Nanomedicinal Strategies To Treat Multidrug-Resistant Tumors: Current Progress

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Nanomedicinal strategies to treat

multidrug-resistant tumors: current progress
Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. P-glycoprotein
is an important and the best-known membrane transporter involved in MDR. Several strategies have been
used to address MDR, especially P-glycoprotein-mediated drug resistance in tumors. However, clinical
success has been limited, largely due to issues regarding lack of efficacy and/or safety. Nanoparticles have
shown the ability to target tumors based on their unique physical and biological properties. To date,
nanoparticles have been investigated primarily to address P-glycoprotein and the observed improved
anticancer efficacy suggests that nanomedicinal strategies provide a new opportunity to overcome MDR.
This article focuses on nanotechnology-based formulations and current nanomedicine approaches to
address MDR in tumors and discusses the proposed mechanisms of action.
KEYWORDS: Brij n drug delivery n efflux transporters n lipid formulation Xiaowei Dong1,2
n nanoparticle n P-glycoprotein n Pluronic n vitamin E TPGS & Russell J Mumper†3
1
Department of Pharmaceutical
Sciences, College of Pharmacy,
Cancer is a leading cause of death worldwide, evade chemotherapy. For example, multidrug University of Kentucky, Lexington,
accounting for 7.9 million deaths in 2007 [201] . resistance (MDR), a term to describe the broad- KY 40536-0082, USA
2
Pharmaceutical & Analytical
Over 85% of human cancers are solid tumors. spectrum resistance to chemotherapy in human Department, Novartis Pharmaceutical
Surgery and radiation are the initial treatments cancer, is one of the most important problems Corporation, East Hanover,
NJ 07936-1080, USA
for most cancers. Chemotherapy with cytotoxic in chemotherapy. MDR is the phenomenon in 3
UNC Lineberger Comprehensive
agents is used as an adjuvant therapy or a single- which exposure of tumor cells to a single cyto- Cancer Center, UNC-Chapel Hill, Chapel
agent therapy especially for the management of toxic agent accounts for cross-resistance to other Hill, NC 27599-7295, USA
†
Author for correspondence:
recurrent disease.��
There are a number of che- structurally unrelated classes of cytotoxic agents. Division of Molecular Pharmaceutics,
motherapeutic agents with established first- ATP-binding cassette (ABC) transporters are Center for Nanotechnology in Drug
Delivery, UNC Eshelman School of
line��
activity against cancer, with the anthracy- transmembrane proteins that utilize the energy Pharmacy, 1044 Genetic Medicine
clines [1] and taxanes [2] generally considered the of ATP hydrolysis to shuttle various substrates Building, CB 7362, 120 Mason Farm
most active. The relative benefits and toxicities across the cell membrane. Normally, ABC trans- Road, University of North Carolina
at Chapel Hill, Chapel Hill,
of individual anticancer agents or combinations porters function as pumps that extrude toxins NC 27599-7362, USA
must be considered, as well as the treatment his- and drugs out of the cell. To date, there are Tel.: +1 919 966 1271
Fax: +1 919 843 1232
tory and clinical status of the patient. Toxicity is approximately 49 known transporters in the [email protected]
one of the most critical issues in chemotherapy ABC family that are classified into seven dif-
since most anticancer agents lack selective effi- ferent families (ABC A through ABC G) [3,4] .
cacy in cancer tissue. Another problem with However, not all have been shown to have a
conventional chemotherapy pertains to the chal- role in MDR. Table 1 provides a summary of the
lenge of delivery. The effectiveness of cancer che- most pertinent MDR-related ABC transport-
motherapy in solid tumors depends on adequate ers and their most studied drug substrates [5] .
delivery of therapeutic agents to tumor cells. P-glycoprotein (P‑gp) is one of the most well-
The biological properties of the solid tumor, described ABC transporters and is overexpressed
which limit the penetration of drugs into neo- in the plasma membrane of MDR tumor cells.
plastic cells distant from tumor vessels, include P‑gp is capable of effluxing various anticancer
abnormal and heterogeneous tumor vasculature, drugs, such as doxorubicin and paclitaxel, out of
interstitium, interstitial fluid pressure (IFP) and the cells. P‑gp inhibitors (e.g., verapamil) have
cell density. However, even if anticancer drugs been developed to overcome P‑gp-mediated
are located in the tumor interstitium, they can MDR. However, some P‑gp inhibitors do not
have limited efficacy because cancer cells are have good selectivity and also block normal cell
able to develop mechanisms of resistance. Drug function of P‑gp, for example, in the intestines or
resistance has emerged as a major obstacle limit- at the blood–brain barrier (BBB), and therefore
ing the therapeutic efficacy of chemotherapeu- increase toxicity. A refinement of this concept is
tic agents. These mechanisms allow tumors to the incorporation of both the therapeutic drug
10.2217/NNM.10.35 © 2010 Future Medicine Ltd Nanomedicine (2010) 5(4), 597–615 ISSN 1743-5889 597
Review Dong & Mumper
Table 1. Multidrug resistance-related ATP-binding cassette transporters and their substrates.

Subfamily Genes Established anticancer drugs Published target Ref.
for nanomedicine?
ABC1 ABC A2/ABC2/STGD Estramustine, mitoxantrone No
ABCA3/ABC3 Daunorubicin, Ara-C, mitoxantrone No
and etoposide
MDR/TAP ABC B1/MDR1/P-GP/ Anthracyclines, vinca alkaloids, taxanes, Yes [113–117,122–124,
PGY1 etoposide, teniposide, imatinib, irinotecan, 127–132,
SN-38, bisantrene, colchicines, methotrexate, 137–139,141,
mitoxantrone, saquinivir, actinomycin D 143–145,152–154]
and others
ABC B4/MDR3/PFIC3/ Daunorubicin, doxorubicin, vincristine, No
PGY3 etoposide and mitoxantrone
ABC B5 Doxorubicin, camptothecin, 10-OH No
camptothecin and 5-FU
ABC B11/BSEP/PFIC2/ Paclitaxel No
SPGP
CFTR/MRP ABC C1/MRP1 Anthracyclines, vinca alkaloids, methotrexate, Yes [53]
antifolate antineoplastic agents, etoposide,
imatinib, irinotecan, SN‑38, arsenite, colchicine,
mitoxantrone, saquinivir and others
ABC C2/MRP2/CMOAT Vinca alkaloids, cisplatin, etoposide, No
doxorubicin, epirubicin, metotrexatetaxanes,
irinotecan, SN‑38, topotecan, arsenite,
mitoxantrone and saquinivir
ABC C3/MRP3/ Etoposide, tenoposide and metotrexate No
CMOAT2
ABC C4/MRP4/MOATB 6‑mercaptopurine, 6‑thioguanine, irinotecan, No
SN‑38, topotecan, AZT, metotrexate and PMEA
ABC C5/MRP5/MOATC 6‑mercaptopurine, 6‑thioguanine, irinotecan, No
5‑FU, cisplatin, AZT, metotrexate and PMEA
ABC C6/MRP6/ Etoposide, doxorubicin, daunorubicin, No
MOATE/PXE teniposide and cisplatin
ABC C10/MRP7 Taxanes and vinca-alkaloids No
ABC C11/MRP8 6‑mercaptopurine, 5‑FU and PMEA No
WHITE ABC G2/BCRP/MXR/ Mitoxantrone, camptothecin, anthracycline, No
ABCP etoposide, teniposide imatinib, flavopiridol,
bisantrene, methotrexate, AZT and others
5-FU: 5-fluorouracil; ABC: ATP-binding cassette; AZT: 3’-azido-2’,3’-deoxythymidine; CTFR: Cystic fibrosis transmembrane regulator; MDR: Multidrug resistance;
MRP: Multidrug resistance protein; PMEA: 9-(2-phosphonylmethoxyethyl)adenine; TAP: Transporter associated with antigen presentation.
Adapted from [5].
and the P‑gp inhibiting agent into the same drug the tumor interstitium is also characterized by
carriers (e.g., nanoparticles) for simultaneous the absence of an anatomically well-defined
delivery into the cell. functioning lymphatic network. Therefore,
Nanoparticles have been developed to the clearance of nanoparticles via lymphatics
enhance the intracellular concentration of drugs is generally seriously compromised in neoplas-
in cancer cells while avoiding toxicity in nor- tic tissues, so that an additional retention of
mal cells using both passive and active target- nanoparticles in the tumor interstitium has
ing. The nanosize particles can pass through been observed. This particular concept known
leaky and hyperpermeable tumor vasculature as the EPR effect results in intratumoral drug
and accumulate in the tumor vicinity utilizing accumulation, which is even higher than that
the enhanced permeability and retention (EPR) observed in plasma and other tissues. In addi-
effect. Moreover, vascular permeability-enhanc- tion to passive targeting by the EPR effect,
ing factors, such as bradykimin, nitric oxide active targeting may also be pursued by tar-
and VEGF, facilitate extravasation of macro- geting nanoparticles with a tumor cell-specific
molecular drugs within tumor tissues, as well ligand. More importantly, it has been suggested
as surrounding normal tissues. Furthermore, that nanoparticles may be able to circumvent
598 Nanomedicine (2010) 5(4) future science group

Nanomedicinal strategies to treat multidrug-resistant tumors: current progress Review
P‑gp-mediated resistance. The mechanisms gradient from the vascular compartment to
of carriers to overcome P‑gp have been pro- interstitial space of tumors [15] . Furthermore,
posed based on various drug delivery systems, uniform elevation of IFP results in a negligible
including N‑(2-hydroxypropyl)methacrylamide flow inside tumors [16] . Thus, the uniformly
(HPMA) drug conjugates, Pluronic® micelles, elevated IFP impedes the delivery of therapeu-
hybrid lipid nanoparticles, lipid-based nano- tic drugs across both the blood vessel wall and
capsules and nanoparticles, liposomes and interstitium in solid tumors. Studies have dem-
cyanoacrylate-type nanoparticles. Reported onstrated that there are no functional lymphatic
mechanisms included enhancement of cellular vessels inside solid tumors [17–19] . Functional
uptake of drug via endocytosis and ion-pair lymphatic vessels are present in the tumor mar-
formation, ATP depletion, influence of func- gin and the peritumoral tissue to mediate tumor
tion and expression of P‑gp, and change of P‑gp growth and metastases. The lack of lymphat-
downstream signaling pathways. ics in tumors reduces the effective outflow of
interstitial fluid, partially contributing to the
Barriers in chemotherapy for the increase of tumor IFP. However, the positive
treatment of solid tumors aspect of the absence of lymphatics for drug
The development of therapeutic drugs against delivery is that drugs can not be drained out
cancer has been focused on finding innova- of tumors via the lymphatic system once they
tive approaches to selectively deliver anticancer locate inside tumors. Moreover, since a blood
drugs to solid tumors, while minimizing injury supply is crucial for growth, tumor cells have
to healthy tissues. However, the efforts are con- the ability to recruit new blood vessels in vari-
fronted by physiological barriers at the tumor ous ways through a process termed angiogenesis.
level and drug resistance at the cellular level. The fact that the survival of a tumor critically
Physiological characteristics of solid tumors depends on its blood supply provides a common
related to drug delivery include: abnormal blood opportunity for the destruction of solid tumors
vessel architecture and function; interstitial if drug concentrations in the bloodstream
fluid pressure, also known as interstitial hyper- remain high for an appropriate period.
tension; and lack of lymphatics [6,7] . Unlike Therapeutic drugs will face another major
normal microvessels, tumor vessels resulting barrier – drug resistance – after they penetrate
from angiogenesis are dilated, tortuous and het- in tumors. MDR remains the main cause of the
erogeneous in their spatial distribution [8–10] . failure of the use of conventional chemotherapy
The flow of blood through tumor vessels varies to treat common solid tumors [20] . Frequently,
according to tumor types and microenviron- resistance is intrinsic to the cancer, but as ther-
ment, so that the penetration of drugs in solid apy becomes more and more effective, acquired
tumors is difficult. The disorganized structure resistance has also become common. A variety
of solid tumors causes poor drug delivery to the of mechanisms contribute to acquired drug
central region in large tumors. Consequently, resistance to a broad range of anticancer drugs,
the microenvironment in solid tumors may also including: expression of one or more energy-
contribute to drug resistance by limiting drug dependent transporters that bind to and efflux
penetration, thereby exposing the tumor to lower anticancer drugs from cells, leading to insen-
than efficacious concentration [11] . Nonetheless, sitivity to drug-induced apoptosis [21] ; altered
large interendothelial junctions, increased num- targets; and induction of drug-detoxifying
bers of fenestrations and abnormal basement mechanisms [22] . A summary of the reported
membranes are often found in tumor vessels. mechanisms of drug resistance is presented in
The ‘leakiness’ of tumor vessels generates gap Figure 1. The initial MDR was reported in the late
openings that are significantly larger than those 1960s and early 1970s. Drug-resistant mamma-
observed in normal tissues [11–14] . This vascu- lian cell lines were then established for studying
lar permeability in solid tumors leads one to this phenomenon. A common feature of these
develop tumor-targeting carriers that are small drug-resistant cell lines was the overexpression
enough to enter through tumor vascular open- of P‑gp when compared with the drug-sensitive
ings, without passing through those in normal parent cell lines [23,24] . So far, overexpression of
tissues. The abnormal structure and function drug transporters is the most common reason
of blood and lymphatic vessels in solid tumors for MDR. P-gp is an important and best-known
cause IFP elevation whereas IFP in normal tis- membrane transporter involved in MDR. In
sues is approximately 0 mm/Hg. An increase in humans, closely related genes, MDR1 and
tumor IFP reduces the transcapillary pressure MDR2 or MDR3, encode highly homologous
future science group www.futuremedicine.com 599

intestine, the colon and the adrenal cortex [37,38] .

1. Efflux pump
The activity of P‑gp in normal tissues suggested
an important role by transepithelial transport
to prevent cytotoxic compounds in the environ-
ment and diet from entering the body, although
ATP ATP
the physiological role of P‑gp remains a subject
2. Altered cell cycle checkpoints of speculation. Studies in P‑gp-knockout mice
3. Alteration in detoxification system demonstrated that P‑gp had no exclusive and
4. Alterations in membrane lipids essential physiological function on fertility. The
5. Altered drug targets mice grew and developed into adulthood nor-
6. Induction of emergency genes
mally. However, these mice were very sensitive
to MDR-related anticancer drugs. Moreover,
Increase repair
mechanisms or more of these drugs accumulated in the CNS
inhibit apoptosis of the mice, indicating a major role of P‑gp at
the BBB [39–41] .
P‑gp can remove many different drugs from
cells to decrease intracellular accumulation of
Figure 1. Summary of the mechanisms in
which cultured cancer cells have been
anticancer drugs. Drugs may be pumped out by
shown to become resistant to cytotoxic P‑gp as they enter the plasma membrane, or even
anticancer drugs. The efflux pumps at the as they are inside the cells. These drugs include
plasma membrane include P-glycoprotein, many of the commonly used natural product
multidrug resistance protein family members anticancer drugs, such as doxorubicin, vinblas-
and breast cancer resistance protein.
Adapted from [42] .
tine, etoposide and paclitaxel, as well as many
commonly used pharmaceuticals, ranging from
P‑gp. However, only the MDR1 gene has been antiarrhythmics and antihistamines to choles-
linked to the MDR. The MDR1 gene is highly terol-lowering statins and HIV protease inhibi-
expressed in many clinically resistant tumors. tors [5,42] . Although the detailed mechanism of
In some cases its expression at diagnosis has drug efflux by P‑gp is unknown, the predicted
been proven to be an adverse prognostic factor. transport cycle of P‑gp involves the change of
In other cases, MDR1 appeared after relapse structure of ATP-binding domains after binding
from remission, suggesting that P‑gp was a of drug substrates, stimulation of ATP hydro-
survival mechanism in a subclone of cancer lysis, and rearrangement of P‑gp shape caused
cells that eventually reoccured [25–30] . Studies by ATP binding and hydrolysis. The final step
in leukemias, myelomas and some childhood involving the conformational change of P‑gp
cancers demonstrated that P‑gp expression cor- results in the release of the drug into the extra-
related with poor response to chemotherapy. cellular space. ATP hydrolysis is necessary for
Moreover, the early clinical trials testing P‑gp resetting of P‑gp [43] .
modulation in acute leukemia in the presence
of P‑gp modulators resulted in clinical relapse Seven strategies to overcome MDR
and reduction of P‑gp expression [31,32] . These The strategies to overcome MDR are summarized
clinical evidences demonstrated that P‑gp plays in the following sections.
a significant role in clinical drug resistance.
P‑glycoprotein is an ATP-dependent trans- Modification of
membrane transporter that can transport a chemotherapy regimens
broad range of structurally unrelated com- Noncross-resistant chemotherapeutic regimens
pounds out of the cells. The human P‑gp is a utilize the largest number of active agents at the
170‑kDa protein containing 1280 amino acids. highest possible doses, assuming that mutations
The topology of P‑gp was proposed to contain conferring drug resistance will not convey resis-
12 transmembrane domains with six extracel- tance to all of the agents in the regimen and,
lular loops and two hydrophilic regions (ATP- also, high-dose chemotherapy regimens could
binding domains), containing nucleotide-bind- be given to cancer patients. This approach
ing domains that are characteristics of the ABC assumes that despite resistance to standard
family of transporters (Figure 2) [33–36] . P‑gp is doses of anticancer drugs, a dose–response rela-
expressed at significant levels in human normal tionship still exists for these tumors and that
tissues, such as the biliary canaliculi of the liver, high doses of chemotherapy might overcome
the proximal tubules of the kidneys, the small this resistance.

Inactivation of MDR-associated not transported but affect transporter function.
genes by targeting specific mRNA The mechanism of reversal of transporters is
for degradation discussed later.
Antisense oligonucleotides and catalytic RNAs
have successfully reduced P‑gp, MRP and Use of nanotechnology-based
BCRP expression and sensitized drug-resistant formulations & nanomedicine
cells [44–47] . The most recent development tar- approaches to overcome MDR
geted to mRNA degradation is based on the Recently, several different formulations encapsu-
RNA interference post-transcriptional gene lating anticancer drugs that are P‑gp substrates
silencing mechanism. Both siRNA (which has have been developed. Paclitaxel vitamin E emul-
a transient effect) and shRNA (which has lon- sion (TOCOSOL), containing the P‑gp inhibi-
ger term effects) silence gene expression of P‑gp, tor d-a-tocopherol polyethylene glycol 1000
MRP and BCRP in MDR cancer cells [48–53] . To succinate (TPGS) as an excipient, was evalu-
limit the exposure of normal cells to the inhibitor ated in a Phase II clinical trial for drug resis-
(siRNA) and the anticancer drug and maximize tance. The results showed promising efficacy
synergy, both P‑gp-targeted siRNA and pacli- when TOCOSOL was administrated weekly
taxel were coencapsulated into poly(d,l-lactide- in patients with refractory cancers [65] . Partial
co-glycolide) (PLGA) nanoparticles. Biotin was reversal of drug resistance was also observed
also attached to the nanoparticles to target biotin when liposomal doxorubicin was given to cell
receptors on cancer cells. In vitro and in vivo stud- cultures [66] . This topic is discussed in greater
ies demonstrated that the biotin-functionalized detail in the sections below.
nanoparticles encapsulating paclitaxel and siRNA
partially overcame tumor drug resistance [54] . Inhibition of MDR using peptides
Synthetic P‑gp-derived peptides corresponding
Use of monoclonal antibodies to fragments from the extracellular loops of the
for P‑gp murine P‑gp were coupled to polyethylene gly-
A monoclonal antibody to P‑gp has been shown col (PEG) and inserted into liposomes. These
to inhibit tumor growth in an athymic nude peptides have been shown to reverse MDR.
mouse model [55,56] . However, there are some After immunization with these peptide-loaded
issues with the antibody approach; for exam- liposomes and treatment with doxorubicin, an
ple, MRK-16, a specific monoclonal antibody increase of 83% survival time was observed in
for P‑gp, may target MDR1-expressing cells mice inoculated with P388R cells. No auto-
in normal tissues. Thus, the potential of this immune responses were detected in immu-
approach to lead to unacceptable toxicities could nized mice. However, complete eradication of
be overlooked in certain mouse models. tumors did not occur. These results indicate a
potential new approach to break immune toler-
Development of new anticancer ance towards MDR1 protein and consequently
drugs that are not substrates of P‑gp modulate sensitivity of resistant tumors to
The modified drug analogs can affect the binding chemotherapy [67–69] .
of analogs to P‑gp, and consequently P‑gp cannot
recognize the analogs. Two taxane analogs, DJ-927
(Phase I) [57,58] and ortataxel (Phase II) [59,60] ,
designed to overcome drug resistance, have been Out
evaluated in clinical trials. Other novel taxane
analogs, such as BMS-184476 (Phase I) [61,62]
and RPR 109881A (Phase II) [63,64] , were also Cell membrane
claimed to have a broad spectrum of activity both
in sensitive and resistant tumor cell lines.
In
Use of inhibitors of ABC transporters
NH2 ATP COOH
to reverse MDR ATP
This is an important approach receiving a great
deal of attention. The inhibitors of ABC trans- Figure 2. Topology model of P-glycoprotein. Each hydrophobic domain is
porters can be classified into two groups. Some followed by a hydrophilic domain (ATP-binding domain) containing a nucleotide-
inhibitors can transport themselves and then binding site that is located at the cytoplasmic face of the membrane and couples
act as competitive antagonists. The others are ATP hydrolysis.

The clinical success has been limited in the the contribution of these inhibitors to reverse
attempts to overcome MDR. A large number clinical drug resistance needs to be defined in
of a new generation of drug analogs have been clinical trials.
developed as non-P‑gp substrates. However,
most taxane analogs have not demonstrated Nano-based drug delivery systems
greater therapeutic indexes in vivo, or have for cancer
shown toxicity to normal tissues, although they In the pharmaceutical field, the development of
were designed and shown not to be P‑gp sub- the first viable��
��
nanocarrier dates back approxi-
strates [62] . Another means to overcome MDR is mately 40 years, when the first example of a
to develop ABC transporter inhibitors. Studies liposome was described [75] . However, the most
on compounds, including the calcium channel important scientific advancements on develop-
blocker verapamil, to reverse vincristine resis- ment of nanoscale vehicles with distinct physi-
tance in murine leukemia cells opened the door cal and biochemical properties for drug delivery
for the development of inhibitors of P‑gp to over- applications have only taken place within the last
come P‑gp-mediated drug resistance [70,71] . The two decades. The most common examples of
therapeutic results from previous clinical trials these nanoparticles include polymeric nanopar-
using first- and second-generation inhibitors of ticles, dendrimers, nanoshells, liposomes, lipid-
ABC transporters have generally been negative or based nanoparticles, magnetic nanoparticles and
only modestly positive and have not fulfilled the virus nanoparticles. One of the most appealing
promise of the preclinical data. There are several properties of nanoparticles is their size, resulting
reasons for the failure of many of these inhibitors in distinct features that are not available from
to show beneficial effects. One of the reasons individual molecules alone or equivalent materi-
for failure is that the inhibitors are weak and als at a larger scale. Nanoparticles have emerged
nonspecific. The requirement for the use of high as one approach to overcome both the lack of
inhibitor concentration (e.g., >10 µM verapamil) specificity of conventional drugs and delivery
was not achievable in clinical trials. Additional barriers in solid tumors [76–82] .
toxicities of anticancer drugs due to the inhibi- Nanoparticles have the potential to improve
tion of transporters in normal tissues remain a the therapeutic index of currently available drugs
concern for the more potent inhibitors. Another by increasing drug efficacy, lowering drug toxic-
reason for failure is the observed programmed ity and achieving steady state therapeutic lev-
pharmacokinetic drug interaction resulting from els of drugs over an extended period of time.
coadministration of inhibitors and anticancer Nanoparticles can also improve drug solubility
drugs. For example, a modest pharmacokinetic and drug stability, allowing the development
interaction between verapamil and doxoru- of potentially effective new chemical entities
bicin in humans was observed [72] . In addition, that have been stalled during the preclinical or
some second-generation inhibitors of P‑gp are clinical development owing to suboptimal phar-
substrates of cytochrome P-450. Competition macokinetic or biochemical properties. Finally,
of these P‑gp inhibitors for cytochrome P-450- the flexible surface chemistry of nanoparticles
mediated oxidative reactions may lead to also allows for possible conjugation of targeting
undesirable pharmacokinetic interactions [73] . ligands for active targeted delivery.
Increased toxicity of the anticancer drugs may A schematic representation for different
occur due to both pharmacokinetic effects and mechanisms by which nanoparticles enhance
inhibition of a protective function of P‑gp in drug delivery to solid tumors is shown in
normal tissues. To date, clinical trials with the Figure 3 [76] . The effectiveness of cancer therapy in
third generation inhibitors are ongoing, includ- solid tumors depends on adequate delivery of the
ing trials with compounds LY335979-targeted therapeutic agent to tumor cells. Many antican-
P‑gp, GF120918-targeted P‑gp and BCRP, cer drugs have a marginal selectivity for malig-
R101933-targeted P‑gp and XR9576-targeted nant cells because they target the reproductive
P‑gp and MRP1. However, toxicity issues are apparatus in cells having high proliferation rates.
still associated with this generation. For exam- However, anticancer drugs having this mecha-
ple, XR9576 demonstrated high potency in both nism of action result in high toxicities against
in vitro and in vivo studies and showed no effect rapidly dividing normal cells, such as hair fol-
on the pharmacokinetics of several anticancer licles, germ cells and hematopoietic cells. Other
drugs in a Phase I study. However, a Phase III anticancer drugs are distributed nonspecifically
study in non-small-cell lung cancer has been in the body where they affect cancer and normal
stopped due to increased toxicity [74] . Therefore, cells. Therefore, the side effects associated with

Receptor Tumor
Nucleus
Blood vessel
Nanoparticles
Intravenous injection
Normal vessels have

a tight endothelium
Angiogenic tumor vessels
are leaky and permeable Nanomedicine © Future Science Group (2010)
Figure 3. Enhanced drug delivery to solid tumors using nanoparticles. (A) Passive targeted
delivery. After intravenous injection, nanoparticles accumulate in tumors through leaky and
permeable tumor vasculature and impaired lymphatic system (e.g., enhanced permeability and
retention effect). (B) Active targeted delivery. Ligand-coated nanoparticles bind to a cancer cell
receptor resulting in cell-specific recognition and improved drug delivery to solid tumors.
chemotherapy limit the dose achievable to the cancers or even in genetically engineered mouse
tumor and also result in suboptimal treatment models [84,85] . If, in fact, human tumors lack the
due to excessive toxicities. Thus, the delivery of inherent leakiness required for the accumulation
drugs to solid tumors remains difficult owing of nanoparticles by the EPR effect, then this will
to the physiological barriers, as described above. have profound effects on future nanomedicinal
The role of tumor vasculature as a potential strategies for targeting solid tumors. As a con-
target for solid tumors has been elucidated since sequence, one may have to develop strategies to
the late 1970s. In terms of the EPR effect, the enhance the convection of nanoparticles from the
small physical dimensions of nanoparticles enable vasculature across the endothelial membrane to
them to partially penetrate through biological and gain access to the solid tumors. Alternatively, one
physiological barriers of tumors that are unique to may have to employ anticancer strategies target-
tumors and normally impermeable for larger par- ing the endothelium adjacent to solid tumors that
ticles. In this manner, passive targeted delivery to may lead to an anticancer effect (e.g., using nano-
tumors based on the EPR effect may be achieved particles to deliver potent antiangiogenic factors
due to the physicochemical properties of a carrier perhaps in combination with drug[s]).
and the pathophysiological condition of a target. Another important prerequisite for passive
For such a passive targeting mechanism to take targeted delivery is that the plasma concentra-
place, physiochemical parameters of nanoparti- tion of the drug must remain high and long;
cles, including particle size and surface properties, meaning that drug-coated nanoparticles must
are crucial. The desirable nanoparticles should be sustained in the bloodstream long enough to
have a certain particle size along with long blood reach or recognize solid tumors. Nanoparticles,
circulation. The pore cut-off size of extravasa- unlike microspheres (>1 µm), are small enough
tion through transvascular gaps in most experi- to be safely dosed via intravenous administra-
mental tumors is in the range of 380–780 nm tion. In the bloodstream, a major defense sys-
depending on the tumor types, whereas the tight tem of the body, the reticuloendothelial system
endothelial junctions of normal vessels typically (RES), which is also known as the mononuclear
are between 1 and 10 nm [11,83] . It was proposed phagocytes system, rapidly removes nanoparticles
that transvascular transport of the particles in from the blood and becomes a major obstacle to
the tumors resulted from interendothelial or long circulation of nanoparticles. The first step of
transendothelial open junctions rather than by clearance of nanoparticles by RES is opsonization,
endothelial phagocytosis or vesicles. To achieve in which nanoparticles are recognized as foreign
this extravasation in solid tumors, an average par- particles and are coated with opsonin proteins
ticle size of less than 300 nm was suggested to be a to make them more recognizable to phagocytic
requirement [11] . It should be noted there has been cells. Phagocytic cells mainly include Kupffer
some recent debate as to whether the EPR effect cells of the liver and fixed macrophages of the
is an artifact of mouse xenograft models, and spleen. A large number of researchers have been
whether this same type of effect exists in human motivated to develop ‘stealth’ nanoparticles to

avoid the uptake of nanoparticles by the RES. It advances of lipid-based nanoparticle systems for
has been repeatedly demonstrated that the opso- improved drug delivery offer a great potential for
nization of hydrophobic particles occur more the administration of anticancer drugs. The main
quickly than that of hydrophilic nanoparticles, advantages of these systems includes low toxic-
owing to the enhanced adsorbability of blood ity of carriers themselves, solubilization of poorly
serum proteins on hydrophobic surfaces [86,87] . water-soluble drugs, high drug loading, and pro-
Modification of the nanoparticle surface with tection of drugs against chemical and biological
chains of hydrophilic and flexible polymers can degradation related to the administration route,
shield nanoparticles from the opsonins and, there- prolonged circulation, targeting delivery and con-
fore, prevent elimination by the cells of the RES. trolled release. In addition, more than one anti-
The most commonly used polymers are PEG, cancer drug may be coencapsulated into colloidal
poly(ethylene oxide) and poly(propylene oxide), carriers for combined cancer chemotherapy [93] .
or their combinations. Such polymers can be put Lipid-based nanoparticles are generally comprised
on the nanoparticle surface by covalently grafting, of biocompatible and biodegradable lipids and,
entrapping and adsorption. However, there are no therefore, may be less toxic than many types of
absolute rules or methods available to completely polymeric nanoparticles prepared from synthetic
and effectively block the opsonization of nanopar- polymers. Once the particle size is reduced to sub-
ticles although research in this area has been ongo- micron levels, the surface area of the nanoparticles
ing for over 30 years. Modification of nanopar- increases substantially, which the saturation solu-
ticle surface is complicated and case dependent. bility also increases with the reduction of par-
The thickness of the layer is crucial but hard to ticle size, leading to an increase in the dissolution
control and will vary within different types of rate. The encapsulation of drugs into the carriers
nanoparticles and coating strategies. However, it provides protection of the drugs from the influ-
is noteworthy that the effective stealth properties ence of physiological conditions. Furthermore,
provided by these barrier layers depend largely on the carrier may have prolonged circulation; thus,
the PEG molecular weight, surface chain density the required therapeutic levels of the drugs in
and conformation [88] . In addition to clearance the blood for the extended time interval, and
of nanoparticles by phagocytosis, nanoparticles a better targeting effect, may be more readily
are also subjected to splenic filtration, a non- achieved. In addition, by choosing the excipients
phagocytic uptake process. The width of interen- and compositions of the nanoparticles, controlled
dothelial cell slits of the spleen is approximately release can be explored to further reduce acute
200–500 nm [89] . A study of the biodistribution toxicity. As described previously, nanoparticles
of polystyrene nanospheres (60–250 nm), coated may be passively targeted to solid tumors by the
or uncoated with hydrophilic polymers, was car- EPR effect or even actively targeted by placing
ried out in rats. In this study, coating of nano- the ligand on the surface of nanoparticles. Lipid-
spheres with hydrophilic polymers dramatically based nanoparticles have become an increasingly
reduced uptake of particles by liver, regardless of important field of research for delivering antican-
particle sizes. However, coated nanospheres were cer drugs in terms of these potential benefits. The
sequestered by the spleen, apparently depending primary types of lipid-based nanoparticles inves-
on the particle size. The size and deformability of tigated have been liposomes, micelles, nanoemul-
nanoparticles play critical roles in their clearance sions, nanocapsules and solid lipid nanoparticles.
by this mechanism in human spleens. For rigid These, as well as some other important systems,
nanoparticles, the size to achieve long circulation will be discussed in the following sections. All
should not exceed 200 nm. Otherwise, nanopar- are potential drug carriers administered by dif-
ticles should be deformable enough to pass splenic ferent routes, including oral [94,95] , topical [96,97]
filtration [90,91] . and parenteral [98,99] .
The innovations in combinatorial chemis-
try and high throughput screening, focused on Drug delivery systems to overcome
achieving potency and high activity of small mol- P‑gp-mediated drug resistance
ecule anticancer drugs, are leading to a shift of the & their possible mechanisms
chemical and physical properties of new chemical As mentioned previously, MDR is a major imped-
entities towards more lipophilic and poorly water- iment to the success of cancer chemotherapy. P-gp
soluble molecules. As a result, approximately 40% was the first multidrug transporter discovered,
of potential drug candidates never enter further and remains the best characterized and most
development, such as a formulation development clinically relevant to date. As such the majority of
stage, due to their poor water solubility [92] . The clinical trials have focused on P‑gp, as highlighted

in Table 1. P‑gp is the product of the MDR1 gene modulate the activity of P‑gp. P‑gp, an efflux
and effluxes drugs without chemical modifica- pump located in the apical membranes of intes-
tion. Approximately 50% of the anticancer drugs tinal absorptive cells, can reduce the absorption
used clinically today are substrates of P‑gp [100] . of drugs and consequently decrease the oral bio-
The emergence of drug resistance has made many availability. Thus, the lipid formulation strategy
of the chemotherapy drugs ineffective. Different for enhancing absorption of drugs that are P‑gp
strategies attempting to overcome P‑gp-mediated substrates became an attractive topic and has been
drug resistance have been developed as previously extensively reviewed for oral delivery [100,102–104] .
described. Therefore, this section focuses on over- Caco‑2 and MDCK cells expressing P‑gp are the
coming P‑gp-mediated drug resistance using drug most widely used cell models to study the oral
delivery systems. Unlike the potentially more absorption. Most of the surfactants inhibiting
serious effects of the active P‑gp inhibitors, drug P‑gp are nonionic. They can be divided into two
delivery systems may be inhibitors of P‑gp with classes according to the chemical structure [102] .
low pharmacological activity and reduced side The first class of surfactants exhibit a hydrophilic
effects. The formulations discussed here to over- head group and a hydrophobic tail responsible
come MDR are summarized in Table 2 and will be for membrane anchoring, including triglycer-
highlighted in the following sections. ides, Cremophor EL, Solutol HS-15, vitamin E
TPGS, Tween 80 and Brij 35. The second class
P‑gp inhibition by of surfactants, which lack a typical membrane
surfactant-based formulations anchor, includes PEG and polyethylene oxide
In 1972, a published study demonstrated that (EO)–polypropylene oxide (PO) block copoly-
Tween 80 enhanced the cytotoxicity of actino- mers (Pluronics or poloxamers). All surfactant
mycin D and daunomycin in Chinese hamster inhibitors contain a unit that comprises hydro-
resistant cells [101] . Since this report, a number of gen bond acceptor groups such as ester groups
lipid and polymeric excipients present in phar- and polyoxyethylene sequences, which could
maceutical formulations have been reported to form hydrogen bonds with the transmembrane
Table 2. Formulations to overcome multidrug resistance and their proposed mechanisms.

Formulations Proposed mechanisms Status Ref.
Liposomes Endocytosis In vitro [117]
Interaction of liposomes with P‑gp In vitro [114]
Coencapsulation of a P‑gp inhibitor (verapamil) In vitro [123]
Polymethacrylate NPs Endocytosis In vitro [133]
Polyisohexylcyanoacrylate NPs No endocytosis In vitro [134–136]
Saturation of P‑gp by high concentration of the drug
Formation of an ion pair between NP degradation In vivo
product and the drug
Polymer–lipid hybrid NPs Phagocytosis In vitro [132]
AOT–alginate NPs Not established In vitro [129]
Solutol HS-15-based lipid nanocapsules Interaction of the released intracellular free solutol HS-15 In vitro [138]
with MDR efflux pump
Redistribution of intracellular cholesterol In vivo
Lipid-based nanoparticles containing Brij 78 Endocytosis In vitro [140,141]
Inhibition of P‑gp In vivo
ATP depletion
HPMA copolymer–doxorubicin conjugates Endocytosis In vitro [143–149]
Inhibition of drug detoxification systems In vivo
Inhibition of cellular defensive mechanisms
Pluronic® block copolymer micelles Change in membrane microviscosity In vitro [152–161]
Inhibition of drug efflux transporters In vivo
ATP depletion Phase II
Influence of cell apoptosis signaling
Inhibition of the GSH–GST detoxification system
Inhibition of mitochondria respiratory chain and decrease
of oxygen consumption
AOT: Sodium bis(2-ethylhexyl) sulfosuccinate; GSH: Glutathione; GST: Glutathione-S-transferase; HPMA: N-(2-hydroxypropyl)methacrylamide;
MDR: Multidrug resistance; NP: Nanoparticle; P-gp: P-glycoprotein.

sequences of P‑gp, which are rich in hydrogen layers of aqueous media separating the lipid lay-
bond donor groups. Provided that the binding ers. The particle size of small unilamellar vesicles,
affinity of surfactants is higher than that of the which are comprised of a single, lipid outer layer
drug, the surfactants may be used to inhibit P‑gp with an aqueous core, is in the range 20–80 nm.
and, therefore, enhance drug absorption. The The surface of the liposomes may be charged
inhibitory effects of surfactants on P‑gp efflux or uncharged based on the selection of differ-
are related to the structure of surfactants, such as ent phospholipids. There are many methods to
the length of the hydrophilic chain and hydro- prepare liposomes, including precipitation [112] .
philic–lipophilic balance (HLB). TPGS 1000 Liposomes may be used to load both hydrophobic
has been reported to influence drug efflux well and hydrophilic drugs. Hydrophilic drugs reside
below its reported critical micelle concentration in the aqueous core, whereas hydrophobic drugs
(CMC) of 0.02 wt% [105] . A structure–activity tend to remain in the lipid layers. Hydrophobic
relationship study was carried out to understand drugs are added during the formation of lipo-
the influence of PEG chain length on apical somes. Hydrophilic drugs may also be loaded
efflux transporters in Caco-2 cell monolayers [106] . during formation, but for charged drugs the
TPGS analogs containing different PEG chain pH-gradient method may be used wherein a pH
lengths (molecular weight from 200 to 6000 Da) gradient between the internal and external aque-
were synthesized. The results suggested that PEG ous domains drives the drug into the interior of
chain length was essential to influence rhodamine the liposomes by partitioning through the mem-
123 efflux in vitro. TPGS 1000 turned out to be brane. Liposomes have poor loading capacity for
one of the most potent analogs to inhibit P‑gp hydrophobic drugs that cannot be dissolved in
efflux. The effect of HLB values of excipients sufficient amounts in the phospholipid bilayer or
on P‑gp modulation was also evaluated for their sequestered in the liposome core. Furthermore,
effects on the uptake of epirubicin in Caco-2 after intravenous administration, such drugs
cells [107] . Surfactants with enhanced efficacy in often rapidly partition from the bilayers into cells,
this study, including Tween 20, Tween 80, Brij or bind to serum proteins, preventing accumula-
30 and Myrj 52, consisted of a polyethylene and tion at the target site. Several liposomal drugs are
intermediate hydrocarbon chain. The character- now marketed including Ambisome® (ampho-
istics of the surfactants allow them to partition tericin B), Doxil® (doxorubicin hydrochloride)
between lipid bilayers and P‑gp domains. The and Visudyne® (verteporfin) to name a few.
optimal HLB value to enhance epirubicin uptake Liposomal delivery systems have been shown
was in the range of 10 to 17. A related study on to inhibit P‑gp efflux [66,113–117] . The proposed
Pluronic block copolymers with varying length of mechanisms included bypassing P‑gp through
EO and PO segments was performed in bovine an endocytosis pathway [117] and direct interac-
brain microvessel endothelial cells [108] . The most tion with P‑gp. The interaction of liposomes
efficacious block copolymers exhibited intermedi- with P‑gp was proved by complete inhibition of
ate length of 30–60 PO blocks and a relatively photoaffinity labeling of P‑gp by azidopine [114] .
hydrophobic structure (HLB <20; e.g., Pluronic However, other studies demonstrated that lipo-
P85 with 40 PO blocks and an HLB of 16). The somes had limited effectiveness in addressing
common mechanisms of surfactants to inhibit P‑gp-mediated resistance in laboratory in vitro
P‑gp may include binding competition of drugs models of cellular resistance and in clinical stud-
with surfactants resulting from an interaction ies [118–121] . Liposome formulations containing
between surfactants and P‑gp, and membrane both an anticancer drug and a P‑gp inhibitor
fluidization leading to an indirect protein desta- have been studied recently. The results showed
bilization [108–111] . However, the latter mecha- that liposomal coencapsulated drugs had better
nism may not be the case for some surfactants. responses in both in vitro and in vivo resistant
For example, TPGS tends to make lipid bilayers models compared with a single drug [122–124] .
more, rather than less, rigid [110] . Moreover, liposomal targeting delivery sys-
tems have been investigated to overcome P‑gp-
Liposomes mediated drug resistance [123] . For example, doxo-
Liposomes have been, and continue to be, the rubicin and verapamil were coencapsulated into
most intensively researched colloidal drug deliv- liposomes with 95 and 70% loading efficiency,
ery systems even for more than four decades after respectively. To achieve active targeting, human
their discovery. Liposomes are normally com- transferrin (Tf) was conjugated to the liposomes
posed of phospholipids that spontaneously form to target Tf receptors, which are overexpressed in
multilamellar, concentric bilayer vesicles, with leukemia cells. In resistant leukemia K562 cells

(Tf receptor+), Tf-conjugated coloaded liposomes doxorubicin. In addition, it was demonstrated
showed 5.2- and 2.8-times greater cytotoxic- that PIBCA nanoparticles did not enter cells via
ity than nontargeted coloaded liposomes and an endocytosis pathway and efflux of doxorubi-
Tf-conjugated doxorubicin liposomes, respec- cin in nanoparticles had a similar profile with
tively. It was concluded that TfR-targeted lipo- free doxorubicin. Mechanistic studies found that
somes coloaded with doxorubicin and verapamil nanoparticles could deliver a high concentra-
were effective in selective targeting and reversal tion of doxorubicin close to or adhered onto the
of drug resistance in cells [123] . cell membrane, resulting in saturation of P‑gp;
the formation of an ion pair between cyanoac-
Polymer, lipid nancapsules rylic acid (a nanoparticle degradation product)
& nanoparticles and doxorubicin could also mask the positive
Nanocapsules have a liquid core (generally an charge of doxorubicin and facilitate diffusion
oil) surrounded by a polymeric membrane struc- of doxorubicin across cell membranes [134,135] .
tured by polymers or a combination of hydro- However, in vivo studies using MDR tumors
philic/lipophilic surfactants. Vegetable oils and demonstrated that these nanoparticles were not
triglycerides with medium- and long-chain fatty efficacious in vivo, perhaps due to poor deliv-
acids are the common components for the lipid ery to the tumors [136] . A new polymer–lipid
cores. The drugs are confined to the lipid core, hybrid nanoparticle (PLN) system was used to
which serves as a reservoir to allow a high drug increase the cytotoxicity of doxorubicin in resis-
loading for hydrophobic drugs and a slow release tant cells [132] . Doxorubicin uptake and retention
profile. Thus, nanocapsules are pharmaceutically from doxorubicin-loaded nanoparticles were sig-
attractive for water-insoluble drugs. nificantly enhanced compared with free doxoru-
Solid lipid nanoparticles made from bio- bicin. Blank PLNs did not improve doxorubicin
degradable or biocompatible solid lipids were uptake and retention in resistant MDA-MB-435/
developed in the beginning of the 1990s as LCC6MDR1 cells. These results indicated that
an alternative colloidal carrier system for con- the PLNs did not influence P‑gp activity by them-
trolled drug delivery. Solid lipid nanoparticles selves. The results also revealed that phagocytosis
are matrix systems in which the drug is physi- was an important pathway for PLN to enter the
cally and uniformly dispersed. The release of a cells. Based on this pathway, doxorubicin-loaded
drug incorporated in the lipid matrix occurs due PLNs could bypass P‑gp, leading to enhanced
to degradation of the particles by lipases present doxorubicin uptake in resistant cells [137] .
at the site of injection, leading to a prolonged Recently, sodium bis(2-ethylhexyl) sulfosuccinate
release of drugs from the solid lipid nanopar- (AOT)–alginate nanoparticles were evaluated for
ticles [125] . A comprehensive review on solid lipid their potential to overcome P‑gp-mediated drug
nanoparticles can be found in the literature [126] . resistance. Doxorubicin-loaded AOT–alginate
A number of studies have investigated encapsu- nanoparticles enhanced the cytotoxicity of doxo-
lation of anticancer drugs into polymer nanopar- rubicin in resistant NCI/ADR-RES cells. It was
ticles and lipid nanoparticles (or nanocapsules) to observed that: the uptake of rhodamine was sig-
overcome P‑gp-mediated drug resistance [127–132] . nificantly increased using rhodamine-entrapped
Among them, polyalkylcyanoacrylate nanoparti- nanoparticles in resistant cell; blank nanopar-
cles were the earliest ones investigated in resistant ticles improved rhodamine accumulation in a
cell lines [130] . The results showed that nonbiode- dose-dependent manner in resistant cells; and the
gradable polymethacrylate nanoparticles can be enhancement in rhodamine accumulation was
internalized by an endocytosis process and reverse not due to membrane permeabilization. However,
P‑gp-mediated drug resistance in vitro [133] . For the mechanism of AOT–alginate nanoparticles to
in vivo studies, biodegradable doxorubicin-loaded overcome P‑gp-mediated drug resistance has not
polyisohexylcyanoacrylate (PIHCA) nanoparti- been established [129] . As mentioned previously,
cles were developed. These PIHCA nanoparticles the surfactant solutol HS-15, a mixture of free
showed more cytotoxicity than free doxorubicin PEG 660 and PEG 660 hydroxystearate, could
in doxorubicin-resistant C6 cells. Later on, more inhibit P‑gp. Solutol HS-15-based lipid nano-
rapidly biodegradable PIBCA nanoparticles were capsules (LNC) containing paclitaxel or etopo-
formulated to load doxorubicin. Doxorubicin side were studied for their potential to overcome
uptake from PIBCA nanoparticles was differ- MDR [138,139] . Paclitaxel-loaded LNCs were
ent than that from PIHCA nanoparticles, as shown to significantly reduce cancer cell survival
doxorubicin-loaded PIBCA nanoparticles caused in comparison with Taxol in 9L cells and F98
higher cellular doxorubicin uptake than free cells. Solutol HS-15 on its own did not improve

the effects of paclitaxel. Similarly, paclitaxel- slowly released the drug in the cellular cytoplasm.
loaded LNCs significantly reduced tumor mass However, paclitaxel-loaded PLGA nanoparticles
in vivo, whereas Taxol did not have a significant did not show significant cytotoxicity in resistant
effect in an MDR-expressing F98 subcutaneous NCI/ADR-RES cells. It was proved that P‑gp
glioma model. The mixture of solutol HS-15 and activity did not affect the uptake and retention of
paclitaxel did not improve tumor responses in this nanoparticles themselves. Thus, the inefficiency
in vivo model. This indicated the importance of of paclitaxel-loaded PLGA nanoparticles could
the nanocarrier itself for the anticancer effect on result from the active efflux of the drug in cyto-
MDR. The study also showed that LNC internal- plasm by P‑gp. P‑gp could not only extract the
ization was not mediated by clathrin-dependent drug when the drug diffused into the cell through
endocytosis. It was assumed that LNC endocy- the lipid bilayer, but also pump out the drug
tosis involves one or both of the two known cho- present in the cytoplasm. Consequently, the effi-
lesterol-enriched membrane microdomains. The ciency of overcoming P‑gp based on endocytosis
consecutive intracellular cholesterol movements of nanoparticles may be limited.
would constitute the core of the LNC inhibitory
effects on MDR. Thus, according to these mech- Polymer–drug conjugates
anism studies, the investigators proposed that the Poly(N-[2-hydroxypropyl]methacrylamide)
inhibition of the MDR efflux pump by LNCs (polyHPMA) and HPMA copolymers have been
could result from the interaction of the released proposed by several groups as potential drug
intracellular free Solutol HS-15 with MDR efflux delivery systems. HPMA is a water-soluble, non-
pump and redistribution of intracellular choles- immunogenic synthetic polymer. HPMA copo-
terol [138] . Recently, doxorubicin and paclitaxel- lymer–doxorubicin conjugates have shown the
loaded lipid-based nanoparticles containing Brij potential to overcome drug resistance [143–145] . A
78 as a surfactant were used to overcome P‑gp- series of studies on HPMA–doxorubicin conju-
mediated drug resistance. These drug-loaded gates addressed multiple mechanisms of MDR in
nanoparticles showed six- to nine-fold lower IC50 addition to P‑gp-mediated drug resistance. After
values in P‑gp overexpressing human cancer cells the HPMA–doxorubicin conjugate was inter-
than those of free drugs [140] . Paclitaxel nanoparti- nalized by an endocytosis pathway, the spacer
cles showed marked anticancer efficacy in a nude between the polymer and the drug was cleaved by
mouse HCT-15 xenograft model via intratumoral an enzymatic hydrolysis reaction in the lysosomal
injection [141] and in a nude mouse NCI/ADR- compartment of the cells, resulting in the release
RES xenograft model after intravenous injection of the drug from the conjugate. Chronic exposure
[140] as compared to all control groups. A series of sensitive A2780 cells to HPMA–doxorubicin
of in vitro cell assays were used to understand conjugates did not induce MDR as measured by
the underlining mechanisms. Enhanced uptake quantification of MDR1 gene expression; inhi-
and prolonged retention of doxorubicin were bition of MPR gene expression and a decrease
observed with nanoparticle-based formulations in of resistance against Taxol was evident [146] . By
P‑gp-overexpressing cells. Calcein acetoxymeth- contrast, repeated exposure to free doxorubicin
ylester assays and ATP assays confirmed that led to an increased resistance to doxorubicin
Brij 78 and blank nanoparticles inhibited P‑gp and Taxol, and upregulation of the MDR1 gene.
and transiently depleted ATP. The change in the Further in vitro mechanistic studies on overcom-
mitochondrial potential and mitochondrial swell- ing MDR revealed that HPMA–doxorubicin
ing were observed to be dominant in MDR cells, conjugates inhibited: drug detoxification systems
suggesting Brij 78 and nanoparticles influence by suppressing the expression of genes encod-
the mitochondrial respiratory chain. It was con- ing glutathione and UDP; and cellular defensive
cluded that nanoparticles may be used to target mechanism by activating apoptosis signaling
both drug and biological mechanisms to over- pathways and downregulating the expression
come MDR via P‑gp inhibition and ATP deple- of the bcl-2 protein family and mechanisms of
tion [140] . It is noteworthy that the drugs delivered DNA repair, replication and synthesis leading to
into MDR cells by PLGA nanoparticles are sus- more DNA damage [147,148] . These results indi-
ceptible to efflux by P‑gp [142] . PLGA nanopar- cated that underlying mechanisms triggered by
ticles were taken up by cells via endocytosis, macromolecular carriers can modulate the bio-
resulting in an increase of cellular concentration logical response of the cell at a molecular level,
of the drug encapsulated into the nanoparticles. resulting in an overall increased cytotoxicity.
Following entry, nanoparticles were retained in The ability of HPMA–doxorubicin conjugates
the cytoplasm for a sustained period of time and to overcome MDR in vivo was demonstrated in

solid tumor mouse models of sensitive human after parenteral administration. The dilution of
ovarian carcinoma A2780 and resistant A2780/ the formulation by physiological fluids may cause
AD tumors [149] . HPMA–doxorubicin conjugates the disassociation of the micelles as the concen-
significantly decreased tumor size by 28-fold in tration of the surfactants used to solubilize the
sensitive tumors and 18-fold in resistant tumors, drugs may be lower than their CMC.
whereas free doxorubicin only reduced tumor size More recently, polymer micelles prepared
by 2.8-fold in sensitive tumors and had no effect from amphiphilic copolymers for solubiliza-
in the resistant tumor model as compared with tion of poorly soluble drugs as an alternative
the control. The underlying mechanisms were also to lipid-based surfactant systems have attracted
investigated for the in vivo study. An enhanced much attention. Polymer micelles offer a more
accumulation of HPMA–doxorubicin conjugates versatile structure, biodegradability and lower
in the tumor was observed and attributed to the CMC, which may lead to better in vivo stability
EPR effect. The permeability of blood vessels and more conjugation chemistries for linking
decreased concomitantly with the downregulation ligands to the surface of the colloidal system.
of vascular growth and permeability (VEGF) gene Polymer micelles are self-assembled from block
in polymer-treated tumors. The other proposed copolymers comprising a hydrophobic block
in vitro mechanisms, such as downregulation of (e.g., polylactic acid) with a hydrophilic block.
the expression of genes responsible for the activ- As a result of a common progression of develop-
ity of efflux pumps, detoxification and apoptosis, ment of ‘stealth’ systems for intravenous admin-
were also demonstrated in the in vivo studies. istration, PEGylation approaches were used to
form stealth micelles to enhance circulation
Pluronic micelles time. Furthermore, the PEG corona can act
Micelles are the most basic colloidal drug delivery as a diffusion barrier for hydrophobic drugs to
systems and are formed spontaneously in nature. reduce the burst release characteristic of drug-
In the body, colloidal micellar species compris- loaded micelles [150] . Thus, the hydrophilic block
ing endogenous surfactants and lipid digestion on the copolymer typically contains PEG seg-
products (i.e., bile salt mixtures) facilitate the ments with a molecular weight from 1 to 15 kDa.
absorption of highly insoluble fatty acids and Similar to micelles formed with conventional
fat soluble vitamins. Micelles have a particle size surfactants, polymeric micelles comprise the
normally within a 5–100 nm range, are thermo core of the hydrophobic blocks stabilized by the
dynamically stable and form spontaneously by corona of hydrophilic chains in water. However,
association of amphiphilic molecules, such as compared with the conventional micelles, poly-
surfactants, under defined concentrations and meric micelles are more stable upon the relatively
temperatures. The concentration of a monomeric high dilution conditions experienced in vivo. For
amphiphile at which micelles appear is termed example, some amphiphilic copolymers have
the critical micelle concentration (CMC). The CMC values as low as 10-6 M [151] .
formation of micelles is driven by the decrease of Pluronics are inert block copolymers compris-
free energy in the system owing to the removal ing of poly(EO) (hydrophilic) and poly(PO)
of hydrophobic fragments from the aqueous (hydrophobic). Pluronics are different from
environment and the re-establishment of the HPMA copolymers due to their amphiphilic
hydrogen bond network in water. Hydrophobic nature. Their surfactant properties allow them
fragments of the amphiphilic molecules form the to self-assemble into micelles with a hydrophobic
core of a micelle, while hydrophilic moieties form PO inner core and a hydrophilic EO outer shell.
the shell of the micelle. When used as drug car- However, similar to HPMA copolymers, Pluronic
riers in aqueous media, micelles solubilize mol- block copolymer micelles have also been shown to
ecules of poorly soluble nonpolar drugs within overcome drug resistance. Extensive studies with
the micelle core, while polar drugs could be Pluronic block copolymer micelles have been
adsorbed on the micelle surface, and substances reviewed [152–154] . SP1049C-containing doxoru-
with intermediate polarity distribute along sur- bicin in the mixed micelles of Pluronic L61 and
factant molecules in intermediate positions. One F127 is in clinical trials to treat ��
metastatic ade-
limitation of micellar systems is the relatively low nocarcinoma of the upper GI tract. In addition,
hydrophobic volume of the interior of micelles, SP1049C showed more efficient accumulation in
leading to limited drug loading. Another limi- tumors than free doxorubicin, while distribution
tation of conventional micellar systems is the of SP1049C in normal tissues was similar to that
danger of drug precipitation upon the dilution of doxorubicin [155] . Efficacy of SP1049C was con-
of the solubilized drug with physiological fluids firmed in in vivo experiments in both sensitive

and resistant tumor models, including P388 and the pro-apoptotic activity of the drug and pre-
P388/ADR murine leukemia, Sp2/0 and Sp2/0- vented the activation of the antiapoptotic cellu-
Dnr murine myeloma, 3LL-M27 Lewis lung car- lar defense [162] ; decreasing glutathione (GSH)
cinoma, MCF-7 and MCF-7/ADR human breast intracellular levels and glutathione-S-transferase
carcinomas, and KBv human oral epidermoid car- (GST) activity, indicating the inhibition of the
cinoma [153,155] . However, the toxicity of SP1049C GSH–GST detoxification system [163] ; and inhib-
was similar to that of free doxorubicin. This sug- ited mitochondria respiratory chain and decreased
gested that SP1049C did not improve the toxicity oxygen consumption in MDR cells, accompanied
profile of free doxorubicin (e.g., cardiotoxicity), by a decrease in mitochondria membrane poten-
which was improved by liposomal doxorubicin. tial, production of reactive oxygen species and
However, there were no additional side effects release of cytochrome C. Eventually, this results in
reported for SP1049C. Disintegration of micelles Pluronic-enhanced drug-induced apoptosis [164] .
in biological fluids��
upon dilution to a concen-
tration below its CMC is a common concern Conclusion & future perspective
regarding using micelles for drug delivery. The The increasing importance of overcoming MDR
biodistribution and pharmacokinetics of Pluronic in tumors has become emphasized in the last few
P85 micelles suggested that the elimination of P85 decades. Great improvements in the application
was controlled by the renal elimination of P85 of nanotechnology as drug delivery systems have
unimers and not by the rate of micelle disinte- offered the possibility of more potential treat-
gration [156] . However, micelle disintegration had ments for MDR. Commonly used pharmaceuti-
been reported with other Pluronic micelles. To cal excipients have been explored for the ability to
further address the potential of micelle disintegra- inhibit P‑gp. This has, in turn, led to the develop-
tion, Pluronic L121 and Pluronic P-105 micelles ment of several nanoparticle-based drug delivery
were chemically modified to form a network or systems that have incorporated these excipients to
crosslink. Therefore, the CMC of the micelles was overcome MDR. Despite the fact that the mecha-
greatly reduced and the stability was enhanced, nisms to overcome MDR using these nanopar-
while their ability to inhibit P‑gp function still ticles are complicated and not fully understood,
remained [157,158] . improved anticancer efficacy on MDR in tumors
The complex mechanisms associated with the has been confirmed in vitro and in vivo. Moreover,
effects of Pluronic block copolymers on MDR some drug-loaded nanoparticles to treat MDR
cells have been thoroughly studied. These mech- in tumors are now in human clinical trials. It is
anisms include altering membrane microviscos- therefore anticipated that current development of
ity [159,160] . It was suggested that unimers (single nanoparticles may provide new strategies for the
block copolymer molecules) are responsible for treatment of MDR.
biological modification as the effect of Pluronic However, many challenges remain for nano-
copolymer occurred at concentrations below their medicine to overcome MDR. Drug-loaded
CMC. The hydrophobic PO chains of Pluronic nanoparticles still have the chance to distrib-
unimers insert into the hydrophilic regions of the ute within normal tissues. Most of the current
membrane, resulting in alterations of the mem- nanoparticles aimed at MDR utilize the EPR
brane structure, and decrease in its microviscosity effect to pursue passive targeted delivery to solid
(membrane fluidization); inhibiting drug efflux tumors. Therefore, more efficacious targeting
transporters, such as P‑gp and MRPs, through strategies for nanoparticles are still needed. Active
inhibition of P‑gp ATPase activity; and depleting targeted delivery could be achieved by attaching
intracellular ATP levels [159–161] . As these pumps tumor specific antibodies or other ligands on the
are energy dependent, attenuation of these pumps nanoparticle surface, or using external techniques
was related to energy deprivation and abolishment (e.g., ultrasound, to enhance drug uptake at the
of pump-associated ATPase activity. Thus, it can tumor site). There also exists the need to con-
be surmized that Pluronic-mediated direct and tinue to understand the biological mechanisms
indirect energy depletion leads to cessation of by which these nanomedicines overcome MDR.
the operation of efflux pumps, and consequently Although more research articles are published
sensitizes resistant cell lines to chemotherapeutic about the mechanisms, relatively few in vivo stud-
agents. A linear correlation between the extent ies have been performed to date. More detailed
of ATP depletion and chemosensitization elicited studies on mechanisms would help direct the
was established, further influencing cell apop- application of current delivery systems or lead
tosis signaling. Doxorubicin-loaded Pluronic to the discovery of alternative novel delivery
block copolymer P85 significantly enhanced systems. Furthermore, MDR itself is a complex

phenomenon and contains different mechanisms. Financial & competing interests disclosure
P‑gp remains one of the best studied mechanisms, This work was supported, in part, by grant R01 CA115197
so most of the current formulation approaches from the NIH to Russell J Mumper.The authors have no
have focused on P‑gp-mediated drug resistance. other relevant affiliations or financial involvement with
Additional understanding of the mechanisms of any organization or entity with a financial interest in or
how nanoparticles address the biological aspects financial conflict with the subject matter or materials dis-
of MDR may lead to novel nanoparticles that cussed in the manuscript apart from those disclosed.
could effectively address MDR as well as other No writing assistance was utilized in the production of
potential resistance mechanisms. this manuscript.
Executive summary
Barriers in chemotherapy for the treatment of solid tumors
Physiological characteristics of solid tumors present a barrier in chemotherapy as they result in poor drug delivery and
therapeutic outcomes.
Many cancer drugs will face multidrug resistance.
Strategies to overcome P-glycoprotein-mediated drug resistance
Strategies include:
- Modification of chemotherapy regimens
- Inactivation of MDR-associated genes by targeting specific mRNA for degradation
- Development of new anticancer drugs that are not substrates of P-glycoprotein (P‑gp)
- The use of inhibitors of P‑gp to reverse P‑gp-mediated drug resistance
- The use nanotechnology-based formulations and nanomedicine approaches to overcome P‑gp-mediated drug resistance
- Inhibition of P‑gp-mediated drug resistance using monoclonal antibodies or peptides
Nano-based drug delivery systems for cancer
Nanoparticles may target solid tumors based on the enhanced permeability and retention effect to enhance tumor uptake
and accumulation.
Lipid-based nanoparticles offer a great potential to formulate poorly water soluble anticancer drugs.
Drug delivery systems to overcome P‑gp-mediated drug resistance & their possible mechanisms
Pharmaceutical excipients have shown the ability to inhibit P‑gp and enhance drug uptake.
Several drug delivery systems have been investigated to overcome MDR, including surfactant-based formulations, liposomes, polymer
and lipid nanocapsules and nanoparticles, polymer–drug conjugates and micelles.
7 Fukumura D, Jain RK: Tumor 13 Shubik P: Vascularization of tumors: a review.

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Nanomedicinal Strategies To Treat Multidrug-Resistant Tumors: Current Progress

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Nanomedicinal strategies to treat

Table 1. Multidrug resistance-related ATP-binding cassette transporters and their substrates.

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intestine, the colon and the adrenal cortex [37,38] .

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Normal vessels have

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Table 2. Formulations to overcome multidrug resistance and their proposed mechanisms.

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7 Fukumura D, Jain RK: Tumor 13 Shubik P: Vascularization of tumors: a review.

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