Journal of Controlled Release 170 (2013) 365–372

Contents lists available at ScienceDirect

Journal of Controlled Release

journal homepage: www.elsevier.com/locate/jconrel

Review

nab-Paclitaxel mechanisms of action and delivery

Denise A. Yardley ⁎
Sarah Cannon Research Institute, 250 25th Avenue North, Suite 100, Nashville, TN 37203, USA

a r t i c l e i n f o a b s t r a c t

Article history: Taxanes are a key chemotherapy component for several malignancies, including metastatic breast cancer
Received 20 November 2012 (MBC), ovarian cancer, and advanced non-small cell lung cancer (NSCLC). Despite the clinical benefit
Accepted 16 May 2013 achieved with solvent-based (sb) taxanes, these agents can be associated with significant and severe toxic-
Available online 11 June 2013
ities. Albumin-bound paclitaxel (Abraxane; nab®-Paclitaxel), a novel solvent-free taxane, has demonstrated
higher response rates and improved tolerability when compared with solvent-based formulations in patients
Keywords:
nab-Paclitaxel
with advanced MBC and NSCLC. The technology used to create nab-paclitaxel utilizes albumin to deliver
Mechanism of action paclitaxel, resulting in an advantageous pharmacokinetic (PK) profile. This review discusses the proposed
Mechanism of delivery mechanism of delivery of nab-paclitaxel, including an examination into a hypothesized greater ability to
Taxane leverage albumin-based transport relative to sb-paclitaxel. An advantageous PK profile and the more efficient
Cancer use of albumin-based transport may contribute to the preclinical finding that nab-paclitaxel achieves a 33%
higher tumor uptake relative to sb-paclitaxel. Another possible contributing factor to the tumor accumulation
of nab-paclitaxel is the binding of albumin to secreted protein acidic and rich in cysteine (SPARC), although
the data supporting this relationship between SPARC and nab-paclitaxel remain largely correlative at this
point. Recent data also suggest that nab-paclitaxel may enhance tumor accumulation of gemcitabine in pan-
creatic cancer treated with both agents. Additionally, a possible mechanistic synergy between nab-paclitaxel
and capecitabine has been cited as the rationale to combine the two agents for MBC treatment. Thus,
nab-paclitaxel appears to interact with tumors in a number of interesting, but not fully understood, ways.
Continued preclinical and clinical research across a range of tumor types is warranted to answer the
questions that remain on the mechanisms of delivery and antitumor activity of nab-paclitaxel.
© 2013 Elsevier B.V. All rights reserved.

Contents

1. Taxanes: an introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365

2. The development of nab-paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
3. Mechanism of delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
4. Tumor accumulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
5. Clinical experience with nab-paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Disclosure statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370

1. Taxanes: an introduction breakthrough for the treatment of a wide range of cancers. The
first publication on the isolation of Taxol from the extracts of Pacific
Taxane development over the past 40 years, from the isolation of yew trees took place in 1971 [1]. Subsequent work to understand the
paclitaxel to the development of next-generation taxanes, such as antileukemic and tumor inhibitory properties of paclitaxel established
albumin-bound paclitaxel (nab-paclitaxel), has served as a major the agent's mechanism of action of as an inhibitor of mitosis [2,3]. Pac-
litaxel was found to inhibit the depolymerization of microtubules, a
process necessary for normal cell division [2–4]. Specifically, microtu-
⁎ Tel.: +1 615 329 7272. bule stabilization blocks cells in G2 and M phases of the cell cycle
E-mail address: dyardley@tnonc.com. resulting in cell death [4]. This effect on cells undergoing mitosis likely

0168-3659/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jconrel.2013.05.041
366 D.A. Yardley / Journal of Controlled Release 170 (2013) 365–372

explains the selectivity of paclitaxel for proliferating cells over quiescent
cells.
Difficulties with formulation slowed the clinical development of
paclitaxel. A key component of this challenge was the high insolubility
of paclitaxel in water [5,6]. However, after an exhaustive search for
excipients that could allow parenteral administration, researchers
considered the most viable option to be a castor oil derivative known
as Cremophor® EL (BASF SE) [5]. The current formulation of paclitaxel
solubilizes paclitaxel in a 1:1 solution of Cremophor EL and dehydrated
ethanol to arrive at solvent-based (sb-) paclitaxel (Taxol®, Bristol-
Myers Squibb) [5]. Docetaxel, a semisynthetic analogue of paclitaxel
shares a similar mechanism of action and is also highly insoluble; the
current clinical formulation of docetaxel uses polysorbate 80 (Tween®
80, Sigma-Aldrich) to allow administration [5,7].
Encouraging results from a number of clinical trials has led to the
approvals of sb-paclitaxel and docetaxel as a treatment component in
numerous cancer types [7,8]. Taxanes are now considered a corner-
stone of therapy for many disease states, in part due to the results
of trials showing that superior clinical benefit with respect to overall
response rate (ORR), progression-free survival (PFS), and overall
survival (OS) can be achieved with taxane-based therapy [9–15].
2. The development of nab-paclitaxel
While the development of docetaxel led to promising efficacy
results relative to sb-paclitaxel in a phase III metastatic breast cancer
(MBC) trial (both agents delivered once every 3 weeks [q3w]) [16],
the less favorable toxicity profile of docetaxel—(significantly higher
rates of grade ≥ 3 neutropenia, febrile neutropenia, asthenia, periph-
eral edema, sensory neuropathy, nausea, stomatitis, diarrhea, infec-
tion, motor neuropathy, skin disorders, and vomiting)—suggested
that the need to improve taxane-based therapy had not been entirely
met. Indeed, both sb-paclitaxel and docetaxel are associated with
a number of adverse events, including hypersensitivity reactions,
peripheral neuropathy, and neutropenia (Table 1) [7,8,16]. Weekly
sb-paclitaxel has emerged as the preferred schedule because of the
OS advantage and lower incidence of serious toxicity compared
with q3w in patients with MBC [17]. However, neurotoxicity remains
an important treatment-limiting toxicity for weekly paclitaxel [18]. In
a phase III trial, the weekly schedule of sb-paclitaxel resulted in a sig-
nificantly higher rate of grade 3 neuropathy compared with the q3w
schedule (Table 2; 24% vs. 12%; p = 0.0003) [18]. The solvents used in
the commercial formulations of both sb-paclitaxel and docetaxel can
increase the risk for both hypersensitivity and peripheral neuropathy
Table 1
Toxicities and treatment exposure of sb-paclitaxel and docetaxel in a head-to-head
single-agent trial of greater than first-line MBC [16].
sb-Paclitaxel Docetaxel p value
175 mg/m2 q3w 100 mg/m2 q3w
(n = 222) (n = 222)
Grade ≥3 adverse events occurring in ≥10% of patients in either arm, n (%)a
Neutropenia 121 (54.5) 207 (93.2) b0.0001
Febrile neutropenia 4 (1.8) 33 (14.9) b0.001
Anemia 16 (7.2) 23 (10.4) NS
Asthenia 11 (5.0) 46 (20.7) b0.001
Stomatitis 0 24 (10.8) b0.001
in some patients [5]. Because of the risk of hypersensitivity, patients
receiving either sb-paclitaxel or docetaxel are pretreated with corti-
costeroids, and patients receiving sb-paclitaxel are also routinely
pretreated with antihistamines [7,8].
nab-Paclitaxel was initially developed to avoid the toxicities typi-
cally associated with Cremophor EL in sb-paclitaxel [19]. In contrast
to sb-paclitaxel and docetaxel, nab-paclitaxel does not utilize non-
ionic surfactants to solubilize paclitaxel, which are known to con-
tribute to toxicity and entrap paclitaxel within solvent based
micelles [5]. nab-Paclitaxel is formulated with human serum albu-
min at a concentration similar to the concentration of albumin in
the blood [20]. Formulation of nab-paclitaxel takes place through
high-pressure homogenization in which albumin and paclitaxel are
combined to create particles with a mean diameter of 130 nm
[20,21]. This process does not covalently link albumin to paclitaxel
[22]. Upon injection, the nab-paclitaxel particles dissolve into sol-
uble albumin–paclitaxel complexes, and paclitaxel may bind and
unbind albumin (injected or endogenous) or other biomolecules,
or it may exist in a free/unbound state (see Mechanism of
Delivery section) [21,23]. Formulation with albumin allows nab-
paclitaxel to be reconstituted with a simple saline solution [21].
As such, nab-paclitaxel is administered without steroid or antihis-
tamine prophylaxis for hypersensitivity reactions [21]. Perhaps
because nab-paclitaxel delivery is not complicated by solvents, a
higher dose can be administered relative to sb-paclitaxel. In a
pivotal phase III MBC trial of nab-paclitaxel and sb-paclitaxel at
the label-indicated doses as ≥ first-line therapy in patients with
MBC, the dose of paclitaxel delivered was 49% higher for patients
receiving nab-paclitaxel vs sb-paclitaxel, suggesting that higher
dose intensity is feasible with nab-paclitaxel [19].
3. Mechanism of delivery
Classic thought on drug distribution holds that the free, or un-
bound, fraction of drug is the active fraction because drug bound to
proteins or other macromolecules might be unable to cross cell
membranes [24]. In clinical studies, sb-paclitaxel has been shown to
be highly protein bound in plasma, with Cremophor EL further
decreasing the free/unbound fraction of drug [24,25]. To examine
the effect that formulation has on the pharmacokinetics (PK) of pac-
litaxel, a randomized crossover PK study was carried out in patients
with cancer receiving either sb-paclitaxel at 175 mg/m2 q3w over
a 3-hour infusion or nab-paclitaxel at 260 mg/m2 q3w over a
30-minute infusion [23]. In this study, mass spectrometry was used
to identify whether circulating paclitaxel was free/unbound or not.
In this report, paclitaxel associated with Cremophor EL would not
have been identified as unbound drug. The key finding of the study
was that the formulation of nab-paclitaxel allowed a much higher frac-
tion of unbound paclitaxel for nab-paclitaxel vs. sb-paclitaxel (6.3% vs.
2.4%, p b 0.001). Furthermore, the maximal concentration of unbound
Table 2
Toxicities of sb-paclitaxel delivered weekly or q3w in a head-to-head trial of first-line
MBC [18].
Most frequent grade ≥3 sb-Paclitaxel q3w sb-Paclitaxel qw p value
adverse events occurring 175 mg/m2 80 mg/m2
in either arm, %a (n = 225)b (n = 346)b

Treatment exposure Leukopenia 9 8 NR

Treatment cycles received, 4 (35) 6 (32) NR Granulocytopenia 15 8 .017
median (maximum) Lymphopenia 12 19 NR
Relative dose intensity, 1 (0.72–1.00) 1 (0.62–1.00) NR Sensory neuropathyc 12 24 .0003
median (range)
NR, not reported.
Discontinuation due to 8 26 0.001 a
Adverse event data were listed only for the patients accrued to CALGB 9840, not
adverse events, %
the combined population that included patients combined from trial CALGB 9342.
b
NR, not reported. The paper lists these numbers as the limited set, which was the set evaluated for
a
Grade ≥3 sensory neuropathy occurred in 9 (4.1%) and 16 (7.2%) patients in the safety.
c
sb-paclitaxel and docetaxel arms, respectively. All cases were grade 3.
 D.A. Yardley / Journal of Controlled Release 170 (2013) 365–372
paclitaxel was about 10-fold higher for nab-paclitaxel (1284 ng/mL vs.
122 ng/mL, p b 0.000001), and the systemic exposure (AUCINF) of
unbound paclitaxel was about 3-fold higher for nab-paclitaxel
(1159 h*ng/mL vs. 410 h*ng/mL, p b 0.000005). A likely explanation
for these differences lies in the entrapment of paclitaxel in Cremophor
EL-based micelles in the solvent-based formulation of paclitaxel
[24,26,27]. Consistent with the effect of micellar entrapment on pacli-
taxel distribution, Sparreboom et al. found that nab-paclitaxel achieves
a higher plasma clearance and a larger volume of distribution vs.
sb-paclitaxel in preclinical studies [28]. It has been suggested that
micellar entrapment could affect the PK linearity of sb-paclitaxel
[24,26]. Table 3 lists selected PK studies on sb-paclitaxel and nab-
paclitaxel and gives the authors' characterizations of PK linearity for
the two agents [21,24,26,29–31].
Although investigations into the distribution of unbound drug are
important, it is also critical to consider that in human blood, paclitaxel
is highly bound to proteins and other biomolecules. As stated previ-
ously, Kumar et al. demonstrated that when sb-paclitaxel is adminis-
tered to humans, approximately 95% of paclitaxel binds to other
molecules [25]. Albumin and alpha-1-acid glycoprotein contributed
equally to this binding, with a minor fraction of paclitaxel bound to li-
poproteins. Furthermore, albumin is known to be a ubiquitous carrier
of biomolecules in the blood [32], which prompts the consideration of
how albumin may influence the transport of nab-paclitaxel to tumors.
Circulating albumin must cross endothelial cells to reach tumors, and
albumin has been reported to accomplish this in at least 2 ways
(Fig. 1): receptor-mediated transcytosis and the enhanced perme-
ation and retention (EPR) effect [33–36]. It has been hypothesized
that nab-paclitaxel may take advantage of each of these mechanisms
to reach the tumor microenvironment [37,38].
To initiate transcytosis, albumin binds to an albumin-specific re-
ceptor, such as glycoprotein 60 (gp60). This effects a process of cell
membrane invagination to form vesicles, which are then transported
through the endothelial cell before fusing with the membrane of the
other side of the cell thereby releasing the vesicle contents to the
interstitial space [33,34].
Experiments designed to characterize the level of transport of nab-
paclitaxel vs sb-paclitaxel across a layer of endothelial cells in culture
found that more than 4-fold more nab-paclitaxel was transported
across the cells compared with sb-paclitaxel (Fig. 2) [37]. Furthermore,
a mixture of Cremophor EL and ethanol well below clinically relevant
levels inhibited the binding of paclitaxel to both albumin and endothe-
lial cells. This suggests that Cremophor EL may hinder the capacity of
paclitaxel to use albumin-based transport mechanisms to the tumor
microenvironment (Fig. 2).
The EPR effect posits that the vasculature around tumors is leaky,
allowing molecules below a certain size to escape the circulation through
gaps between endothelial cells [35,36]. The second facet of the EPR effect
is that lymphatic drainage to return leaked molecules to the circulatory
system is compromised around tumors, leading to the collection of
molecules such as albumin in the tumor microenvironment.
Considering the effects of formulation on unbound drug concentra-
tion and albumin-bound drug, it appears that nab-paclitaxel holds 2
biodistribution advantages over sb-paclitaxel. First, it results in a greater
fraction of unbound paclitaxel; second, it may result in a higher fraction
Table 3
Pharmacokinetic linearity of sb-paclitaxel and nab-paclitaxel.
Primary author Year of publication sb-Paclitaxel nab-Paclitaxel
Gianni 1995 Not linear NA
Van Tellingen 1999 Not linear NA
Brouwer 2000 Not linear NA
Gelderblom 2002 Linear 3-compartment NA
Ibrahim 2002 NA Linear
Nyman 2005 NA Linear
367
of albumin-bound paclitaxel, which may explain the greater efficiency
of transcytosis across endothelial cells [23,37].
4. Tumor accumulation
Studies have shown that a large fraction of injected albumin-
conjugated molecules accumulate in proximity to tumors [39,40]. As
discussed above, albumin may reach tumors by receptor-mediated
transport mechanisms or by the EPR effect. It has been hypothesized
that cancer cells may consume albumin from the tumor microenvi-
ronment and then metabolize it, possibly enhancing tumor growth
[22,41]. Desai et al. conducted experiments in mice bearing xenograft
tumors from injected human breast cancer cells to determine wheth-
er formulation played a role in the tumor uptake of paclitaxel [37]. In
these experiments, paclitaxel in both formulations was radioactively
labeled and the amount of labeled paclitaxel that eventually reached
tumors was quantified. When equal amounts were injected, the re-
searchers found that a third more paclitaxel from the nab-paclitaxel
formulation was taken up by tumors. The authors suggested that nab-
paclitaxel reached a higher tumor accumulation vs. sb-paclitaxel due
to both the lack of drug-sequestering solvent micelles and enhanced
albumin-mediated transcytosis. A subsequent report of similar experi-
ments suggested that nab-paclitaxel may achieve some degree of tumor
selectivity relative to sb-paclitaxel, although the mechanisms responsi-
ble for this possibility were not characterized [42].
Another molecular mechanism proposed to play a potential role in
the tumor accumulation of nab-paclitaxel is the prevalence of albumin-
binding proteins such as secreted protein acidic and rich in cysteine
(SPARC) in proximity to tumors [38]. According to this theory, proteins
such as SPARC may exist at higher-than-normal levels in the tumor
interstitium. Thus, these proteins could sequester paclitaxel bound to al-
bumin in tumors at levels higher than those in healthy tissues. High
SPARC expression correlates with disease progression across a range of
tumor types [43–56]; however, some clinical data have suggested a
correlation between SPARC expression in the tumor and/or tumor
microenvironment and positive clinical outcomes in patients receiv-
ing nab-paclitaxel [38,57–59]. Other studies have failed to show
such a correlation [60,61]. Thus, further studies delineating the molecu-
lar relationship between SPARC and nab-paclitaxel are warranted.
In a phase I/II advanced pancreatic cancer trial, Von Hoff et al.
reported promising efficacy of nab-paclitaxel plus gemcitabine in the
form of an ORR of 48% and a median OS of 12.2 months [57]. An analysis
of the relationship between median OS and SPARC expression found
that patients with high SPARC expression demonstrated a median OS
of 17.8 months, whereas patients with low SPARC expression had a
median OS of 8.1 months (p = 0.0431). The activity of nab-paclitaxel
plus gemcitabine was further evaluated in preclinical studies reported
alongside the clinical findings described above [57]. These experiments
were carried out in mice bearing xenograft tumors of human pancreatic
cancer origin. A 2.8-fold enrichment of gemcitabine in xenograft tumors
was conferred by combination treatment with nab-paclitaxel relative to
tumors in mice treated with gemcitabine only. The authors postulated
that at least one underlying mechanism for this effect was that nab-
paclitaxel may have depleted the stromal barrier in the tumor microen-
vironment and thus augmented circulation to the tumor, thereby
allowing gemcitabine greater access to tumors. In further support of
this were the observations of decreased numbers of collagen fibers
and an approximate 3-fold increase in the staining for mNestin, a marker
of endothelial cells. However, the exact mechanism by which nab-
paclitaxel leads to this stromal reduction remains unclear. To date,
experiments to test the effect of sb-paclitaxel on tumor stroma have
not been performed.
A separate preclinical study investigating the mechanisms of
antitumor activity of nab-paclitaxel plus gemcitabine in pancreatic
tumors used a different experimental paradigm than the aforemen-
tioned Von Hoff et al. study [62]. This study used a genetically
368 D.A. Yardley / Journal of Controlled Release 170 (2013) 365–372
Fig. 1. Two routes of albumin to reach tumors. The left half of the figure shows albumin
metabolism of a growing tumor, whereas the right half reflects the cytotoxic effect on
tumor cells from the uptake of albumin-bound paclitaxel. Albumin and albumin-bound
paclitaxel are hypothesized to reach the tumor interstitium by both transcytosis and
the EPR effect.
engineered mouse model of pancreatic cancer that replicates the
molecular and clinical features of the disease, including resistance to
gemcitabine. The study demonstrated that combination treatment
with nab-paclitaxel and gemcitabine resulted in significantly smaller
tumors compared with gemcitabine alone. Additionally, the study
showed an enhancement of gemcitabine levels in tumors conferred
by the addition of nab-paclitaxel to gemcitabine similar to the effect
seen in the Von Hoff et al. study described above [57]. However, a
different mechanism was ascribed to account for the higher tumor
levels of gemcitabine: a downregulation by nab-paclitaxel of the
gemcitabine-metabolizing enzyme cytidine deaminase (CDA) rather
than a nab-paclitaxel-specific effect on tumor stroma. The authors
found that exposure to paclitaxel leads to the production of reactive
oxygen species (ROS), which in turn destabilize CDA, thus preventing
the breakdown of gemcitabine in cancer cells (Fig. 3). The key role of
ROS in this process was demonstrated by an experiment in which an
ROS scavenger, N-acetylcysteine (NAC), negated the ability of
paclitaxel to stabilize gemcitabine. The authors also noted that the
tolerability of nab-paclitaxel allows a dose sufficient to induce
synergistic activity with gemcitabine. Because mice cannot tolerate
doses of sb-paclitaxel as high as those of nab-paclitaxel [37], it is
unclear whether sb-paclitaxel could achieve the same degree of
combinatorial activity with gemcitabine in this experimental para-
digm as nab-paclitaxel.
A recently completed phase III study in the metastatic setting
(ClinicalTrials.gov trial number NCT00844649) [57] and an ongoing
pilot study in the neoadjuvant setting [63], both evaluating the
combination of nab-paclitaxel plus gemcitabine, may provide further
insight into these hypotheses. A press release on the results of the
phase III metastatic pancreatic cancer trial announced that the study
met its primary endpoint by demonstrating a significantly longer median
overall survival for nab-paclitaxel plus gemcitabine vs gemcitabine alone
[64]. Detailed analyses from that trial may shed light toward the mecha-
nism(s) by which nab-paclitaxel leads to higher tumor levels of
gemcitabine. In the neoadjuvant trial alluded to above [63], tumor
samples are being collected, which will allow an assessment of
nab-paclitaxel-induced effects on tumor stroma. Preliminary results
(n = 10 evaluable pancreatic adenocarcinoma samples) have sug-
gested that treatment with 2 cycles of nab-paclitaxel 125 mg/m2
plus gemcitabine 1000 mg/m2 qw 3/4 led to disruption of the tumor
stroma as revealed by less abundant collagen fibers around tumors.
Final results of this trial may help to answer whether the nab-
paclitaxel-induced stromal depletion seen in xenograft mouse models
also occurs in humans with pancreatic cancer [57,63].
Similar to the synergistic effect postulated above for nab-paclitaxel
and gemcitabine in pancreatic cancer, accumulating evidence suggests
that taxanes may also alter tumor physiology in a way that enhances
the activity of capecitabine treatment. To achieve antitumor activity,
capecitabine must be converted to the active fluoropyrimidine
5-fluorouracil by three enzymes located in the liver and directly in
the tumors [65,66]. The last enzyme to act in this process, known
as thymidine phosphorylase, has been shown to be preferentially
expressed at higher levels in some tumors than in the surrounding
normal tissues [67]. Furthermore, preclinical and clinical studies
have shown that taxane treatment may increase levels of this en-
zyme, suggesting a biological rationale for combining taxanes with
capecitabine [68–70]. This mechanistic synergy together with
nab-paclitaxel clinical data suggesting efficacy and tolerability ad-
vantages over sb-paclitaxel, led Schwartzberg et al. to examine the
combination therapy of nab-paclitaxel with capecitabine in a phase
II MBC study [66]. The trial reported encouraging efficacy findings,
including a response rate of 61%; however, data on nab-paclitaxel's
effect on levels of thymidine phosphorylase were not reported.
5. Clinical experience with nab-paclitaxel
The unique properties of nab-paclitaxel described in this review may
account for the differences seen in the efficacy and safety profiles vs. the
solvent-based taxanes sb-paclitaxel and docetaxel [19,71]. For example,
in a phase III MBC trial, patients receiving nab-paclitaxel exhibited
a higher ORR (33% vs. 19%, p = 0.001) and a longer time to tumor
progression (23.0 vs. 16.9 weeks, hazard ratio = 0.75, p = 0.006)
compared with those receiving sb-paclitaxel (Table 4) [19]. As for toler-
ability (Table 5) in this trial, patients receiving nab-paclitaxel had a
lower rate of grade 4 neutropenia (9% vs. 22%, p b 0.001) and a higher
rate of grade 3 sensory neuropathy (10% vs. 2%, p b 0.001). The median
time to improvement of grade 3 sensory neuropathy to grade ≤ 2 was
numerically shorter for nab-paclitaxel (22 vs. 79 days) [72].
The results of a phase III trial comparing nab-paclitaxel plus
carboplatin vs. sb-paclitaxel plus carboplatin for the first-line treat-
ment of advanced non-small cell lung cancer (NSCLC) have recently
been published (Tables 4 and 5) [73]. The positive findings for nab-
paclitaxel plus carboplatin led to FDA approval of the combination
as first-line treatment for patients with locally advanced or meta-
static NSCLC who are not candidates for curative surgery or radiation
therapy [21]. The nab-paclitaxel plus carboplatin group demonstrat-
ed a significantly higher ORR in the intent-to-treat population (33%
vs. 25%, p = 0.005) and trends toward both a longer progression-
free survival (PFS; 6.3 vs. 5.8 months, p = 0.214) and OS (12.1 vs.
11.2 months, p = 0.271). Patients in the nab-paclitaxel arm
experienced less grade ≥ 3 neuropathy, neutropenia, arthralgia,
and myalgia but higher rates of thrombocytopenia and anemia. In-
terestingly, the difference in ORR in patients with squamous histol-
ogy (41% vs. 24%, p b 0.001) was higher than in the intent-to-treat
population, suggesting that squamous cell non-small cell lung cancer
may be more responsive to treatment with a nab-paclitaxel-based
regimen. This intriguing finding warrants further examination in
mechanistic studies and clinical trials.
Phase III trials on nab-paclitaxel were recently completed in pancre-
atic cancer and melanoma, disease states in which taxane-based treat-
ments have not traditionally demonstrated sufficient activity for label
 D.A. Yardley / Journal of Controlled Release 170 (2013) 365–372
Fig. 2. nab-Paclitaxel and albumin-mediated transport (adapted from Desai et al. 2006
[37]). A, Increasing concentrations of Cremophor EL/ethanol inhibit the ability of paclitaxel
to bind to albumin. B, nab-Paclitaxel achieves a 4-fold higher degree of transcytosis across
endothelial cells compared with sb-paclitaxel.
Reprinted from Clinical Cancer Research, 2006, 12/4, 1317–1324, Desai, N, et al., Increased
antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of
cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based
paclitaxel, with permission from AACR.
indications. These studies were predicated on nab-paclitaxel-based
phase II studies that showed promising results in both of these cancer
types [57,74], suggesting again something unique about how nab-
paclitaxel vs. the other taxanes may be interacting with these tumors.
In addition, growing evidence support not only the activity but also
the feasibility of nab-paclitaxel in the neoadjuvant as well as adjuvant
treatment of breast cancer [60,75–77].
6. Conclusions
nab-Paclitaxel was developed in the wake of clinical data showing
promising efficacy but less than ideal safety profiles for the taxanes
sb-paclitaxel and docetaxel. Its formulation without solvents allows
nab-paclitaxel to avoid the toxicities associated with the excipients
in the current commercial formulations of sb-paclitaxel and docetaxel
that may limit the ability to deliver these agents [5]. Thus, nab-
paclitaxel represents a taxane option that may provide clinical benefit
combined with a reasonable toxicity profile.
In addition to facilitating an advantageous therapeutic index, nab-
paclitaxel may also afford a benefit in terms of pharmacokinetic
profile. Specifically, nab-paclitaxel has demonstrated a larger volume
of distribution, more rapid clearance, a higher fraction of unbound drug,
and higher systemic exposures and maximal concentrations of unbound
drug relative to sb-paclitaxel [23,28]. Because its drug delivery is not com-
plicated by drug entrapment in solvent micelles, nab-paclitaxel continues
to demonstrate pharmacokinetic advantages relative to sb-paclitaxel
[23,28].
While preclinical experiments suggest that nab-paclitaxel achieves a
higher uptake by tumors vs. sb-paclitaxel [37], which may be explained
by the pharmacokinetic advantages described above, it is also possible
369
Fig. 3. Paclitaxel destabilizes CDA via ROS in cultured pancreatic cancer cells (adapted
from Frese et al. [62]). KPC cells were pretreated with paclitaxel (P) and/or NAC and
(A) incubated with CM-H2DCFDA to assess intracellular ROS via flow cytometry
(n = 3). B, protein lysates were generated from KPC cells treated for 36 h with
10 μmol/L P and/or 5 mmol/L NAC and immunoblotted for indicated proteins. C, KPC
cells were pretreated with 10 μmol/L P and/or 5 mmol/L NAC for 36 h and incubated
with 1 μmol/L gemcitabine for 1 h. Intracellular dFdCTP was measured (n = 3).
Reprinted from Cancer Discovery, 2012, 2/3, Frese KK, et al., nab-Paclitaxel Potentiates
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that nab-paclitaxel is more able to take advantage of the normal trans-
port properties of albumin than the other taxanes. Specifically, albumin
has been shown to accumulate in tumors by means of the EPR effect
[35,36], and albumin is also thought to cross endothelial cells by
receptor-mediated transcytosis [33,34]. Supporting the idea that
nab-paclitaxel may leverage endothelial cell transcytosis to reach
the tumor interstitium, in vitro experiments have shown that nab-
paclitaxel is 4-fold more efficient than sb-paclitaxel at crossing layers
of endothelial cells [37]. It is thought that tumors may take in albumin
as a source of nutrients [22,40,41], possibly explaining how albumin-
bound drugs appear to be optimized to reach tumors (Fig. 1).
Much research remains to be done to fully understand how
the unique formulation of nab-paclitaxel may allow it to interact
differently with tumors. For example, although some correlative
clinical data suggest that SPARC may play a role in the function of
nab-paclitaxel [38,57,59], further research will be required to shed
light as to how this occurs. Another example that emphasizes this
need for more mechanistic research is the differing proposals from
two separate research groups to explain the shared finding that
370 D.A. Yardley / Journal of Controlled Release 170 (2013) 365–372

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