGD,
showed improved tumor penetration and anti-tumor activity
in mice bearing peritoneal tumors [58]. The iRGD peptide
10 P. WANG ET AL.
probes could be imaged, and therefore by co-administration
with anti-tumor compounds can accomplish theranostics, can­
cer detection, and killing tumor cells simultaneously [74]: this
significantly simplifies the treatment of PM. Moreover, iRGD is
expected to be combined with HIPEC or PIPAC treatments to
deliver the drug into substantially large and numerous PM.
3.4. Preventing and overcoming MDR
Tumor therapy is a difficult problem worldwide, and one of
the main reasons for this is the development of MDR. MDR is
defined as the resistance of tumor cells to some chemother­
apeutic agents, with different structures and mechanisms.
MDR is developed by various factors of tumor microenviron­
ment or molecule, including: (1) limited tumor penetration; (2)
up-regulation of drug efflux transporters on cell membrane;
(3) changing of drug target; (4) activation of survival pathways,
and more. The most common mechanism is the over-
expression of ATP-binding cassette (ABC) drug efflux transpor­
ters, which causes significant efflux of chemotherapeutic com­
pounds [75]. To prevent and overcome MDR, numerous
strategies including the development of novel drug carriers,
modulation of chemotherapy dosing schedule, and combina­
tion with drug efflux transporter inhibitors, have been
adopted (Figure 4), however, studies in IP delivery systems
are rare.
90% of the chemotherapy failures for ovarian cancer are
caused by MDR, and this leads to late-stage PM and low
survival rates. The standard first-line treatment of ovarian
cancer consists of CRS followed by six cycles of platinum
and taxane injection every three weeks [45]. After each
dose of cytotoxic agent, treatment-free periods are necessary
for healthy tissues to recover: however, during these treat­
ment-free periods, surviving tumor cells rapidly resume their
proliferation, resulting in the development of drug resistance
and treatment failure. Previous work suggests that the cell
apoptosis in intermittent docetaxel or carboplatin treated
groups was equal or less compared with that in the
untreated group, indicating serious MDR in the treatment-
free periods [76]. To prevent and overcome MDR, metro­
nomic chemotherapy has been widely investigated by
in vitro cytotoxicity tests and in vivo pharmacodynamics stu­
dies involving IP administration. The strategy of more fre­
quent administration is termed metronomic chemotherapy,
by which the treatment-free period is eliminated or
decreased. Metronomic chemotherapy of non-cell-cycle-
specific agents (carboplatin) and cell cycle specific agents
(taxanes) by IP route achieved a continuous drug exposure
to tumor cells, increased tumor growth inhibition, greater
abrogation of cell proliferation, and greater angiogenesis,
compared with intermittent treatment at the same dose
[76]. A docetaxel-encapsulated injectable chitosan-
phospholipid hydrogel system (DTX-PoLigel) was used as
a sustained release drug carrier for IP therapy of PM of
SKOV3 cancer cell to elucidate the efficacy of metronomic
chemotherapy [48]. However, the mechanisms thereof war­
rant further in-depth investigation.
Another effective approach is utilizing the drug efflux trans­
porter inhibitors combined with chemotherapeutic com­
pounds, to decrease the drug efflux from tumor cells. Most
drug efflux transporter inhibitors are not tumor-selective,
which may lead to high drug accumulation in healthy tissues
and therefore toxic side effects. Cepharanthine (CEP) is the
competitive inhibitor of both P-gp and MRP7 [77]. Following IP
injection of CEP/DTX-PoLigel, very strong synergism could be
observed in HeyA8-MDR cells and a mouse model, including
increased apoptosis, higher intracellular docetaxel levels,
decreased docetaxel efflux, and enhanced tumor inhibition,
compared with single PoLigel-(DTX) or bolus DTX+CEP [75].
This may be attributed to the synergism of CEP and the local
sustained-released drug delivery system.
In addition, a combination of drug delivery system and
environmental stimulus has been utilized to prevent MDR
and target tumor cells both in vitro and in vivo. The combi­
nation of cold-responsive HCLPN-D nanoparticles and ice
cooling has been demonstrated to kill MDR ovarian tumor
cells efficiently and their CSCs both in vitro and in vivo, and
overcome the MDR [78]. Three possible mechanisms were
proposed: (1) HCLPN-D nanoparticles selectively target the
tumor due to the targeting capability of HA; (2) At lower
temperatures, the structure of HCLPN-D nanoparticles is
damaged due to the cold-sensitive properties of PF127,
resulting in burst release of doxorubicin in the cytoplasm
of tumor cells; (3) the activity of efflux pumps is reduced at
low temperatures by depriving their energy supply, how­
ever, it is difficult to create a low temperature for tumors at
depth in the internal organs. It is an important challenge to
prevent and overcome MDR for the chemotherapy of
tumors. It is believed that, if more strategies are applied in
the treatment of PM via the IP route, the anti-tumor efficacy
will be significantly increased and MDR can be prevented
and overcome.
4. Development of suitable vectors of therapeutic
gene for PM by IP route
Gene therapy has been shown to be effective for many
genetic diseases. For PM, therapeutic genes can be delivered
directly to tumors by IP injection, with high therapeutic effi­
ciency and tumor specificity, but without inducing toxic side
effects to healthy organs or cells. The gene vectors are the key
points for gene therapy (Figure 5). This section will focus on
the pharmaceutical modification of gene vectors, including
viral and non-viral vectors (Table 3).
4.1. Virus-mediated IP gene therapy
Viral vectors, such as adeno-associated virus and lentivirus,
have been used for delivering therapeutic genes to treat
various cancers (colon cancer, prostate cancer, and gastric
cancer) [79]. In tumor therapy, the adenovirus lacks tumor-
specificity, which may cause toxicity in normal tissues, thus, it
is necessary to improve their tumor-specificity and deliver
therapeutic genes directly to tumor cells. One approach is to

Figure 5. Schematic diagramof gene therapy. A: Mechanism of gene therapy. B: Stimuli-responsive vectorsmediated gene therapy. C: Combination of gene and
chemotherapeutic drugs.
modify therapeutic genes with tumor targeting. Modification
with the complex 5ʹ un-translated regions (UTRs) can provide
a tumor-targeting property to the herpes simplex virus thymi­
dine kinase suicide gene (HSV-TK) [80]. The other method is
the preparation of tumor targeted viral vectors. Mannan-
conjugated adenovirus (Man-Ad5) was formed by coupling
mannan to the surface of the adenovirus, and used as tumor
targeted vectors for cancer IP treatment [81]. IP injection of
Man-Ad5-PTEN further improved the anti-tumor activity upon
combination with chemotherapeutic agents, and significantly
prolonged the survival of mice bearing IP H22 cells.
4.2. Cationic polymer-based non-viral gene vectors with
high transfection efficient
Although viral-mediated gene therapy has high transfection
efficiency and has been performed in numerous clinical trials,
this treatment always induces severe side effects and the clinical
application is limited. Compared with viral vectors, non-viral
vectors exhibit some advantages, including easy large-scale pro­
duction, stability, non-immunogenic response and safe applica­
tion, however, the transfection efficient is not satisfactory due to
their poor serum stability, high endosomal entrapment, and
limited intracellular release. To overcome this problem, many
cationic polymers have been synthesized to develop gene nano-
drug delivery systems with high transfection efficiency.
A series of cationic, methacrylamide polymers has been
investigated as gene vectors for IP treatments of cancer.
Polyethyleneimine (PEI) is one of the most useful polycation
materials for gene vectoring, because PEI can bind and con­
dense abundant oligonucleotides and protect them from
degradation [82]. Following IP injection, PEI polyplex vectors
showed high gene transfection activity in an ovarian cancer
xenograft model [83], however, its non-biodegradability and
serious toxicity cannot be ignored. The cytotoxicity is asso­
ciated with the increase of their chain length and transfection
efficiency. To enhance transfection efficiency without increas­
ing toxicity, short PEI chains are conjugated with other linking
agents, such as PEG, Pluronic, PLA, PCL, etc. For example,
PEGylated PEI (PEG-PEI) can spontaneously self-assemble
with oligonucleotides to form nanoscale and micelle-like com­
plexes (PICs) with high colloidal stability, a long circulation
time, and reduced toxicity. The further to improve the tumor
selectivity, PICs were conjugated with a laminin-derived
EXPERT OPINION ON DRUG DELIVERY 11
peptide A5G27 (acted as both a targeting peptide and anti-
migratory agent). Following IP injection, A5G27-PICs/siRNA
efficiently inhibited tumor growth and prolonged survival of
mice bearing PM of SK-OV-3 tumor cells [84].
In addition, heparin was chemically conjugated to low-
molecular-weight PEI to form a HPEI nanogels (75 nm) [85].
The transfection efficiency of HPEI nanogels was comparable
to PEI25K, used as the ‘gold standard’ to evaluate transfection
efficiency of gene vectors. Importantly, HPEI nanogels showed
lower toxicity and improved blood compatibility compared
with PEI25K. Modification of PEI with HA gives the synthesized
HA-PEI macrophage-targeting properties, which was utilized
to deliver MicroRNA-125b for IP gene therapy [86].
Cationic polymer, poly (P[Asp(DET)])-based mixed micelles
also can be used as vectors for immunogene therapy with
desirable biodegradability and the ability to escape from
endosomes [87]. PEGlated P[Asp(DET)] (PEG-b-P[Asp(DET)])
were developed and showed reduced cytotoxicity, prolonged
circulation in vivo, but reduced transgene expression com­
pared with P[Asp(DET)] micelles. Interestingly, mixed polyplex
micelles (composed of PEG-b-P[Asp(DET)] and P[Asp(DET)])
exhibited a high transfection efficiency and reduced toxicity
in IP immunogene therapy of PM in a mouse model [88].
4.3. Stimuli-responsive gene vector mediated IP gene
therapy
Stimuli-responsive gene vectors, based on cationic polymers,
have been developed to increase the transfection efficiency
and reduce side effects. A cationic polymer, poly
(N-[2-(acryloyloxy)ethyl] -N-[p-acetyloxyphenyl]- N,
N-diethylammoniumchloride) (PQDEA), was synthesized for
gene delivery, and had enzyme-responsive charge-reversal
properties [2]. The cationic PQDEA formed stable complexes
with the TRAIL suicide gene plasmid (PQDEA/pTRAIL). The
cationic PQDEA was hydrolyzed to anionic poly(acrylic acid)
due to intracellular esterases. Subsequently, the structure of
the complexes was broken, and the encapsulated TRAIL sui­
cide gene was released and expressed in tumor cells. The
serum-ascites stability of PQDEA/pTRAIL was improved by
further coating with a lipid layer (LPQDEA/pTRAIL).
Compared with PEI25K/pTRAIL, LPQDEA/pTRAIL showed
higher transfection/expression in HeLa cells, and significant
HeLa cell apoptosis both in vitro and in vivo. Furthermore, IP
 12
P. WANG ET AL.

Table 3. Pharmaceutical modification of gene vectors, including viral and nonviral vectors.
Vectors Modification Therapeutic gene Type of tumor Antitumor efficacy and Toxity
1 PEGylated Polyethyleneimine (PEI) Laminin-derived siRNA Ovarian carcinoma cells were Efficiently inhibited tumor growth and prolonged survival of mice model.
polyplexes [71] peptide A5G27 injected intraperitoneally
2 PEI [72] Heparin Plasmid expressing vesicular C-26 colon cells were Significantly inhibited the growth and migration of C-26 colon carcinoma,
stomatitis virus matrix injected intraperitoneally and prolonged the survival in a mouse model.
protein (pVSVMP)
3 Hydroxypropyl methacrylate- - a reporter gene Ovarian cells was propagated HPMA-DMAE polyplexes are promising gene delivery systems for gene
dimethylaminoethanol (HPMA-DMAE) intraperitoneally therapy of cancer, attributed to their high transfection activity, low
polyplexes [73] cytotoxicity, and HA resistance.
4 poly(β-amino ester) polymers C32–117 [74] - Promoter-regulated diphtheria ovarian cancer cells were Growth of ovarian tumor in the peritoneum was effectively inhibited and
toxin (DT-A) gene injected intraperitoneally the survival of a mouse model was significantly prolonged, with minimal
nonspecific cytotoxicity.
5 Poly (P[Asp(DET)]) [75] PEG-b-P[Asp(DET)] GM-CSF gene Pancreatic cancer inoculated Inhibited tumor growth and prolonged the survival of mouse model. The
intraperitoneally safety potentials have been confirmed in mice and cynomolgus
monkeys.
6 Poly (N-[2-(acryloyloxy)ethyl] Coating with lipid TRAIL suicide gene plasmid HeLa cells were inoculated Did not cause tumor resistance or relapse after a two weeks treatment-free
-N-[p-acetyloxyphenyl]- N, layer into the right flank belly period, and exhibited a prolonged survival in a good health
N-diethylammoniumchloride) (PQDEA) [2] cavities.
7 Poly[(2-acryloyl)ethyl(p-boronic acid benzyl) Coating with cationic pTRAIL gene A549 cells were injected in Effectively delivered pTRAIL to tumor tissues and exhibited improved
diethylammonium bromide] (B-PDEAEA) polymers the right peritoneal antitumor activity in a mouse model.
polyplexes [76] cavities
8 Gold nanoparticles [77] C225-conjugate pDNA/p53 SKOV3 cells were injected Showed significant accumulation in SKOV3 cells and inhibition of tumor
subcutaneously in the growth in a mouse model.
right flank region
9 Calcium carbonate microflowers [78] - pDNA - -
10 Nanoparticles(DPP) composed of MPEG-PLA Low-dosage paclitaxel VSVMP SKOV3 cancer cells were Migrations of SKOV3 cancer cells in a mouse model were inhibited
and DOTAP [84] injected intraperitoneally effectively.
11 PEGylated cationic liposome [85] TPM siRNA Pancreatic tumor cells were Combination of TPM and PCat/siSurvivin improved the transfection of
injected intraperitoneally siRNA and antitumor efficacy by synergistic effects.
12 PEG coating poly(Propyleneimine) (PPI) Luteinizing Hormone- siRNA Ovarian cancer cells were Improve the antitumor efficacy of chemotherapeutic agents through
nanoparticles [106] Releasing Hormone- inoculated different cellular pathways.
conjugate intraperitoneally
13 Polymeric nanoparticles [107] Cholesterol siKRASG12D,Anti-miR-210, and Orthotopic pancreatic tumor Modulated tumor microenvironment and exhibited combined anticancer
AMD3100 activity in pancreatic cancer cells.

injection of LPQDEA/pTRAIL did not cause tumor resistance or
relapse after a two-week treatment-free period, and exhibited
prolonged survival and good health.
A reactive oxygen species (ROS)-responsive charge-
switchable cationic polymer, poly[(2-acryloyl)ethyl(p-boronic
acid benzyl) diethylammonium bromide] (B-PDEAEA), could
be converted into negatively charged polyacrylic acid by the
high level of intracellular ROS to promote the quick and
efficient release of encapsulated genes [89]. The B-PDEAEA
polyplexes showed enhanced transfection activity compared
to PEI in serum-free medium, but were rendered ineffective in
the presence of serum proteins. To improve the serum stabi­
lity, B-PDEAEA polyplexes were coated with cationic 1,2-dio­
leoyl-3-trimethylammonium-propane(DOTAP)/Chol or DC-Chol
/Dioleyl phosphatidyl ethanolamine (DOPE) to prepare two
cationic lipopolyplexes [90]. The two cationic lipopolyplexes,
used as vectors of therapeutic gene pTRAIL, exhibited higher
transfection efficiency both in vitro and in vivo, compared with
PEI and lipofectamine 2000. The mechanisms of action thereof
may be such that the cationic lipid coating prevented
B-PDEAEA polyplexes from dissociation by serum proteins,
promoted cellular internalization, enhanced lysosomal escape,
and nuclear entry. In addition, the cationic polymers induced
intracellular ROS elevation, which triggered the ROS-
responsive charge-switch and promoted gene pTRAIL release
for nuclear entry. IP injection of the two cationic lipopoly­
plexes delivered pTRAIL to tumor tissues and exhibited
improved anti-tumor activity in mice bearing PM. Thus, sti­
muli-responsive vectors are promising for gene therapy, with
desirable transfection efficiency and safety.
4.4. Inorganic materials-based IP gene therapy
Inorganic nanoparticles having unique advantages, such as
flexibility in terms of particle size and surface modification
capabilities can also be used as gene vectors. Gold nanoparti­
cles (AuNPs) are widely used as vectors to deliver nucleic acid
into the cells and protect them from nucleases or other envir­
onmental agents. T C225-conjugated AuNPs were utilized as
vectors of pDNA/p53 to form a gene therapeutic system (Au-
C225-p53DNA) [91]. In Au-C225-p53DNA, C225 was used as
a targeting agent aimed at EGFR (a molecular target of ovarian
cancers). In addition, C225 also worked as a therapeutic agent
to block EGFR and subsequently inhibit cancer cell growth
[92]. IP injection of Au-C225-p53DNA showed significant accu­
mulation in SKOV3 cells and inhibition of tumor growth in
a mouse model. Calcium carbonate also can be used as an
inorganic vector to improve the transfection efficiency of ther­
apeutic genes. A naked pDNA solution was mixed with
a suspension of calcium carbonate micro-flowers (flower-
shaped particles, c. 50 um in diameter) to mimic the rubbing
effect and enhance pDNA transfer [93]. An IP injection of
micro-flower suspension delivered pDNA to all intraperitoneal
organs in mice. Compared with commercially available cal­
cium carbonate, the micro-flowers exhibited slower sedimen­
tation, a lower effective dose, and higher transfection
EXPERT OPINION ON DRUG DELIVERY 13
efficiency at low concentrations. Two potential (but unproven)
mechanisms were proposed: (1) transient pores are generated
by friction, which is an important factor in hydrodynamics-
based transfection [94], (2) enhancement of macro-pinocytosis
facilitates the transfer of pDNA.
4.5. Combination of gene therapy and other treatments
Combination of gene and chemotherapeutic agents at their
nontoxic doses is a potential strategy for tumor therapy due to
their synergistic effects. Combination of phosphoglycerate
kinase 1 (carried by adenoviral vector) and 5-fluorouracil
(5-FU) showed improved anti-tumor effects in PM-bearing
mice, compared with single 5-FU [95]; however, the serious
systemic toxicity cannot be ignored, and thus, non-viral
mediated gene therapies are often investigated in combina­
tion with other agents.
Some microtubule-arresting drugs (such as paclitaxel) have
been proven to improve gene transfection efficiency, and can
be co-applied with therapeutic genes in tumor therapy [96].
The underlying mechanism may be such that low dosage
paclitaxel promoted endosome/lysosome escape and nuclear
entry of the genes by inducing cell synchronization at the G2-
M phase. Low-dosage paclitaxel encapsulated nanoparticles
(P-DPP), delivered the co-encapsulated paclitaxel and VSVMP
to the same tumor cells and provided a good platform for
their synergistic action [97]. Combination of paclitaxel loaded
TPM also could increase the efficacy of siRNA therapy [98].
Positively charged PEGylated cationic liposome (PCat) formed
multi-lamellar structures with negatively charged siRNA and
improved their stability and cellular uptake [99]. In addition,
the combination of TPM and PCat-siSurvivin could improve
the transfection of siRNA and anti-tumor efficacy by synergis­
tic effect: a combinatorial therapy involving cisplatin and
siRNA-mediated DJ-1 protein suppression was tested for meta­
static ovarian cancer [100]. PEG-coated poly (propyleneimine)
(PPI) nanoparticles were further conjugated with Luteinizing
hormone-releasing hormone (LHRH) peptide to be used as
tumor cell targeting vectors of siRNA. In conclusion, the com­
bination of IP gene therapy and chemotherapeutic agents
seems to be a potent strategy with which to improve the anti-
tumor efficacy through different cellular pathways.
Combinatorial therapy with multiple genes by different
mechanisms could provide desirable efficacy and safety due
to their synergistic effects. Cholesterol-modified polymeric
nanoparticles (PCX), containing a triple therapeutic gene,
were developed as vectors with high tumor accumulation,
low systemic toxicity, and improved anti-tumor efficacy for
the IP treatment of metastatic pancreatic cancer [101].
Moreover, chimeric gene fusion has been developed to pro­
vide synergistic effects or overcome some disadvantages of
the single gene in tumor therapy. p53-Bad, designed by com­
bining p53 with the mitochondrial pro-apoptotic factor Bad,
could target the key driver p53 mutation and facilitate mito­
chondrial priming to overcome drug resistance in ovarian
cancer cells.
14 P. WANG ET AL.

5. Conclusion the tumor tissue for a long time. In addition, the therapeutic
agents must selectively accumulate in tumor tissue and pene­
This article focuses on the pharmaceutical modification and
trate the peritoneal surface/tumor nodules. All of these pro­
optimization of IP drug delivery systems, which lead to
blems can be resolved by pharmaceutical technologies,
enhanced anti-cancer efficacy and safety in IP treatment of
including preparation of novel drug delivery systems, modify­
PM. To increase the concentration of drugs in the abdominal
ing traditional drug carriers, and combination of drug delivery
cavity for a longer time, many researchers have prepared
systems and other physico-chemical therapies. IP gene ther­
long-acting preparations, including microspheres, implants,
apy has also attracted a great deal of attention in the treat­
and multifunctional gels. On the basis of nano-preparation,
ment of PM, with significant tumor selectivity, enhanced anti-
the surface functionalization modification of nanoparticles or
tumor activity, and reduced toxicity. Various gene vectors
preparation of nano-systems by functional materials can
have been developed using pharmaceutical techniques to
improve drug concentrations in the peritoneal cavity and
provide safe, high-efficiency transfection.
reduce systemic toxicity. In addition, to improve the efficacy
Until now, not all anti-tumor agents are suitable for the
of IP treatments, several tumor targeting systems have been
treatment of PM by IP route, in view of the advantages and
studied, including passive targeting, antibody/peptide-
disadvantages of IP therapy. Nontoxic drugs can be perfused
mediated active targeting, some physico-chemical respon­
safely in the peritoneal cavity, without resulting in serious
sive targeting, etc. Meanwhile, some modifications have
toxicity to adjacent organs. Some novel anti-tumor agents
been developed to overcome MDR and the poor permeabil­
and conventional drugs in new application provide good
ity of drug in IP therapy. Finally, gene therapy is a focus of
performance in preclinical studies, but do not produce posi­
much research into tumor treatment, in which vectors of
tive results in clinical trials owing to an ineffective concentra­
therapeutic gene are key factors, thus some vectors with
tion or serious systemic toxicity. Some conventional drug in
increased transfection efficiency and efficacy have been
new application, such as disulfiram, previously exhibited sig­
demonstrated by pharmaceutical strategies.
nificant anti-tumor effects in preclinical studies, however
According to the literature, except for pharmaceutical
returned dissatisfactory results in clinical trials (systemic
modification and optimization, there are many reports of
administration). For these drugs, the IP route may be
improved anti-tumor efficacy of IP therapy, including those
a potential approach to prove their anti-tumor activity.
related to medical devices, synthetic aspects, surgical techni­
Moreover, a combination of anti-tumor agents and conven­
ques, gene therapy, etc. Many satisfactory experimental
tional drugs (not for tumor therapy) by the IP route may show
results have been exhibited at cellular level and in animals
enhanced anti-tumor efficacy and safety. Collectively, IP ther­
(even pigs), however, clinical trials of IP therapy remain rare.
apy is a potential therapy method for PM, providing effective
The reason for this may be that it is difficult to gain approval
concentration of anti-tumor agents in the peritoneal cavity
from institutional research ethics committees: (1) Patients
without causing systemic toxicity.
may suffer from serious side effects and severe pain, such
Intraperitoneal perfusion is commonly used in the clinical
as abdominal distension, abdominal pain and abdominal
treatment of PM, using large volumes of drug solution, to
infection after IP therapy. These side effects have barely
enable these drug solutions to contact with tumors in the
been investigated in the literature. (2) In clinical trials the
peritoneal cavity as much as possible. however, novel drug
efficacy of IP treatment is unclear, because most studies
delivery systems, such as nano/micro system, intelligentised
include both CRS and IP treatments making it impossible to
gel/implants, and therapeutic genes are all injected in small
separate the relative benefit of each treatment strategy
quantities. Thus, it is difficult to make these system act on
alone.
most tumor cells with small sizes and typically uncertain loca­
tion. Especially for patients with advanced ascites, drug deliv­
6. Expert opinion ery systems are further diluted or unstable in ascites, all of
which are key factors affecting the efficacy of IP treatment for
Most PM is caused by the metastasis or exfoliation of tumor
PM. Although IP therapy has exhibited good performance
cells to the peritoneum. PM commonly originates from cancers
both in mouse models and in patients with PM in clinical trials,
confined to the peritoneal cavity, such as colorectal cancer,
clinical application remains limited due to the serious side
ovarian cancer, gastric cancer, pancreatic cancer, and liver
effects and its low acceptability. Further investigations are
cancer. In the peritoneal cavity, distribution of PM is wide,
needed to develop potential IP therapy, focusing on the effi­
with different sizes and typically uncertain location. However,
cacy and safety: (1) keep tumor tissue exposed to high con­
the majority of PM cases are detected at later disease stages,
centration of therapeutic agents for a long time; (2) improve
when large-scale dissemination and drug resistance occur. In
the tumor targeting and tumor penetration to decrease the
addition, PM is closely associated with a high mortality and
toxicity to normal tissue; (3) reduce the risk of infection and
poor prognosis. In selected patients with limited tumor exten­
pain caused by catheters by decreasing the volume of injec­
sion, favorable tumor biology, and a good clinical condition,
tion or using noninvasive injection; (4) introduce more gene
there is an indication for combination of CRS and subsequent
therapy, immunotherapy, and monoclonal-antibody therapy
IV/IP chemotherapy. In the case of IP therapy, one of the major
into the possible IP treatments for PM.
challenges is to provide an efficient local drug level around
 EXPERT OPINION ON DRUG DELIVERY 15

Before IP therapy becomes widely accepted by doctors and PQDEA Poly (N-[2-(acryloyloxy)ethyl] -N-[p-acetyloxyphenyl]- N,
N-diethylammoniumchloride)
patients, there are several necessary conditions to be met:
ROS Reactive oxygen species
pharmacologists choose appropriate anti-tumor drugs, with B-PDEAEA Poly[(2-acryloyl)ethyl(p-boronic acid benzyl) diethylammo­
curative effect and low side effects in IP application. nium bromide]
Pharmacists prepare appropriate drug carriers for targeting DOTAP 1,2-Dioleoyl-3-trimethylammonium-propane
tumor cells or tissues, and provide efficient concentration in DOPE Dioleyl phosphatidyl ethanolamine
AuNPs Gold nanoparticles
the abdominal cavity for a long time. Experts provide optimal
5-FU 5-Fluorouracil
medical devices, which can deliver drugs to the abdominal P-DPP Low-dosage paclitaxel encapsulated nanoparticles
cavity with little inflammation or discomfort. Professional per­ PCat PEGylated cationic liposome
fusionists and doctors implement IP treatment after informing PPI Poly (Propyleneimine)
patients of its advantages and disadvantages. We believe that LHRH Hormone-Releasing Hormone
PCX Cholesterol-modified polymeric nanoparticles
future IP therapy, combined with surgical treatment or sys­
temic chemotherapy, could be widely accepted by patients
and doctors with excellent efficacy and fewer side effects. Funding
Overall, there is still a long way to go until these theoretically
This work was supported by: The National Key Research and Development
possible IP therapies are widely accepted in clinical practice.
Program of China (2017YFC1308900), National Natural Science Foundation
of China (No. 8197111654, No. 81972331), Technological Special Project of
Liaoning Province of China (2019020176-JH1/103), Science and
Abbreviations Technology Plan Project of Liaoning Province (No.2013225585), The Key
PC Peritoneal carcinomatosis Research and Development Program of Liaoning Province (2018225060),
IP Intraperitoneal Science and Technology Plan Project of Shenyang city (19–112–4–099).
CRS Cytoreductive surgery
NCI National Cancer Institute
MDR Multidrug resistance Declaration of interest
HIPEC Hyperthermic intraperitoneal chemotherapy
The authors have no relevant affiliations or financial involvement with any
PIPAC Pressurized intraperitoneal aerosol chemotherapy
organization or entity with a financial interest in or financial conflict with
PL A Poly(dl-lactic acid)
the subject matter or materials discussed in the manuscript. This includes
PLG Poly(lactide-co-glycolide)
employment, consultancies, honoraria, stock ownership or options, expert
PCL-PEG-PCL Poly (e-caprolactone) poly (ethyleneglycol) poly
testimony, grants or patents received or pending, or royalties.
(e-caprolactone)
BMEDA N,N-bis(2-mercaptoethyl)-N9,N9-diethyle thylenediamine
HA Hyaluronic acid
ED-catalase Ethylenediamine-conjugated catalase
Reviewer disclosures
PECE Poly(ethylene glycol)-poly( -caprolactone)-poly(ethylene Peer reviewers on this manuscript have no relevant financial or other
glycol) relationships to disclose.
PECT Poly(ε-caprolactone-co-1,4,8-trioxa [4.6]spiro-9-undeca­
none)-poly(ethylene glycol)-poly (ε-caprolactone-co
-1,4,8-trioxa [4.6]spiro-9-undecanone) ORCID
Plu-CLA Poly(organophosphazenes) and conjugated linoleic acid-
incorporated Pluronic F-127 Xiaofang Che http://orcid.org/0000-0002-9087-1007
RES Reticuloendothelial system
MSNs Mesoporous silica nanoparticles
P-PEG-UCNPs PEG-coated lanthanide-loaded upconversion References
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• This research suggest that intraperitoneal administration of
polymeric nanoparticles to deliver DT-A encoding DNA, com­
bined with transcriptional regulation to target gene expres­
sion to ovarian tumor cells, holds promise as an effective
therapy for advanced-stage ovarian cancer.