Karplab.netNanocarriers as an emerging platform for cancer therapy Nanotechnology has the potential to revolutionize cancer diagnosis and therapy. Advances in protein engineering and materials science have contributed to novel nanoscale targeting approaches that may bring new hope to cancer patients. Several therapeutic nanocarriers have been approved for clinical use. However, to date, there are only a few clinically approved nanocarriers that incorporate molecules to selectively bind and target cancer cells. This review examines some of the approved formulations and discusses the challenges in translating basic research to the clinic. We detail the arsenal of nanocarriers and molecules available for selective tumour targeting, and emphasize the challenges in cancer treatment.
Dan Peer1†, Jeffrey M. KarP2,3†, or receptors on the target cel s. Recent reviews provide perspective on SeungPyo Hong4†, oMiD C. faroKHzaD5, the use of nanotechnology as a fundamental tool in cancer research and nanomedicine3,4. Here we focus on the potential of nanocarriers riMona Margalit6 anD robert langer3,4* and molecules that can selectively target tumours, and highlight the chal enges in translating some of the basic research to the clinic.
1Immune Disease Institute and Department of Anesthesia, Harvard Medical
School, Boston, Massachusetts 02115, USA; 2HST Center for Biomedical
PaSSive anD aCtive targeting Engineering, Department of Medicine, Brigham and Women's Hospital, Harvard
Medical School, Cambridge, Massachusetts 02139, USA; 3Harvard-MIT Division
Nanocarriers encounter numerous barriers en route to their target, of Health Sciences and Technology, Massachusetts Institute of Technology,
such as mucosal barriers and non-specific uptake5,6. To address the Cambridge, Massachusetts 02139, USA; 4Department of Chemical Engineering,
chal enges of targeting tumours with nanotechnology, it is necessary Massachusetts Institute of Technology, Cambridge, Massachusetts 02139,
to combine the rational design of nanocarriers with the fundamental USA; 5Laboratory of Nanomedicine and Biomaterials and Department of
understanding of tumour biology (Box 1).
Anesthesiology, Brigham and Women's Hospital, Harvard Medical School,
General features of tumours include leaky blood vessels and Boston, Massachusetts 02115, USA; 6Department of Biochemistry, George
poor lymphatic drainage. Whereas free drugs may diffuse non- S. Wise Faculty of Life Sciences, and the Center for Nanoscience and
specifical y, a nanocarrier can extravasate (escape) into the tumour Nanotechnology, Tel Aviv University, Tel Aviv, 69978, Israel
tissues via the leaky vessels by the EPR effect7 (Fig. 1). The increased †These authors contributed equally to this review
permeability of the blood vessels in tumours is characteristic of rapid and defective angiogenesis (formation of new blood vessels from existing ones). Furthermore, the dysfunctional lymphatic drainage Cancer remains one of the world's most devastating diseases, with in tumours retains the accumulated nanocarriers and al ows them more than 10 mil ion new cases every year1. However, mortality to release drugs into the vicinity of the tumour cel s. Experiments has decreased in the past two years2 owing to better understanding using liposomes of different mean size suggest that the threshold of tumour biology and improved diagnostic devices and treatments. vesicle size for extravasation into tumours is ∼400 nm (ref. 8), but Current cancer treatments include surgical intervention, radiation other studies have shown that particles with diameters <200 nm are and chemotherapeutic drugs, which often also kil healthy cel s and more effective5,8–10.
cause toxicity to the patient. It would therefore be desirable to develop Although passive targeting approaches form the basis of clinical chemotherapeutics that can either passively or actively target cancerous therapy, they suffer from several limitations. Ubiquitously targeting cel s. Passive targeting exploits the characteristic features of tumour cel s within a tumour is not always feasible because some drugs cannot biology that al ow nanocarriers to accumulate in the tumour by the diffuse efficiently and the random nature of the approach makes enhanced permeability and retention (EPR) effect2. Passively targeting it difficult to control the process. This lack of control may induce nanocarriers first reached clinical trials in the mid-1980s, and the first multiple-drug resistance (MDR) — a situation where chemotherapy products, based on liposomes and polymer–protein conjugates, were treatments fail patients owing to resistance of cancer cel s towards marketed in the mid-1990s. Later, therapeutic nanocarriers based on one or more drugs. MDR occurs because transporter proteins that this strategy were approved for wider use (Table 1) and methods of expel drugs from cel s are overexpressed on the surface of cancer further enhancing targeting of drugs to cancer cel s were investigated. cel s4,11,12. Expel ing drugs inevitably lowers the therapeutic effect and Active approaches achieve this by conjugating nanocarriers containing cancer cel s soon develop resistance to a variety of drugs. The passive chemotherapeutics with molecules that bind to overexpressed antigens strategy is further limited because certain tumours do not exhibit nature nanotechnology VOL 2 DECEMBER 2007 www.nature.com/naturenanotechnology 2007 Nature Publishing Group
Box 1 Rational design of nanocarriers for cancer therapy Nanocarriers can offer many advantages over free drugs. They: For rapid and effective clinical translation, the nanocarrier should: • protect the drug from premature degradation; • be made from a material that is biocompatible, wel • prevent drugs from prematurely interacting with the characterized, and easily functionalized; biological environment; • exhibit high differential uptake efficiency in the target • enhance absorption of the drugs into a selected tissue cel s over normal cel s (or tissue); (for example, solid tumour); • be either soluble or col oidal under aqueous conditions • control the pharmacokinetic and drug tissue for increased effectiveness; distribution profile; • have an extended circulating half-life, a low rate of • improve intracel ular penetration.
aggregation, and a long shelf life.
Table 1 Representative examples of nanocarrier-based drugs on the market
Styrene maleic anhydride-neocarzinostatin zinostatin/Stimalmer Polymer–protein conjugate Hepatocel ular carcinoma Peg-l-asparaginase acute lymphoblastic leukemia Peg-granulocyte colony-stimulating factor neulasta/Pegfilgrastim Prevention of chemotherapy-associated il2 fused to diphtheria toxin ontak (Denilelukin diftitox) immunotoxin (fusion protein) Cutaneous t-cel lymphoma anti-CD33 antibody conjugated to acute myelogenous leukemia anti-CD20 conjugated to yttrium-90 or relapsed or refractory, low-grade, fol icular, or transformed non-Hodgkin's lymphoma anti-CD20 conjugated to iodine-131 relapsed or refractory, low-grade, fol icular, or transformed non-Hodgkin's lymphoma Combinational therapy of recurrent breast cancer, ovarian cancer, Kaposi's sarcoma refractory Kaposi's sarcoma, recurrent breast cancer, ovarian cancer relapsed aggressive non-Hodgkin's albumin-bound paclitaxel nanoparticles Metastatic breast cancer the EPR effect, and the permeability of vessels may not be the same The binding of certain ligands to their receptors may cause throughout a single tumour13.
receptor-mediated internalization, which is often necessary if One way to overcome these limitations is to programme nanocarriers are to release drugs inside the cel 16–18. For example, the nanocarriers so they actively bind to specific cells after a more significant therapeutic outcome was achieved when extravasation. This binding may be achieved by attaching immunoliposomes targeted to human blood cancer (B-cell targeting agents such as ligands — molecules that bind to specific lymphoma) were labelled with an internalizing anti-CD19 ligand receptors on the cell surface — to the surface of the nanocarrier by rather than a non-internalizing anti-CD20 ligand19. In contrast, a variety of conjugation chemistries9. Nanocarriers will recognize targeting nanocarriers to non-internalizing receptors may and bind to target cells through ligand–receptor interactions, sometimes be advantageous in solid tumours owing to the bystander and bound carriers are internalized before the drug is released effect, where cel s lacking the target receptor can be killed through inside the cell (Fig 1). In general, when using a targeting agent drug release at the surface of the neighbouring cel s, where carriers to deliver nanocarriers to cancer cells, it is imperative that the can bind20.
agent binds with high selectivity to molecules that are uniquely It is general y known that higher binding affinity increases expressed on the cell surface. Other important considerations targeting efficacy. However, for solid tumours, there is evidence that are outlined below.
high binding affinity can decrease penetration of nanocarriers due To maximize specificity, a surface marker (antigen or receptor) to a ‘binding-site barrier', where the nanocarrier binds to its target so should be overexpressed on target cells relative to normal cells. strongly that penetration into the tissue is prevented16,21. In addition For example, to efficiently deliver liposomes to B-cell receptors to enhanced affinity, multivalent binding effects (or avidity) may also using the anti-CD19 monoclonal antibody (mAb), the density of be used to improve targeting. The col ective binding in a multivalent receptors should be in the range of 104–105 copies per cell. Those interaction is much stronger than monovalent binding. For example, with lower density are less effectively targeted14. In a breast dendrimer nanocarriers conjugated to 3–15 folate molecules showed cancer model, a receptor density of 105 copies of ErbB2 receptors a 2,500–170,000-fold enhancement in dissociation constants per cell was necessary to improve the therapeutic efficacy of an (KD) over free folate when attaching to folate-binding proteins anti-ErbB2-targeted liposomal doxorubicin relative to its non- immobilized on a surface. This was attributed to the avidity of the multiple folic acid groups on the periphery of the dendrimers22.
nature nanotechnology VOL 2 DECEMBER 2007 www.nature.com/naturenanotechnology 2007 Nature Publishing Group
Passive tissue targeting lymphatic drainage Figure 1 Schematic representation of different mechanisms by which nanocarriers can deliver drugs to tumours. Polymeric nanoparticles are shown as representative
nanocarriers (circles). Passive tissue targeting is achieved by extravasation of nanoparticles through increased permeability of the tumour vasculature and ineffective
lymphatic drainage (ePr effect). active cel ular targeting (inset) can be achieved by functionalizing the surface of nanoparticles with ligands that promote cel -specific
recognition and binding. the nanoparticles can (i) release their contents in close proximity to the target cel s; (i ) attach to the membrane of the cel and act as an
extracel ular sustained-release drug depot; or (i i) internalize into the cel .
tyPeS of targeting agentS Antibodies may be used in their native state or as fragments for targeting (Fig. 2a). However, use of whole mAbs is advantageous Targeting agents can be broadly classified as proteins (mainly because the presence of two binding sites (within a single antibody) antibodies and their fragments), nucleic acids (aptamers), or other gives rise to a higher binding avidity. Furthermore, when immune receptor ligands (peptides, vitamins, and carbohydrates).
cel s bind to the Fc portion of the antibody, a signal ing cascade is Targeting cancer with a mAb was described by Milstein in initiated to kil the cancer cel s. However, the Fc domain of an intact 198123. Over the past two decades, the feasibility of antibody-based mAb can also bind to the Fc receptors on normal cel s, as occurs with tissue targeting has been clinical y demonstrated (reviewed in macrophages. This may lead to increased immunogenicity — the refs 24,25) with 17 different mAbs approved by the US Food and ability to evoke an immune response — and liver and spleen uptake of Drug Administration (FDA)26. The mAb rituximab (Rituxan) was the nanocarrier. An additional advantage of whole/intact antibodies approved in 1997 for treatment of patients with non-Hodgkin's is their ability to maintain stability during long-term storage. lymphoma — a type of cancer that originates in lymphocytes27. Although antibody fragments including antigen-binding fragments A year later, Trastuzumab (Herceptin), an anti-HER2 mAb that (Fab), dimers of antigen-binding fragments (F(ab′)2), single-chain binds to ErbB2 receptors, was approved for the treatment of breast fragment variables (scFv) and other engineered fragments are less cancer28. The first angiogenesis inhibitor for treating colorectal stable than whole antibodies, they are considered safer when injected cancer, Bevacizumab (Avastin), an anti-VEGF mAb that inhibits the systemical y owing to reduced non-specific binding16,30. To rapidly factor responsible for the growth of new blood vessels, was approved select antibodies or their fragments that bind to and internalize within in 200429. Today, over 200 delivery systems based on antibodies cancer cel s, phage display libraries that involve a high throughput or their fragments are in preclinical and clinical trials16,30. Recent approach may be used31,32. This method generates a multitude of developments in the field of antibody engineering have resulted in potential y useful antibodies that bind to the same target cel s but the production of antibodies that contain animal and human origins to different epitopes (a part of a macromolecule that is recognized such chimeric mAbs, humanized mAbs (those with a greater human by antibodies; one receptor may have several epitopes that wil be contribution), and antibody fragments.
recognized by multiple antibodies). For example, through a selective nature nanotechnology VOL 2 DECEMBER 2007 www.nature.com/naturenanotechnology 2007 Nature Publishing Group
Figure 2 Common targeting agents and ways to improve their affinity and selectivity. a, the panel shows a variety of targeting molecules such as a monoclonal antibody
or antibodies' fragments, non-antibody ligands, and aptamers. the antibody fragments f(ab′) and fab′ are generated by enzymatic cleavage whereas the fab′, scfv, and
bivalent scfv (diabody) fragments are created by molecular biology techniques. v : variable heavy chain; v : variable light chain; C : constant heavy chain; C : constant light chain. non-antibody ligands include vitamins, carbohydrates, peptides, and other proteins. aptamers can be composed of either Dna or rna. b, affinity and selectivity can be
increased through ligand dimerization or by screening for conformational-sensitive targeting agents such as affibodies, avimers and nanobodies, as wel as intact antibodies
and their fragments.
process, scFv antibodies have been identified for superior binding combining two or more genes to produce a new protein with desired and internalization properties for prostate cancer cel s33.
properties. Antibodies can be engineered so they bind to their target It is possible to increase the efficacy of antibodies by conjugating with high affinity, and using molecular biology techniques, it is possible a therapeutic agent directly to it for targeted delivery. For example, to design protein-based ligand mimetics based on the structure of a in 2000, the chemotherapeutic drug, calicheamicin, which is receptor. Dimerization of proteins or peptides can increase ligand conjugated with the anti-CD33 antibody (marketed under the trade affinity through divalency — two simultaneous binding events, name Mylotarg), was the first clinical y approved formulation that usual y involving concurrent binding of a protein or a peptide to the targets cancerous cel s. Others include Zevalin and Bexxar, which two Fc domains of an antibody (Fig 2b). For example, dimerization of use anti-CD20 antibodies to target radioisotopes to cancer cel s a low-affinity scFv (also known as diabody) against the ErbB2, led to (Table 1). Although the efficacy of these therapies has been proven, enhanced tumour localization in a mouse tumour model37.
lethal side effects have been observed, likely due to non-specific It is also possible to increase binding affinity and selectivity binding34 between the targeting agent and non-target moieties to cel surface targets by engineering proteins that detect a specific on the cel surface. Another reason could be the interaction of the conformation of a target receptor. In a recent in vivo study using a targeting agent with its target expressed on non-cancerous cel s. For fusion protein consisting of an scFv antibody fragment to target and example, BR96-doxorubicin — an immunoconjugate linked with deliver smal interfering RNA (siRNA) to lymphocytes — a type doxorubicin and comprising an antibody that targets and binds of white blood cel — a 10,000-fold increased affinity for the target to the Lewis-Y antigen (expressed on 75% of al breast cancers) — receptor, integrin LFA-1, was observed18. Integrin LFA-1 is usual y demonstrated significant anti-tumour activity in mouse tumour present in a low-affinity non-adhesive form on naïve leukocytes models. BR96-doxorubicin showed lower toxicity than that resulting (white blood cel s that are not activated by cancer cel s or pathogens from doxorubicin alone and it was efficacious in these animal that enter the body), but converts to the high-affinity adhesive form models35. However, in dogs, an acute enteropathy (pathology of the through conformational changes on activation of the immune system. intestine) was observed presumably due to binding of the conjugate to Therefore, targeting the high-affinity form of LFA-1 enables drugs to Lewis-Y-related antigens expressed by non-targeted gastrointestinal be selectively delivered to the activated and adhesive leukocytes. New epithelial cel s. In Phase II human clinical studies, BR96-doxorubicin classes of targeting molecules can be engineered to target specific immunoconjugates had limited anti-tumour activity and caused conformations. These include smal protein domains, known as severe gastrointestinal toxicity, leading to termination of the study36.
affibodies, that can be engineered to bind specifical y to different Although using genomics and proteomics technology to choose target proteins in a conformational-sensitive manner. Other small appropriate targets is an active area of research, to date no clinical y proteins that act like antibodies — cal ed avimers — are used to bind effective targets have been identified. Creating new technologies to selectively to target receptors through multivalent effects. Nanobodies, enhance selectivity and targeting efficacy with existing targets seem which are heavy-chain antibodies engineered to one tenth of the size more promising. For example, fusion proteins can be created by of an intact antibody with a missing light chain, have been used to nature nanotechnology VOL 2 DECEMBER 2007 www.nature.com/naturenanotechnology 2007 Nature Publishing Group
Table 2 Examples of nano-based platforms and their current stage of development for use in cancer therapy
type of carrier and mean diameter (nm) Drug entrapped or linked
Current stage of development type of cancer (for clinical trials) Polymer–drug conjugates (6–15) Doxorubicin, Paclitaxel, Camptothecin, 12 products under clinical trials reviewed in 3, 61 Platinate, tnP-470 (Phases i–i i) and in vivo liposomes (both Peg and non-Peg coated) lurtotecan, platinum compounds, Several products in clinical trials Solid tumours, renal cel carcinoma, reviewed in 9 (Phases i–i i) and in vivo mesothelioma, ovarian and acute lymphoblastic leukaemia Polymeric nanoparticles Doxorubicin, Paclitaxel, platinum- Several products are in clinical trials adenocarcinoma of the oesophagus, 5, 91, 100, 101 based drugs, Docetaxel (Phases i–i i) and in vivo metastatic breast cancer and acute lymphoblastic leukemia Polymersomes ( 100) Doxorubicin, Paclitaxel Micel es (lipid based and polymeric) Clinical trials (Phase i) Metastatic or recurrent solid tumours refractory to conventional Clinical trials (Phase i) Pancreatic, bile duct, gastric and Platinum-based drugs (carboplatin/ In vivo and in vitro cisplatin), Camptothecin, tamoxifen, nanoshel s (gold-silica) ( 130) no drug (for photothermal therapy) gold nanoparticles (10–40) no drug (for photothermal ablation) nanocages (30–40) Chemistry, structural analysis and In vitro / in vivo Clinical trials (Phase i) Metastatic stomach cancer Doxorubicin, platinum-based drugs, vinblastin, vincristin, topotecan, immunotoxins, immunopolymers, and various drugs, toxins Clinical trials (Phases i–i i) various types of cancer fusion proteins (3–15) bind to carcinoembryonic antigen (CEA), a protein used as a tumour in animal tumour models46–48. One chal enge with targeting receptors marker38–40 (Fig. 2b).
whose expression correlates with metabolic rate, such as folate and Tf, In addition to the rational design of antibodies, high- is that these receptors are also expressed in fast-growing healthy cel s throughput approaches have been used to generate targeting agents such as fibroblasts, epithelial and endothelial cel s. This could lead to such as aptamers, which are short single-stranded DNA or RNA non-specific targeting and subsequently decrease the effectiveness of oligonucleotides selected in vitro from a large number of random the drug and increase toxicity49.
sequences (∼1014–1015). Aptamers are selected to bind to a wide variety The use of peptides as targeting agents — including arginine– of targets, including intracel ular proteins, transmembrane proteins, glycine–aspartic acid (RGD), which is the ligand of the cel adhesion soluble proteins, carbohydrates, and smal molecule drugs. Several integrin αvβ3 on endothelial cel s — results in increased intracel ular aptamers have also been developed to bind specifical y to receptors drug delivery in different murine tumour models50,51. However, RGD on cancer cel s, and thus may be suitable for nanoparticle-aptamer also binds to other integrins such as α5β1 and α4β1 and therefore is conjugate therapy41. For example, docetaxel (Dtxl)-encapsulated not specific to cancer cel s, which may limit its use. In addition to nanoparticles whose surface is modified with an aptamer that targets cel surface antigens, extracel ular matrices (ECMs) overexpressed the antigen on the surface of prostate cancer cel s, were delivered with in tumours, such as heparin sulphate, chondroitin sulphate, and high selectivity and efficacy in vivo42.
hyaluronan (HA), may also serve as effective targets for specific Growth factor or vitamin interactions with cancer cel s represent ECM receptors52,53. Coating liposomes with HA improves circulation a commonly used targeting strategy, as cancer cel s often overexpress time and enhances targeting to HA receptor-expressing tumours the receptors for nutrition to maintain their fast-growing metabolism. in vivo54,55.
Epidermal growth factor (EGF) has been shown to block and reduce tumour expression of the EGF receptor, which is overexpressed tHe arSenal of nanoCarrierS in a variety of tumour cel s such as breast and tongue cancer43. Additional y, based on the same idea, the vitamin folic acid (folate) Nanocarriers are nanosized materials (diameter 1–100 nm) that can has also been used for cancer targeting because folate receptors (FRs) carry multiple drugs and/or imaging agents. Owing to their high are frequently overexpressed in a range of tumour cel s including surface-area-to-volume ratio, it is possible to achieve high ligand ovarian, endometrial and kidney cancer44. Transferrin (Tf) interacts density on the surface for targeting purposes. Nanocarriers can with Tf receptors (TfRs), which are overexpressed on a variety of also be used to increase local drug concentration by carrying the tumour cel s (including pancreatic, colon, lung, and bladder cancer) drug within and control-releasing it when bound to the targets. owing to increased metabolic rates45. Direct coupling of these Currently, natural and synthetic polymers and lipids are typical y targeting agents to nanocarriers containing chemotherapies such as used as drug delivery vectors; clinical y approved formulations drugs has improved intracel ular delivery and therapeutic outcome are listed in Table 1. The family of nanocarriers includes polymer nature nanotechnology VOL 2 DECEMBER 2007 www.nature.com/naturenanotechnology 2007 Nature Publishing Group
Nanobased carriers Biodegradable polymer for cancer detection Surface functionality Spacer group/long circulating agent Targeting molecule(aptamers,antibodies and their fragments) Polymeric carriers Inorganic particle Amphipathic molecule Figure 3 examples of nanocarriers for targeting cancer. a, a whole range of delivery agents are possible but the main components typical y include a nanocarrier, a targeting
moiety conjugated to the nanocarrier, and a cargo (such as the desired chemotherapeutic drugs). b, Schematic diagram of the drug conjugation and entrapment processes.
the chemotherapeutics could be bound to the nanocarrier, as in the use of polymer–drug conjugates, dendrimers and some particulate carriers, or they could be entrapped
inside the nanocarrier.
conjugates, polymeric nanoparticles, lipid-based carriers such as To date, at least 12 polymer–drug conjugates have entered Phase I liposomes and micelles, dendrimers, carbon nanotubes, and gold and II clinical trials (Table 2 and Fig. 3a) and are especial y useful for nanoparticles, including nanoshel s and nanocages (Fig. 3a). These targeting blood vessels in tumours. Examples include anti-endothelial nanocarriers have been explored for a variety of applications such immunoconjugates, fusion proteins57–59, and caplostatin, the first as drug delivery, imaging, photothermal ablation of tumours, polymer-angiogenesis inhibitor conjugates60. Polymers that are radiation sensitizers, detection of apoptosis, and sentinel lymph- chemical y conjugated with drugs are often considered new chemical node mapping3,4,56 (Table 2).
entities (NCEs) owing to a distinct pharmacokinetic profile from nature nanotechnology VOL 2 DECEMBER 2007 www.nature.com/naturenanotechnology 2007 Nature Publishing Group
that of the parent drug. Despite the variety of novel drug targets and release, as wel as non-specific uptake by the mononuclear phagocytic sophisticated chemistries available, only four drugs (doxorubicin, system (MPS), provides additional chal enges for translating these camptothecin, paclitaxel, and platinate) and four polymers carriers to the clinic.
(N-(2-hydroxylpropyl)methacrylamide (HPMA) copolymer, poly-L- Given their long history, liposome-based carriers serve as a glutamic acid, poly(ethylene glycol) (PEG), and Dextran) have been classic example of the chal enges encountered in the development of repeatedly used to develop polymer–drug conjugates3,61.
nanocarriers and the solutions that have been attempted. For example, Polymers are the most commonly explored materials for PEG has been used to improve circulation time by stabilizing and constructing nanoparticle-based drug carriers. One of the earliest protecting micel es and liposomes from opsonization — a plasma reports of their use for cancer therapy dates back to 197962 when protein deposition process that signals Kupffer cel s in the liver to adsorption of anticancer drugs to polyalkylcyanoacrylate remove the carriers from circulation75,80. However, Daunosome nanoparticles was described. Couvreur et al. revealed the release and Myocet are examples of clinical y used liposomes (80–90 nm mechanism of the drugs from the polymer in calf serum, fol owed in diameter) without PEG coating that have been reported to by tissue distribution and efficacy studies in a tumour model63. This exhibit enhanced circulation times, although to a lesser degree than work laid the foundation for the development of doxorubicin-loaded PEGylated liposomes such as Doxil/Caelyx (Table 1).
nanoparticles that were tested in clinical trials in the mid-1980s64. In addition to rapid clearance, another chal enge is the fast Polymeric nanoparticles can be made from synthetic polymers, burst release of the chemotherapeutic drugs from the liposomes. including poly(lactic acid) (PLA) and poly(lactic co-glycolic acid)65, To overcome this phenomenon, doxorubicin, for example, may or from natural polymers such as chitosan66 and col agen67 and may be be encapsulated in the liposomal aqueous phase by an ammonium used to encapsulate drugs without chemical modification. The drugs sulphate gradient81. This method achieves a stable drug entrapment can be released in a control ed manner through surface or bulk erosion, with negligible drug leakage during circulation, even after prolonged diffusion through the polymer matrix, swel ing fol owed by diffusion, residence in the blood stream82. In clinical practice, liposomal systems or in response to the local environment. Several multifunctional have shown preferential accumulation in tumours, via the EPR polymeric nanoparticles are now in various stages of pre-clinical and effect, and reduced toxicity of their cargo (Tables 1 and 2). However, clinical development4,56,68,69. Concerns arising from the use of polymer- long-circulating liposomes may lead to extravasation of the drug in based nanocarriers include the inherent structural heterogeneity of unexpected sites. The most commonly experienced clinical toxic polymers, reflected, for example, in a high polydispersity index (the effect from the PEGylated liposomal doxorubicin is palmar-plantar ratio of the weight-and-number-average molecular weight (Mw/Mn)). erythrodysesthesia (PPE), also cal ed the hand-foot syndrome. There are, however, a few examples of polymeric nanoparticles that PPE — a dermatologic toxicity reaction seen with high doses of many show near-homogenous size distribution70.
types of chemotherapy — can be addressed by changing the dosing Lipid-based carriers have attractive biological properties, and scheduling of the treatment83. Other chal enges facing the use of including general biocompatibility, biodegradability, isolation of liposomes in the clinic include the high production cost, fast oxidation drugs from the surrounding environment, and the ability to entrap of some phospholipids, and lack of control ed-release properties of both hydrophilic and hydrophobic drugs. Through the addition encapsulated drugs.
of agents to the lipid membrane or by the alteration of the surface To achieve temporal release of two drugs, polymers and chemistry, properties of lipid-based carriers, such as their size, phospholipids can be combined as a single delivery agent (polymer charge, and surface functionality, can easily be modified. Liposomes, core/lipid shel ). After locating at a tumour site through the EPR polymersomes, and micel es represent a class of amphiphile-based effect, the outer phospholipid shel releases an anti-angiogenesis particles. Liposomes are spherical, self-closed structures formed by agent, and the inner polymeric nanoparticle subsequently releases a one or several concentric lipid bilayers with inner aqueous phases. chemotherapy agent in response to local hypoxia — shortage of oxygen. Today, liposomes are approved by regulatory agencies to carry a range This strategy led to reduced toxicity and enhanced anti-metastatic of chemotherapeutics26,71,72 (Table 1).
effects in two different mouse tumour models, emphasizing the Polymersomes have an architecture similar to that of liposomes, advantages of a mechanism-based design for targeted nanocarriers84.
but they are composed of synthetic polymer amphiphiles, including Organic nanoparticles include dendrimers, viral capsids and PLA-based copolymers73,74 (Table 2). However, as with polymer nanostructures made from biological building blocks such as proteins. therapeutics, there are stil no clinical y approved strategies that use Abraxane is an albumin-bound paclitaxel nanoparticle formulation active cel ular targeting for lipid-based carriers.
approved by the FDA in 2005 as a second-line treatment for metastatic Micel es, which are self-assembling closed lipid monolayers breast cancer. Abraxane was designed to address insolubility problems with a hydrophobic core and hydrophilic shel , have been encountered with paclitaxel. Its use eliminates the need for toxic successful y used as pharmaceutical carriers for water-insoluble solvents like Cremophor EL (polyoxyethylated castor oil), which has drugs (Table 2)75. They belong to a group of amphiphilic col oids been shown to limit the dose of Taxol that can be administered85.
that can be formed spontaneously under certain concentrations Dendrimers are synthetic, branched macromolecules that form and temperatures from amphiphilic or surface-active agents a tree-like structure whose synthesis represents a relatively new field (surfactants) (Fig. 3a). An example of a polymeric micel e under in polymer chemistry. Polyamidoamine dendrimers have shown clinical evaluation is NK911, which is a block copolymer of promise for biomedical applications because they (1) can be easily PEG and poly(aspartic acid). NK911, which consists of a bound conjugated with targeting molecules, imaging agents, and drugs, doxorubicin fraction ( 45%) (Fig. 3b) and a free drug76, was (2) have high water solubility and wel -defined chemical structures, evaluated for metastatic pancreatic cancer treatment. Another (3) are biocompatible, and (4) are rapidly cleared from the blood carrier is NK105, a micel e containing paclitaxel, was evaluated through the kidneys, made possible by their smal size (<5 nm), which for pancreatic, colonic and gastric tumour treatment77.
eliminates the need for biodegradability. In vivo delivery of dendrimer– Lipid-based carriers pose several chal enges, which represent methotrexate conjugates using multivalent targeting results in a general issues in the use of other targeted nanocarriers such tenfold reduction in tumour size compared with that achieved with as polymeric nanoparticles. For example, upon intravenous the same molar concentration of free systemic methotrexate22,46. injection, particles are rapidly cleared from the bloodstream by This work provided motivation for further pre-clinical development, the reticuloendothelial defence mechanism, regardless of particle and a variety of dendrimers are now under investigation for cancer composition78,79. Moreover, instability of the carrier and burst drug treatment and are extensively reviewed elsewhere86,87. Although nature nanotechnology VOL 2 DECEMBER 2007 www.nature.com/naturenanotechnology 2007 Nature Publishing Group
promising, dendrimers are more expensive than other nanoparticles share a similar function of expel ing chemotherapy drugs from the and require many repetitive steps for synthesis, posing a chal enge for cel s12. Several studies have demonstrated the possibility of using nanocarriers to bypass the MDR transporters. SP1049C is a non-ionic Inorganic nanoparticles are primarily metal based and have (pluronic or also known as poloxamer) block copolymer composed the potential to be produced with near monodispersity. Inorganic of a hydrophobic core and hydrophilic tail that contains doxorubicin. materials have been extensively studied for magnetic resonance SP1049C has been shown to circumvent p-glycoprotein-mediated drug imaging and high-resolution superconducting quantum interference resistance in a mouse model of leukaemia and is now under clinical devices88. Inorganic particles may also be functionalized to introduce evaluation91,92. Folate receptor-mediated cel uptake of doxorubicin– targeting molecules and drugs. Specific types of recently developed loaded liposomes into an MDR cel line was shown to be unaffected by inorganic nanoparticles include nanoshel s and gold nanoparticles.
P-glycoprotein (Pgp)-mediated drug efflux, in contrast to the uptake of Nanoshel s (100–200 nm) may use the same carrier for both free doxorubicin93. In an attempt to reverse MDR, vincristine-loaded imaging and therapy (Table 2). They are composed of a silica core lipid nanoparticles conjugated to an anti-Pgp mAb (MRK-16), showed and a metal ic outer layer. Nanoshel s have optical resonances that greater cytotoxicity in resistant human myelogenous leukaemia cell can be adjusted to absorb or scatter essential y anywhere in the lines than control non-targeted particles — a response attributed to electromagnetic spectrum, including the near infrared region (NIR, the inhibition of the Pgp-mediated efflux of vincristine by MRK-1694. 820 nm, 4 W cm–2), where transmission of light through tissue is Additional reports have addressed the chal enge of MDR using polymer optimal. Absorbing nanoshel s are suitable for hyperthermia-based therapeutics95, polymeric nanoparticles96, lipid nanocapsules97 and therapeutics, where the nanoshel s absorb radiation and heat up the micel es98 within cel lines or in mouse tumour models. Combination surrounding cancer tissue. Scattering nanoshel s, on the other hand, treatments with targeted nanocarriers for selective delivery of drugs are desirable as contrast agents for imaging applications. Recently, and MDR pump inhibitors wil likely address some of the problems a cancer therapy was developed based on absorption of NIR light posed by resistant tumours.
by nanoshel s, resulting in rapid localized heating to selectively kil tumours implanted in mice. Tissues heated above the thermal into tHe future damage threshold displayed coagulation, cel shrinkage and loss of nuclear staining, which are indicators of irreversible thermal damage, The choice of an appropriate nanocarrier is not obvious, and the whereas control tissues appeared undamaged37,89.
few existing comparative studies are difficult to interpret because A similar approach involves gold nanocages which are smal er several factors may simultaneously affect biodistribution and (<50 nm) than the nanoshel s. These gold nanocages (Table 2) can be targeting. In addition, developing suitable screening methodologies constructed to generate heat in response to NIR light and thus may for determining optimal characteristics of nanocarriers remains also be useful in hyperthermia-based therapeutics90. Unlike nanoshel s elusive. Therefore, successful targeting strategies must be determined and nanocages, pure gold nanoparticles (Table 2) are relatively experimental y on a case-by-case basis, which is laborious. In easy to synthesize and manipulate. Non-specific interactions that addition, systemic therapies using nanocarriers require methods cause toxicity in healthy tissues may impede the use of many types that can overcome non-specific uptake by mononuclear phagocytic of nanoparticles, but using inorganic particles for photo-ablation cel s and by non-targeted cel s. It is also not clear to what extent this significantly limits non-specific toxicity because light is local y is possible without substantial y increasing the complexity of the directed. However, inorganic particles may not provide advantages nanocarrier and without influencing commercial scale-up. Improved over other types of nanoparticles for systemic targeting of individual therapeutic efficacy of targeted nanocarriers has been established in cancer cel s because they are not biodegradable or smal enough to be multiple animal models of cancer, and currently more than 120 clinical cleared easily, resulting in potential accumulation in the body, which trials are underway with various antibody-containing nanocarrier may cause long-term toxicity.
formulations99. For the clinician, in addition to enhancing confidence through the ability to image the type and location of the tumour, it tHe CHallengeS of MultiDrug reSiStanCe is imperative to construct appropriate therapeutic regimens. When targeting cel surface markers presents a significant chal enge, as The delivery of drugs through targeted nanocarriers that are in the case for solid tumours, targeting tumour vasculature or the internalized by cel s provides an alternative route to diffusion of drugs extracel ular matrix surrounding the tumour microenvironment may into cel s. This approach may al ow targeted carriers to bypass the be necessary. In the case of circulating cancer cel s, as in leukaemia activity of integral membrane proteins, known as MDR transporters, and lymphoma, a therapy that targets surface antigens with high which transport a variety of anticancer drugs out of the cancer cel and affinity and includes a carrier with a long circulating half-life may produce resistance against chemotherapy11. The molecular basis of be the most efficacious. Similar to combination drug strategies that cancer drug resistance is complex and has been correlated to elevated may be personalized to optimize treatment regimens, oncologists in levels of enzymes that can neutralize chemotherapeutic drugs. More the near future may be presented with the ability to choose specific often, however, it is due to the overexpression of MDR transporters nanocarrier/targeting molecule combinations which could lead to that actively pump chemotherapeutic drugs out of the cel and reduce improved therapeutic outcomes and reduced costs.
the intracel ular drug doses below lethal threshold levels. Because Although we are stil far from Nobel Prize winner Paul Ehrlich's not al cancer cel s express the MDR transporters, chemotherapy ‘magic bul et', many believe that we wil soon enter an era in which wil kil only drug-sensitive cel s that do not or only mildly express nanocarrier-based approaches wil represent an important modality MDR transporters, while leaving behind a smal population of drug- within therapeutic and diagnostic oncology.
resistant cel s that highly express MDR transporters. With tumour recurrence, chemotherapy may fail because residual drug-resistant doi:10.1038/nnano.2007.387 cel s dominate the tumour population.
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Cher confrère, Marcq-en-Barœul, le 6 Juin 2016 Recommandations 2016 pour les voyageurs Zika, sexe et moustiques…voilà l'été Zika s'ajoute à la liste des arbovirus, après la dengue et le chikungunya, dans les recommandations sanitaires 2016 pour les voyageurs. Santé publique France insiste aussi dans le Bulletin épidémiologique hebdomadaire sur la prévention contre le paludisme et la fièvre jaune dans les zones d'endémie ainsi que les infections sexuellement transmissibles. « L'infection à virus Zika est venue s'ajouter à la liste de plus en plus longue des infections émergentes à prendre en compte au retour de voyage », expliquent les Pr Éric Caumes et Daniel Camus, président et vice-président du Comité des maladies liées aux voyages et des maladies d'importattion (CMVI). « Le risque de malformations neurologiques d'importance a été estimé à 1 % des grossesses de femmes infectées » soulignent-ils dans le dernier numéro du « BEH » consacré aux recommandations sanitaires pour les voyageurs. Elles invitent les femmes enceintes au report de tout voyage en zone d'épidémie et, aux femmes vivant en zone d'épidémie et aux voyageuses en âge de procréer qui s'y rendent, de différer tout projet de grossesse tant que l'épidémie est active. Le bulletin précise que l'infection par cet arbovirus de la même famille que la dengue et la fièvre jaune se révèle asymptomatique dans 70 à 80 % des cas. Et quand les symptômes sont présents, la présentation clinique est fruste, pouvant associer, à des degrés divers, arthralgies, œdèmes des extrémités, fièvre modérée, céphalées, douleurs rétro-orbitaires, hyperhémie conjonctivale et exanthème maculo-papuleux. Les signes persistent de 2 à 5 jours. Toute personne de retour depuis moins de 15 jours d'une zone endémique et présentant au moins un des symptômes associés au Zika doit être signalée à l'ARS et faire l'objet d'une demande de confirmation biologique.
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