262 Recent Patents on Anti-Cancer Drug Discovery, 2009, 4, 262-272

Nanoparticle Albumin - Bound (NAB) Technology is a Promising Method

for Anti-Cancer Drug Delivery
Qiang Fu, Jin Sun, Wenping Zhang, Xiaofan Sui, Zhongtian Yan and Zhonggui He*

Department of Biopharmaceutics, School of Pharmacy, No. 103 of Wenhua Road, Shenyang 110016, PR China

Received: January 14, 2009; Accepted: March 5, 2009; Revised: March 17, 2009
Abstract: Albumin is a versatile drug carrier in anti-cancer drug delivery system and it also has an actively targeting
capacity to tumors. Recently, nanoparticle albumin-bound (nab™) paclitaxel (nab-paclitaxel; Abraxane®) has been
approved in 2006 for use in patients with metastatic breast cancer who have failed in the combination chemotherapy, and
so the nab-technology has attracted much interest in the anti-cancer drug delivery system. The details about the
preparation, characterization and evaluation of nab-paclitaxel (ABI-007) are discussed. The pharmacokinetics,
pharmacodynamics and the clinical trials of ABI-007 are also reviewed. Furthermore, the recent applications of nab-
technology in the anti-cancer drug delivery systems are summarized by virtue of the patents pertaining to nab-technology.
To sum up, nab-technology has a great potential of being applied extensively in the field of anti-cancer agents delivery in
the future in order to acquire the good safety and better therapeutical effect.
Keywords: Nab- technology, anti-cancer drug, paclitaxel, albumin.

INTRODUCTION docetaxel [4], are formulated into aqueous injections with

With an increase in patient population of cancer, cancer
is becoming a leading reason of death worldwide and the
number of death was up to 7.9 million (around 13% of all
deaths) in 2007 [1]. A principal treatment strategy until now
for cancer has been the chemotherapy with the utilization of
anti-cancer agents alone or in combination.
It has been reported that 40% or more of the drug
candidates belongs to either biopharmaceutical class II (low
solubility and high permeability) or class IV (low solubility
and low permeability); that is, their poor aqueous solubility
have elicited a big barrier in drug delivery, which will impair
the drug dissolution and absorption in the gastrointestinal
tract, and the barrier in the preparation of intravenous
injections. In the recent years, it has been found that the
majority of the effective anti-cancer agents also belong to the
above two classes [2]. So the difficult problems, how to
administrate, how to act effectively and safely, are put
forward.
Various administration pathways have been utilized by
the antineoplastics, and intravenous (IV) injection is more
popular in that it provides the most rapid action and full
availability of the drug among all the administration routes.
Solvent-based delivery vehicles are major intravenous
approaches for formulating poorly soluble anti-cancer
agents. But obviously, the distinguished characteristic of the
solvent-based delivery system is the large amounts of the
conventional surfactants and solvents contained within the
formulation, which may cause serious side effects, including
hypersensitivity reactions, neutropenia and neuropathy, even
death. Two classic anti-cancer agents, paclitaxel [3] and
*Address correspondence to this author at the No. 59 Mailbox, Department
of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical
University, No. 103 of Wenhua Road, Shenyang 110016, PR China;
Tel/Fax: 86-24-23986321; E-mail: hezhonggui@gmail.com
the help of Cremophor (Taxol) and Tween 80 (Taxotere),
respectively. And the side effects are frequent and remark-
able for the patients who receive them.
Exploiting an improved formulation of anti-cancer agents
is such an arduous task for the experts in pharmacy that no
significant progress was made for a long time, but good
news for the cancer patients is that FDA has approved
nanoparticle albumin-bound (nab™) paclitaxel (nab-
paclitaxel; Abraxane®) for treating metastatic breast cancer.
Most important, the formulation is free of conventional
surfactants in the water-based injections. Nab-paclitaxel,
stable and negatively charged nanoparticles with size of
approximately 0.1-0.2μm, is prepared by encapsulating
paclitaxel in albumin nanoparticle. It can pass through the
leaky capillary junctions in the tumor bed more easily than
through the normal vessels in healthy tissue, and then be
taken selectively by the tumor tissues and cells. It is also
hypothesized that the specific delivery to tumors is achieved
via receptor-mediated transcytosis and binding to secreted
protein acidic rich in cysteine (SPARC) on the surface of the
tumor. The clinical data have shown that Abraxane offers
several improvements over the conventional, solvent- and
Cremophor-based paclitaxel (Taxol), including lower
toxicities, shorter administrating time, higher efficacy and
without premedication. Recently, Abraxane is under further
evaluation for the first-line treatment of other kinds of
malignancies as a single agent and in combination therapy,
such as non-small-cell lung cancer (NSCLC), ovarian cancer,
and malignant melanoma.
It is generally acknowledged that nab-technology is a
breakthrough for anti-cancer drug delivery system. To
introduce the promising and useful nab-technology, this
review will highlight the preparation, characterization,
pharmacokinetics and clinical trials of nab-paclitaxel, and

1574-8928/09 $100.00+.00 © 2009 Bentham Science Publishers Ltd.

Nab Technology for Anti-Cancer Agents Recent Patents on Anti-Cancer Drug Discovery, 2009, Vol. 4, No. 3 263

will emphasize the recent applications and prospects of nab-

technology in the delivery of anti-cancer agents.

1. PREPARATION, CHARACTERIZATION AND

EVALUATION OF NAB-PACLITAXEL

1.1. Preparation Process of Nab-Paclitaxel

Preparation of nab-paclitaxel is based on emulsion-
evaporation cross-link method. The preparation schematic of
ABI-007 is shown in the Fig. (1). The oil phase is added
drop by drop to the aqueous phase, human serum albumin
(HSA) solution (1% w/v) presaturated with 1% chloroform.
A crude emulsion is formed when the mixture subjected to a
low shear forces at low rotating speed. A final emulsion is
produced by homogenizing the crude emulsion at a high
pressure and recycling the emulsion through homogenizer.
The albumin nanosuspensions, with particle size less than
200nm, are yielded by removing the solvent. The resulting
dispersion is translucent and the typical diameter of the
resulting paclitaxel nanoparticles is 140-160nm. And an
aseptic filter membrane (pore 220nm) is usually used for
sterilization by filtering out the impurity, bacteria and etc.
What is more, if necessary, ultrafiltration-technology can be
applied for further purification to eliminate small conta-
minated molecules. In order to improve the stability of the
products, lyophilization is always employed to prepare the
Fig. (1). Schematic of preparation processes of ABI-007 [10]. (The oil phase
solid powders of nab-paclitaxel [5-10].
employed generally contains 30mg paclitaxel dissolved in 0.55ml
Although the description provided above is specific to chloroform, another 0.05ml ethanol is also added in the oil phase. The water
paclitaxel, it is understood that the similar operating proce- phase is 29.4ml human serum albumin (HSA) solution (1% w/v)
dure can also be applied to other drugs after appropriately presaturated with 1% chloroform).
minor modification, such as doxitaxel, rapamycin, 17-
allylamino- geldanamycin, dimeric thiocolchicine and etc.

A low phase fraction of the ethanol added in the
1.2. Characterization of the Nanoparticle Albumin- organic phase is preferred to generate particles with
Bound Paclitaxel small particle size.
Due to the denaturation and coagulation of protein when
A research was conducted to make sure whether a
exposed to high temperature and high pressure, it is higher drug concentration or a lower concentration can
impossible to apply traditional methods of sterilization, such produce smaller size, with the other parameters are
as autoclaving. Therefore, it is necessary and significant to fixed. It was found that the lower drug concentration
tailor and control particle size of the final nanoparticles well produced larger particles than higher concentration.
below 200nm, capable of employing filtration sterilization This directly contradicts the conventional nanoparticle
method. The particle size of nab-technology based products dispersions stabilized by surfactants.
on sale or under development is shown in the Table 1 [11].
The carrier albumin must be in a sufficient amount to
As far as the above considerations are concerned, we would stabilize the paclitaxel in an aqueous suspension and to
like to present some factors that influence the particle sizes reduce the sedimentation rate of the paclitaxel nano-
of the final products as follows: particle suspensions in an aqueous medium. And the
Table 1. Particle Size of Some Nab-Technology Based Products amount of albumin in the formulation depended on the
[11] size and density of nanoparticles [12].

It is acknowledged that the homogenization pressure
Items Particle Size (nm) determines the particle size of the suspensions to a
great extent. The pressure can be in the range of 100 up
ABI-007 (Abraxane) 130nm to 100000 psi, and preferably in the range of 2000 up to
60000psi, and can be in a presently preferred range of
ABI-008 130nm
3000 to 40000psi. The specific pressure needs the
ABI-009 90nm actual optimization during the experiment.
ABI-010 110nm
No significant discipline was found about the relation-
ship between the cycle numbers and the particle size.
ABI-011 90nm The optimum cycle numbers should be determined
according to the experimental data.
264 Recent Patents on Anti-Cancer Drug Discovery, 2009, Vol. 4, No. 3
1.3. Evaluation of Nab-Paclitaxel Nanoparticle
1.3.1. Role of Albumin in the Nab-Paclitaxel Nanoparticle
Albumin is the most abundant smallest protein in human
plasma and is the only excipient in the final product of this
technology. As for nab-paclitaxel, it serves not only as a
targeting ligand, but also as a carrier in drug delivery and a
stabilizer in the formulation.
1.3.1.1. A Targeting Ligand to Cancers
An essential requirement for anti-cancer agents’ delivery
system is their selectively targeting capability to the tumors.
It is demonstrated that albumin contributes a lot for nab-
paclitaxel targeting capability. And a novel albumin trans-
porter mechanism was elucidated recently and the targeting
ability of nab-technology based products can be realized by
either active or passive targeting.
In the case of the active targeting, the albumin contained
in the nab-paclitaxel is thought to facilitate receptor-media-
ted endothelial transcytosis of albumin-bound plasma cons-
tituents or albumin-based nanoparticles into the extravas-
cular space. This process is initiated by binding of albumin
to a cell surface, 60kDa glycoprotein (gp60) receptor
(albondin). Specially speaking, gp60 is a receptor found on
endothelial cells of a tumor and has a high binding capacity
to albumin [13-16]. This binding will lead to combination of
gp60 and an intracellular protein (caveolin-1) and
subsequently invagination of the cell membrane to form
transcytotic vesicles. Thus, the transcytosis of albumin
across the endothelium of blood vessels is realized and
antineoplastic agents conjugated or embedded within the
albumin are co-transported to the space surrounding the
tumors [17-22]. Moreover, SPARC, an extracellular matrix
glycoprotein rich in cysteine, is secreted mainly by multiple
types of tumor tissues but absent in normal tissues [23-32]. It
will bind albumin and further facilitates the accumulation of
albumin-bound and -embedded drugs in the tumor
interstitium [23-26, 33, 34]. In short, albumin will be
actively and selectively recognized and bound by the two
different proteins rich in the tumor tissues.
Good targeting activity of nab-paclitaxel is also reached
by passive targeting via enhanced permeability and retention
(EPR) effect [35-37]. During tumor growth, angiogenesis
will result in defective hypervasculature and a deficient
lymphatic drainage system, and then macromolecules or
drug delivery nanoparticles (cutoff size about 300nm) will
preferentially accumulate and diffuse into tumor tissues. The
average particle size of nab-paclitaxel is 130nm, just
between the pore size of normal and tumor vasculature. Such
an appropriate size enables nab-paclitaxel cannot penetrate
the tight endothelial junctions of normal blood vessels, but
can extravasate into tumor tissues and be trapped at the
tumor site. Moreover, owning to lack of efficient lymphatic
drainage in the solid tumor, drugs will further accumulate
and enrich in the tumor extracellular tissues.
The nab-technology based products exert their good
targeting activity through the concerted effects of active and
passive targeting capability. Furthermore, it is possible that
selectively or targetedly distributed nanoparticles of pacli-
taxel at the tumor site allowed for releasing the anti-cancer
He et al.
drug locally in the extracellular area for a long time and
acquired improved therapeutic efficacy.
1.3.1.2. A Carrier in Drug Delivery
The albumin in the formulation generally serves as a
carrier to make the paclitaxel more readily suspendable in an
aqueous medium, and to improve the suspension stability as
compared to the formulations without albumin.
HSA has multiple hydrophobic binding sites and binds a
diverse set of taxanes, especially neutrally and negatively
charged hydrophobic compounds [38]. Two high affinity
binding sites of HSA have been proposed in subdomains IIA
and IIIA, which are highly elongated hydrophobic pockets
with charged positively lysine and arginine residues near the
surface anchoring polar ligands [39-44]. Paclitaxel has been
shown to bind with HSA [45, 46] and docetaxel has been
also shown to bind to human plasma proteins [47].
This can avoid the use of toxic solvents or surfactants to
solubilize the taxane, and thereby can reduce frequent and
remarkable side effects of intravenous administration of the
paclitaxel solvent- and surfactant-based preparations.
1.3.1.3. A Stabilizer in the Formulation
Albumin is a single-chain protein composed of 585
amino acids, of which has a total of 17 disulphide bridges,
one free thiol, and a single tryptophan. When it is exposed to
high shear conditions during homogenization, a coating layer
surrounding the drug particles is produced: the existed
disulfide bonds are disrupted and the novel disulfide bonds
are formed by cysteine of intra- and inter- albumin mole-
cules owning to the local heating and superoxide ions
produced by the cavitation effect. Due to the stretching
property of albumin, this preparation is stabilized sterically.
Moreover, because the isoelectric point of albumin is 5.16,
the particles are all charged negatively in the dispersing
aqueous media. Therefore, the preparation is further electro-
statically stabilized due to the repulsing forces between the
same charges of nanoparticles.
In addition, the dual functionality of albumin as surfac-
tant and cryoprotectant results in better cryoprotection for
albumin than disaccharides, as observed by Liu for lactate
dehydrogenase [48]. It means that the addition of conven-
tional cryoprotectants, such as mannitol, sucrose, glycine and
the like, is not needed in the nab-technology based products.
Furthermore, the product is easily reconstituted with saline
or water, owing to the hydrophilic property of albumin and is
highly bioavailable when administered since there is the
similar binding characteristics to that in vivo blood condition
[45, 49].
1.3.2. Advantages of Nab-Paclitaxel Product over Taxol
Nab-technology has attracted so much attention because
of FDA-approved nab-paclitaxel (ABI-007) on sale without
the addition of any surfactant and organic solvent. And the
data collected from recent research reports has shown that it
is much better than the existing product, Taxol, which
vehicle carrier was composed of polyethoxylated castor oil
(Cremophor) and ethanol to improve paclitaxel's water
solubility. The advantages of ABI-007 are summarized here,
with Taxol as the reference Table 2.
Nab Technology for Anti-Cancer Agents Recent Patents on Anti-Cancer Drug Discovery, 2009, Vol. 4, No. 3 265

Table 2. Advantage Overview of ABI-007 over Taxol Table 3. Various Carcinomas and the Responding Adminis-
tration Method
Items ABI-007 Taxol
Diseases Administration Protocol
Formulation 3-4% Albumin Cremophor (50%) and
ethanol (50%) Carcinoma of the 135mg/m2 over 24 h every 3 weeks
ovary(previously untreated)
Premedication No need Dexamethasone 20mg PO
administered approximately Carcinoma of the 135mg/m2 or 175mg/m2 over 3 h
12 and 6 hours before ovary(previously treated) every 3 weeks
Taxol, diphenhydramine (or
Carcinoma of the breast 175mg/m2 over 3 h every 3 weeks
its equivalent) 50mg I.V. 30
to 60 minutes prior to Non-small cell lung carcinoma 135mg/m2 over 24 h every 3 weeks
Taxol, and cimetidine
AIDS-related Kaposi’s sarcoma 100mg/m2 over 3 h every 2 weeks
(300mg) or ranitidine
(50mg) I.V. 30 to 60
minutes before Taxol.
It is well known that Cremophor and ethanol can leach
Infusion time 30 Minutes 3 Hours or 24 hours plastcizers from PVC bags and the infusion sets routinely
used in clinic [58, 59]. Therefore, in-line filtration systems
Advised injection 260mg/m2 175mg/m2 and feasible containers uncommonly used, such as glass
dose bottles or other non-PVC infusion systems, must be emp-
Pharmacokinetics Linear Nonlinear loyed to store Taxol preparations. This would bring a huge
economical burden to the manufacturer, but nab-paclitaxel
Package PVC bags Glass bottles or other non- can solve the problems completely, because no components
PVC sets and composition of the nab-product reacts with the common
packaging material.

Increased Activity and Efficacy 2. PHARMACOKINETICS OF NAB-PACLITAXEL
Desai et al. assessed anti-cancer activity of ABI-007 and Sparreboom [60] and his colleagues have conducted a
Taxol in nude mice bearing human tumor xenografts, and
study to compare the pharmacokinetics of ABI-007 and
found that ABI-007 has increased antitumor activity com-
Taxol in Sprague-Dawley rats. They radiolabeled hydrogen
pared with equitoxic doses of Taxol [32]. And the clinical atoms of paclitaxel of the two formulations firstly in the m
trials have shown that overall response rate (ORR) and and p positions of the aromatic rings and secondly in the 10,
tumor to progression (TTP), primary and secondary end- 3
, and 2 positions of the paclitaxel ring system. The blood
point of the trial, respectively, are both superior in the ABI- level of paclitaxel was determined by total radioactivity or
007 group [50-53].
HPLC. They studied the tissues distribution pattern of

Decreased Toxicity or Enhanced Safety paclitaxel following administration at 1 day and 5 day,
including gastrointestinal tract, gastrointestinal tract
Despite a 49% or more paclitaxel is intravenously contents, bone, brain, testes, seminal vesicles, prostate, heart,
administrated, ABI-007 still showed a similar safety profile kidneys, liver, lungs, muscle, spleen, pancreas, and residual
compared with Taxol [54, 55]. According to a toxicokinetic carcass. They found that the biodistribution of ABI-007 was
study, ABI-007 is 59-fold less toxic than Taxol, and 29-fold similar to Taxol and the only apparent difference was that
less toxic than the excipients of Taxol [56]. Taxol-treated rats have a 3.6 fold higher radioactivity in lung

Convenience of ABI-007 for Patients and tissue than ABI-007-treated rats at 5 day. The top three high
activity (μg paclitaxel/g tissue) of tissues was liver,
Manufacturers gastrointestinal tract and carcass at 1 day, while liver, testes
Compared with the conventional paclitaxel formulation and lungs at 5 day. Because the sampling time was cons-
Taxol, ABI-007 is convenient for both the patients and the tricted to 1 day and 5 day, the difference in biodistribution
manufacturers. performance between the two formulations at other time-
points cannot be detected.
The administration of Taxol is time-consuming Table 3.
A 24 hours’ infusion will require an overnight stay in the In the same study [60], the elimination of paclitaxel
hospital and even a 3 hours’ delivery still interfere with formulated as Taxol and ABI-007 was also compared. They
one’s common daily life. But nab-paclitaxel can be given gave the rats the two formulations at a single dose of 5mg/kg
within 30 minutes as an outpatient treatment, so that it can and then determined the radioactivity in feces and urines,
improve patient compliance. In addition, all patients should respectively. The urine elimination was complete appro-
be premedicated prior to Taxol administration in order to ximately within 48 hours but a significant sexual dimor-
prevent severe hypersensitivity reactions Table 1 [57]. phism for the renal elimination was observed for the two
However, the complex premedication is neglected when formulations Table 4. Additionally, there is no obvious
ABI-007 replaces the conventional Taxol. difference observed for the fecal elimination route.
266 Recent Patents on Anti-Cancer Drug Discovery, 2009, Vol. 4, No. 3
Table 4. Radioactivity Found in the Excrement After 5 Days of
Administration
Elimination Gender Percentage of Elimination
Routes
Taxol ABI-007
Fecal routes Male 77.76 ± 6.63% 82.09 ± 4.42%
Female 75.77 ± 6.07% 78.70 ± 5.15%
Renal routes Male 8.10 ± 2.03% 9.51 ± 1.82%
Female 12.45 ± 0.74% 14.07 ± 1.66%
In human, paclitaxel is mainly biotransformed to 6-
-
hydropaclitaxel [61, 62] by CYP2C8 and slightly p-hydroxy-
phenyl-C3-paclitaxel by CYP3A4 [63-65]. For Taxol, the
former metabolism pathway is impeded [57] because
Cremophor inhibited the formation of 6-
-hydropaclitaxel in
human liver microsomes. But the special study on the
metabolism of ABI-007 in human is not carried out yet.
A pharmacokinetic research in human was conducted by
Ibrahim and his colleagues [66]. ABI-007 was administrated
intravenously to 16 patients at different doses. They found
that, unlike the conventional Taxol [67-70], peak concen-
tration and area under curve (AUC) of paclitaxel increased
proportionally with dose ranging from 135 to 300 mg/m2
following ABI-007 administration, indicating a linear
pharmacokinetics [66, 71, 72]. Therefore, it is easy to predict
plasma concentration over the clinically relevant dose range
of ABI-007. In comparison with Taxol [60], ABI-007
showed a larger volume of distribution (663.8 vs 433.4L/m2),
suggesting that ABI-007 was extensively distributed and
bound to tissues and extravascular proteins. Moreover, a
higher clearance of ABI-007 was also observed (21.13 vs
14.76L/h/m2) and is dose independent, implying that when
the dose increased, paclitaxel metabolism of ABI-007
formulation is not saturable in the studied dosage range.
Finally, the ranges of major pharmacokinetic parameters of
ABI-007 following 30 minutes I.V. administration are sum-
marized from several literatures in the Table 5 [66, 71, 72].
Table 5. Ranges of the Major Pharmacokinetic Parameters for
30 minutes ABI-007 Intravenous Infusion
Items Values
AUC/DOSE
h*ng/mL per mg/m2 33.2-78.2
CMAX/DOSE (ng/Ml per mg/m ) 2
37.7-88.3
t0.5(h) 13.4-21.6
CL(L/h/m 2) 17.9-30.6
Vz
L/m2) 370-772
3. CLINICAL TRIALS OF NAB-PACLITAXEL
The clinical studies of ABI-007 as a monotherapy in
treating breast cancer have been reviewed by Hawkins et al.
recently [73]. While ABI-007, alone or in combination
He et al.
against various kinds of cancer, is summarized thoroughly
here.
3.1. Single Medication Against Cancers
3.1.1. Treating Metastatic Breast Cancer
In a Phase I study of ABI-007 conducted by Ibrahim
[66], ABI-007 is administered in 30 minutes every 21 days
without premedication. No acute hypersensitivity reactions
(HSR) were observed during the infusion period. The
maximum tolerated dose (MTD) is determined to be
300mg/m2, approximately 70% higher than the conventional
Taxol (175mg/m2). No acute HSR or unexpected toxicity
occurred and hematologic toxicity was mild and not cumu-
lative. Even for the highest dose studied (375mg/m2), there
occurred grade 3 superficial keratopathy, which was easily
resolved with the use of topical lubricating agents.
Significant anti-tumor activity of ABI-007, demonstrated
in preclinical studies, is confirmed in a phase II study in
patients with metastatic breast cancer [51]. The overall
response rate (complete response (CR) and partial response
(PR)) at 300mg/m2 on an every three weeks regimen was
48%. Response rates were higher among patients who had
not received prior treatment than the patients with prior
treatment for metastatic disease (64% vs 21%). Median TTP
was 26.6 weeks for all patients and 48.1 weeks for respon-
ding patients (CR or PR). Median overall survival was 63.6
weeks.
The incidence of grade 2 and grade 3 sensory neuropathy
is 19% and 11%, respectively. No grade 4 sensory
neuropathy is observed. Grade 3 and grade 4 neutropenia
occurred in 27% and 24% of the patients, respectively. No
severe HSR was reported despite the absence of pre-
medication. It is stressed that superficial keratopathy and
blurred vision were not observed despite careful ophthal-
mologic monitoring, suggesting that the ocular toxicities
occurred by chance in the phase I study or only when doses
of ABI-007 was above the MTD.
A phase III trial [50] was conducted in 454 patients at 70
sites to demonstrate the superior efficacy and reduced
toxicity of ABI-007 compared with standard paclitaxel
preparation. 229 patients were assigned to 3-week cycles of
ABI-007 260mg/m2 intravenously without premedication
and the other patients receive the treatment of standard Taxol
175mg/m2 intravenously with premedication. The ORR was
significantly greater (33% vs 19%, respectively; P = 0.001)
and the median TTP was statistically longer for ABI-007
than for standard Taxol for all patients (23.0 vs 16.9 weeks,
respectively; hazard ratio = 0.75; P = 0.006).
Although the patients in the ABI-007 group received an
average paclitaxel dose 49% greater than that received by
patients in the standard Taxol group, the incidence of
treatment-related grade 4 neutropenia was significantly
lower in the ABI-007 group than in the standard Taxol group
(20 of 226 patients, 9% vs 48 of 222 patients, 22%,
respectively; P<0.001). No HSR occurred with ABI-007
despite the absence of premedication and shorter infusion
time. With a higher dose of paclitaxel, treatment- related
grade 3 sensory neuropathy occurred more frequently in the
ABI-007 arm than in the standard Taxol arm (24 patients,
Nab Technology for Anti-Cancer Agents
10% vs 5 patients, 2%, respectively); however, these
episodes improved with the interruption of treatment to
grade 2 or 1 in a median 22 days and were easily managed
with treatment interruption and dose reduction. These
clinical trial results were further tested and confirmed by an
open-label multicenter study of 210 Chinese patients with
metastatic breast cancer [74].
3.1.2. Treating Non-Small-Cell Lung Cancer
The efficacy and safety of ABI-007 has been investigated
for the treatment of NSCLC according to two administration
regimens. One is a weekly administration for three weeks
following one week rest as a four-week-cycle [75]; the other
method has been adopted for the metastatic breast cancer
treatment, 260mg/m2 intravenously in 30 minutes every three
weeks [76]. A delicate difference has been distinguished
between the patients group of phase II study: some patients
receiving prior treatment were included in the first regimen,
but the patients in the second group had not received prior
therapy.
In the first scheme, patients were well tolerated under the
MTD of 125mg/m2 with ABI-007 intravenously for 30
minutes without premedication on days 1, 8, and 15 of a 28-
day cycle. Grade 3 sensory neuropathy and febrile neutro-
penia appeared as dose-limiting toxicities when dose esca-
lated to 150mg/m2.
The results of phase II study demonstrated that the
confirmed response rate for the two regimens were 30% (12
of 40; 95%CI, 16% to 44%) and 16.3% (7 of 43; 95%CI,
5.24% to 27.31%), respectively. Median TTP was 5 (95%CI,
3 to 8 months) and 6 months (95%CI, 3.9 to 6.5 months),
respectively. Median overall survivals were both 11 months
(95%CI, 7 months to not reached, 9.5 to 16.2 months). The
1-year survivals were 41% and 45%, respectively. The major
toxicities of ABI-007 are presented in the Table 6. The
difference existing in the rate of adverse events may not only
from the two regimens, but also from the selection of the
patients.
Table 6. The Toxicities of the Two Regimens for the Treatment
of NSCLC
Toxicities Percentage of Patients*
Any Grade 1 Grade 2 Grade 3
Anemia 92/74 63/56 23/19 8/0
Leucopenia 62/23 23/16 20/7 20/0
Neutropenia 60/49 13/21 28/19 15/9
Fatigue 75/33 28/7 30/19 18/7
Neutropathy 73/65 35/49 23/12 15/5
*The number before and after the line are for the first and second regimen,
respectively.
3.1.3. Treating Prostate Carcinoma, Ovarian Cancer and
other Cancers
Based on the discovery that SPARC and caveolin were
involved in the metastasis of prostate cancer [25, 77-82],
ABI-007 would be used in patients with developed prostate
Recent Patents on Anti-Cancer Drug Discovery, 2009, Vol. 4, No. 3 267
carcinoma, though little information is available about the
clinical trials until now. A case was reported about long-term
treatment status of an ovarian cancer patient with a
significant history of HSR [83]. A patient experienced three
cycles of treatment of ABI-007 without hypersensitivities. It
appeared to offer paclitaxel- induced HSR patients the option
for continued paclitaxel therapy. In addition, it has been
studied in patients with melanoma [84], with advanced
tumors of the tongue [85] and with advanced head and neck
and recurrent anal canal squamous cell carcinoma [55]
through intraarterial infusion.
3.2. Combined Medication Against Cancers
Chemotherapeutic drugs work in different mechanisms to
inhibit the growth of tumors, either by killing the cells or by
stopping them from division. An optimum and concerted
efficacy would be achieved by co-administrating two or
three of them.
It has been reported in the patients that ABI-007 can be
administered in combination with an effective amount of an
antimetabolite agent (such as gemcitabine, capecitabine, and
fluorouracil) for the treatment of breast cancer, NSCLC,
metastatic colorectal cancer, pancreatic cancer, and advanced
solid tumor, or in combination with an effective amount of
an antiangiogenic agent (such as Avastin® (bevacizumab))
for the treatment of breast cancer, lung cancer, ovarian
cancer, and melanoma, or in combination with an effective
amount of a platinum-based agent (such as carboplatin) for
the treatment of: breast cancer, lung cancer; ovarian cancer;
head and neck cancer; and melanoma [12, 86].
3.2.1. Combination with Gemcitabine
Based on the fact that significant antitumor activity has
been shown in the previous trials with paclitaxel plus
gemcitabine [87-94], nab-paclitaxel has been attempted to be
co-administered with gemcitabine.
In a phase I trial of ABI-007 in combination with gemci-
tabine [95], 12 patients with thoracic malignancies were
enrolled. The MTD of ABI-007 is 300mg/m2 on day 1 in
combination with gemcitabine 1000mg/m2 on days 1, 8 day
of a 21-day cycle. This combination therapy was well
tolerated and demonstrated significant activity in NSCLC
and SCLC patients who were previously treated. A
Grade 4 consistent result was shown in another similar phase I trial
conducted lately [96].
0/0
A phase II study was investigated in patients with
0/0
metastatic breast cancer [97, 98]. Patients were treated with
5/0 ABI-007 infusion at a dose of 125mg/m2, followed by the
infusion of gemcitabine at a dose of 1000mg/m2 over 30
0/0 minutes on days 1 and 8 day of a 21-day cycle. A significant
0/0 anti-tumor activity was shown in this study: the confirmed
response rate was 48% (95%CI: 34-63%), median prog-
ression-free survival was 7.9 months (95%CI: 5.3-9.3).
Frequent toxicities of grade 3 or grade 4 were neutropenia
(52%), fatigue (26%), anemia (14%), dyspnea (14%),
thrombocytopenia (12%) and neuropathy (8%).
3.2.2. Combination with Bevacizumab
Anti-vascular endothelial growth factor antibody, beva-
cizumab, is known to enhance antitumor activity of cytotoxic
268 Recent Patents on Anti-Cancer Drug Discovery, 2009, Vol. 4, No. 3 He et al.

drugs. Albumin-bound paclitaxel was also combined with it
The dose of paclitaxel in the nanoparticle formulation
because the prior combination of paclitaxel and bevacizumab and the combined chemotherapeutic agent is reduced as
has shown a significant activity in metastatic breast cancer compared to the corresponding normal dose of each
[99, 100]. Two regimens of combination (80-125mg/m2 when administered alone.
ABI-007 on days 1,8,15 or 170-200mg/m2 every 14 days on
a 28-day cycle and bevacizumab 10mg/kg every 14 days)
The dosing frequency of the drug-containing nano-
particle formulation and the chemotherapeutic agent
were adopted [101]. The ORR was 48.5% and the median
may be adjusted during the treatment course, based on
TTP for responders was 128 days. Toxicity was acceptable
the judgment of physician.
with fatigue, neuropathy, pain, and hypertension being the
most common complaints. Randomized studies are
The nanoparticles formulation and the chemothera-
conducted to confirm the efficacy and safety of this peutic agent can be administered using the same route
combination in treating breast cancer [102]. of administration or different routes of administration.
3.2.3. Combination with Carboplatin
The paclitaxel in the nanoparticles formulation and the
Combining albumin-bound paclitaxel and carboplatin chemotherapeutic agent are administered at a prede-
was tried to compare with conventional Taxol and carbo- termined ratio.
platin in the newly-diagnosed patients [103]. This novel
combination has shown a superior tolerability and efficacy to 4. CURRENT & FUTURE DEVELOPMENTS
the conventional combination [104].
4.1. Statement of the Ongoing Agent
A phase I study has shown that the continued infusion
did not affect either the pharmacokinetics of ABI-007 or the As the sate of the art breakthrough in solving solubility
degree of neutropenia [105], a result similar to the previous problem, nab-technology is applied further in other anti-
data [106, 107]. This progressed combined medication has neoplastic agents. The agents being developed is sum-
aroused interest in the clinical field. 100 patients with marized in the Table 7 [113]. At present, ABI-007 (nab-
previously untreated NSCLC were divided equally to four paclitaxel), the only marketing product until now, was
groups receiving different doses (225, 260, 300, 340mg/m2 ) approved by FDA for struggling against metastatic breast
of nab-paclitaxel as a 30 minutes infusion followed by cancer. The treatment of other indications, such as NSCLC,
carboplatin 6mg/min/ml every three weeks [108]. Subse- overial cancer, melanoma, squamous carcinoma and etc, are
quently, another 75 patients with untreated NSCLC were still under clinical assessment. Besides as a monotherapy in
recruited into 3 cohorts and received nab-paclitaxel weekly cancer treatment, ABI-007 is also being investigated in
using 3 different regimens separately [109]. A higher combination with carboplatin, gemcitabine, capecitabine,
response rate (ORR: 45.33% vs 29%) and less peripheral bevacizumab and etc.
neuropathy (12-28% vs 37%) were observed compared to the Table 7. Nab-Products in Clinical Development [113]
previous every three weeks regimen.
3.2.4. Combination with other Chemotherapeutic Agents Agent Indication Development
Stage
In addition, ABI-007 can also be used in combination
with an effective amount of antimetabolite agent (cape- ABI-007(nab-paclitaxel) Breast(metastatic) Marketed
citabine) [110], or with an effective amount of an alkylating
agent (cyclophosphamide), or with an effective amount of a Breast(adjuvant) Phase
tyrosine kinase inhibitor (gefitinib), or with an effective Breast(metastatic –first Phasefinished
amount of an anthracycline antibiotic, or with an effective line)
amount of a vinca alkaloid (vinorelbine), or with an effective
Breast(paclitaxel Phasefinished
amount of a macrolide (rapamycin), or with an effective
refractory)
amount of a topoisomerase inhibitor or in combination with
two or three of them [102]. Lung (NSCLC) Phasefinished

3.2.5. Triple Drug Combination Overial(advanced) Phase

The nab-paclitaxel in combination with bevacizumab and Melanoma(Advanced) Phasefinished

gemcitabine was proved as a safe regimen [111]. A formal Pancreatic(advanced) Phase

phase II trial has been developed at the University of Miami
to confirm its safety and clinical activity. The combination of ABI-008(nab-docetaxel) Metastatic prostate Phase

nab-paclitaxel, carboplatin and bevacizumab was also shown cancer
to have a promising activity in the first-line patients with ABI-009(nab-rapamycin) Solid tumors Preclinical
non-squamous NSCLC and manageable adverse events finished
[112].
ABI-010(nab-17AAG) Solid tumors Preclinical
In summary, the combination therapy can be imple-
mented according to the general principle as follows [102]: ABI-011(Dual Solid tumors Preclinical
Microtubule and

The agents can be administered simultaneously and/or Topoisomerase-1
sequentially. inhibitor solid tumors)
Nab Technology for Anti-Cancer Agents
ABI-008 (nab-docetaxel), a solvent-free, Tween-free
nanometer-sized form of docetaxel for the treatment of
hormone refractory prostate cancer and metastatic breast
cancer, is under evaluation in Phase
. And the preclinical
data indicated that higher doses of nab-docetaxel can be
delivered with less toxicity compared to the solvent-based
formulation of docetaxel, Taxotere (docetaxel injection)
[114]. Because of its novel mechanism of delivery, nab-
docetaxel may provide a more effective and possibly less
toxic treatment for patients with metastatic prostate cancer
[115].
The active component of ABI-009 is rapamycin, an
inhibitor of mammalian target of rapamycin (mTOR)
overexpressed in various tumors [116]. Because mTOR
pathway is blocked, tumor cell growth and angiogenesis are
both controlled [117]. Pre-clinical study showed that ABI-
009 was well-tolerated and highly effective against breast
cancer xenografts and colon cancer xenografts in vivo [118].
And it also displays linear pharmacokinetics as did ABI-007.
17-Allylaminogeldanamycin (17-AAG), the derivatives
of geldanamycin, can inhibit tumor-derived heat shock
protein 90 (HSP90), and maintain the conformation, stability
and function of many proteins involved in cell surviving
[119]. ABI-010, nab-17AAG, is in preclinical trials. And
pre-clinical studies have displayed significant effects on
suppres-sing HER2 expression and anti-tumor activity [120].
Tumor, enlarging to greater than about two millimeters in
diameter, must have their own blood supply by inducing the
growth of new capillary blood vessels. ABI-011 is effective
in inhibiting the formation of novel microvessel and in
disrupting established microvessels [121]. Furthermore,
thiocolchicine dimmers, the principal agent in ABI-011, can
inhibit both tubulin polymerization and the activity of
topoisomerase
[122]. Although it is just in preclinical
trials, it is considered to be a powerful anti-cancer agent
against the anti-cancer multidrug-resistant tumor cells [123-
125].
4.2. Forward Looking of Nab-Technology
Nab-technology, firstly developed by Abraxis Bio-
sicence, is a preparation process and formulation strategy
proved successful in the application of several poorly soluble
anti-cancer agents. Some products are confirmed to be
superior to conventional formulations in its efficacy, safety
profile and some other aspects. As the technology moves
forward, some drugs withdrawn with poor physicochemical
properties in the drug development stage, will be rescreened
and restudied by the Nab-technology to prepare the suitable
preparations to improve efficacy and safety. Nab-technology
based products will be administrated through multiple
administration routes (such as oral, pulmonary and nasal
delivery) other than given intravenously and will have the
great potential to replace the conventional formulations
containing amounts of surfactants and organic solvents for
solubilization of poorly water soluble anti-cancer agents in
the future in order to acquire the good safety and better
therapeutical effect.
Recent Patents on Anti-Cancer Drug Discovery, 2009, Vol. 4, No. 3 269
ACKNOWLEDGEMENTS
We are grateful for financial support from the National
Basic Research Program of China (973 Program), No.
2009CB930300.
CONFLICT OF INTEREST
The authors have no conflicts of interest that are directly
relevant to the contents of this manuscript.
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