Nano structure based drug delivery system: An approach to treat cancer

Shimab Shahin1*, Ashish Kamboj2, Shahab Anwar3, Peeyush Jain4
  1. Department of Biochemistry, Faculty of Science Jamia Hamdard New Delhi-110062.
  2. British Biological limited Ghaziabad-201206.
  3. Department of Pharmaceutics, Faculty of Pharmacy, LIMT, Greater Noida-201308.
  4. Clinsys Jubilant, Noida.
Corresponding Author: Shimab Shahin E-mail address: [email protected]
Received: 27 May 2011 Accepted: 11 June 2011
Citation: Shimab Shahin, Ashish Kamboj, ShahabAnwar, Peeyush Jain “Nano structure based drugdelivery system: An approach to treat cancer” Int. J.Drug Dev. & Res., April-June 2012, 4(2): 393-407
Copyright: © 2012 IJDDR, Shimab Shahin etal. This is an open access paper distributed under thecopyright agreement with Serials Publication, whichpermits unrestricted use, distribution, andreproduction in any medium, provided the originalwork is properly cited.
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Abstract

Nanotechnology has the potential to offer solutions to these current obstacles in cancer therapies, because of its unique size and large surface-to-volume ratios. Nanoparticles may have properties of self-assembly, stability, specificity, drug encapsulation and biocompatibility as a result of their material composition. Nanoscale devices have impacted cancer biology at three levels: early detection, tumour imaging using radio contrast nanoparticles or quantum dots; and drug delivery using nanovectors and hybrid nanoparticles. Other role of nanotechnology, in management of various diseases and also in drug resistance in leukemia by blocking drug efflux from cancer cells and induce efficient delivery of si RNA into lymphocytes to block apoptosis in sepsis and targeting tumors also. Nanocrystals labeling with immune cells can act as a platform technology for nanoimmunotherapy. This review addresses the advancement of nanoparticles in drug delivery and in cancer therapy.

Key words

Nanoparticle, Cancer Therapy, Drug Delivery system,Drug Targeting, Liposome, Quantum Dots

INTRODUCTION

Nanotechnology refers to the interactions of cellularand molecular components and engineered material,clusters of atoms, molecules, and molecularfragments at the most elemental level of biology.
Such nanoscale objects with dimensions smaller than100 nanometers can be useful by themselves or aspart of larger devices containing multiple nanoscaleobjects.
Nanoscale devices have the potential to radicallychange cancer therapy for the better and todramatically increase the number of highly effectivetherapeutic agents.
Although there have been significant advances indefining the fundamentals of cancer biology, this hasnot translated into similar clinical advances in cancertherapeutics. One area that holds great promise formaking such advances is the area defined as cancernanotechnology, which involves the intersection of avariety of disciplines, including engineering,materials science, chemistry, and physics with cancerbiology. This multidisciplinary convergence hasresulted in the creation of devices and/or materialsthat are themselves or have essential components inthe 1–1000-nm range for at least one dimension andholds the possibility of rapidly advancing the state ofcancer therapeutics and tumor imaging. The newlydeveloping area of “nanohealth” is one hope in thetreatment and cure of cancer that is still the secondleading cause of death next to the cardiovasculardiseases
The therapeutic agents used in cancer treatment aregenerally administered in the systemic circulation.The drug carrier, therefore, must overcomephysiological barriers to reach the tumor cell insufficient concentrations and to reside for thenecessary duration to exert the pharmacologicaleffect.

Delivery systems

The majority of nanotechnology-based devices usefulfor cancer therapeutics have been defined asnanovectors, which are injectable nanoscale deliverysystems. Nanovectors offer the promise of providingbreakthrough solutions to the problems of optimizing efficacy of therapeutic agents while simultaneouslydiminishing the deleterious side-effects thatcommonly accompany the use of both singlechemotherapeutic agents as well as multimodalitytherapeutic regimens.2
Nanovectors are comprised of at least threeconstituents, which include a core material, atherapeutic imaging payload, and a biological surfacemodification, which aids in both appropriatebiodistribution and selective localization of thenanovector and its cytotoxic and/or imaging agent.Although the first type of molecules used to enhancethe selective localization and delivery of nanovectorswere antibodies, more sophisticated recognitionsystems have been devised as a result of ourexpanding knowledge base in cancer biology.
The biological and molecular characteristics ofhuman tumors of different origins continue to bedefined and exploited for cancer therapeutics andtumor imaging, the significance of blood vessels thatdevelop around actively growing tumors as potentialtherapeutic targets has only been widely recognizedand found clinical utility within the past decade. Theprocess of tumor-associated angiogenesis is nowknown to be an essential component of tumorexpansion and metastasis. This realization and theaccompanied potential for development of successfulcancer therapeutics, as well as for tumor imagingstrategies based on tumor-associated vasculature,has opened new doors for the application ofnanotechnology in cancer therapeutics.3
Additionally, the molecules that drive the process oftumor angiogenesis may provide a means to gaugethe timing and extent of individual patient responsesto cancer treatment, which can also be monitoredusing nanovector approaches. One of the mostimportant characteristics of nanovectors is theirability to be functionalized to overcome barriers thatblock access of agents used for treatment of tumorsand for imaging of tumors and their associated vasculature. These biological barriers are numerousand complex. One such barrier is the blood–brainbarrier, which prevents access to brain malignancies,compounding the difficulties in their successfultreatment.4
To achieve breakthrough advances in cancertherapeutics, there are two related and essentialcomponents which must be addressed. The first issuein successful use of nanovectors is recognition of thetumor and the second is the ability of the nanovectorto reach the site of the tumor and associated bloodvessels. The goal is to preferentially achieve highconcentrations of a specific chemotherapeutic agent,a tumor imaging agent, and/or gene therapies at thesite of tumors and associated vasculature. Inaddition, nanovectors must be able to deliver anactive agent to achieve effective anti-tumortreatment, or tumor imaging, which is essential fortumor diagnosis and for monitoring the extent andtiming of an individual patient’s response to antitumortherapy.
The first nanotechnology-based approach to be usedas a means of delivering cancer chemotherapy wasliposomes, which is a type of nanovector made oflipids surrounding a water core. Liposomes are thesimplest form of nanovector and their utility is basedon the significant difference in endothelial structures,defined as fenestrations between normal vasculatureand tumor-associated vessels. The increase infenestrations in tumor neovasculature allows thepreferential concentration of liposome-encapsulatedanti-tumor agent in close proximity to the localtumor site, a phenomenon defined as enhancedpenetration and retention (EPR), which is consideredto be a characteristic of passive targeting of tumors.5
liposomes have been shown to be an effective meansof delivering a diverse group of anti-tumor agentssuch as doxorubicin, as well as the poorly soluble drug paclitaxel. liposomes remain a versatilenanotechnology platform, historically serving as theprototypic nanovector. An approach that was firstused with liposome nanovectors that has found utilitywith other types of nanovectors is PEGylation, amodification of liposome surface characteristicsusing poly(ethylene glycol) (PEG), resulting in whathas been defined as “sterically stabilized liposomes.”This PEG modification of liposomes providesprotection against uptake by resident macrophageswithin the RES biobarrier, thus increasing thecirculation time of liposome-encapsulated anti-tumoragent, resulting in significantly increased therapeuticefficacy. This approach to overcoming rapid uptakeand destruction by resident macrophages within theRES by PEGylation has been used alone or in tandemwith other modifications of liposomes to aid inavoiding or overcoming biobarriers and to moreselectively localize nanovectors.1,5
liposomes have been shown to be an effective meansfor delivery of other agents such as genes andantisense oligonucleotides, and would allow access ofsuch entities as small interfering RNA. As anexample, peptides such as cell penetrating peptides(CPPs) have been used to modify liposomes, allowingthem to be used as a means for intracellular drugdelivery and delivery of proteins such as antibodiesand genes, as well as providing a window for cellularimaging. In addition to liposomes as an example ofthe prototype of nanovectors, there are many othersnow available in the nanotechnology toolbox that arebeing investigated for use in cancer therapeutics andtumor imaging. Polymer-based nanovectors are aspecific area of interest in cance therapeutics and anumber of polymer-based nanovector systems aredescribed. several categories, including polymerconjugates, polymeric nanoparticles, and polymericmicelles.6
Polymeric conjugates that have been investigated foruse as nanovector systems for delivery of anti-tumoragents include the water soluble biocompatiblepolymer N-(2 hydroxypropyl) methacrylamide(HPMA). This polymeric conjugate has been targetedbased on overexpression of hyaluronan (HA)receptors that are present on cancer cells. HPMA–HA polymeric conjugate drug delivery nanovectorsystems have been developed to carry a doxorubicin“payload” and have been shown to have selectivity forendocytosis of the targeted polymeric nanovector tobreast, ovarian, and colon tumor cells, compared toan HPMA polymer with doxorubicin but lacking theHA targeting conjugate.18,19 Copolymer–peptideconjugates have also been developed as nanovectorsusing HPMA in combination with RGD targetingpeptides, which molecularly target radiotherapeuticagents to tumor-associated vasculature, resulting inboth antiangiogenic as well as anti-tumor activity.2,3,7
There are several approaches that exploit activetargeting of long-circulating liposomes to tumor cells,where receptor-mediated internalization is stronglybelieved to bypass tumor cell multidrug-effluxpumps. These strategies utilize tumor-specificmonoclonal antibodies or their internalizingepitopes, or ligands, such as folic acid, which areattached to the distal end of the poly(ethylene glycol)chains expressed on the surface of long-circulatingliposomes. Nevertheless, with such approaches thedelivery part is still passive and relies on liposomeextravasation.8,9
Abraxanee is the only example of a regulatoryapproved (FDA, USA) nanoparticle formulation forintravenous drug delivery in cancer patients. It ispaclitaxel bound to albumin nanoparticles, with amean diameter of 130 nm, for use in individuals withmetastatic breast cancer who have failed combinationchemotherapy or relapse within 6 months ofadjuvant chemotherapy. This formulation overcomespoor solubility of paclitaxel in the blood and allows patients to receive 50% more paclitaxel per dose overa 30-min period.10
Nanoparticles assembled from synthetic polymershave also received much attention in cancer drugdelivery. One interesting example is doxorubicinloadedpoly(alkyl cyanoacrylate) (PACA)nanoparticles. In vitro studies have indicated thatPACA nanoparticles can overcome drug resistance intumor cells expressing multidrug-resistance-1-typeefflux pumps. The mechanism of action is related toadherence of PACA nanoparticles to tumor cellplasma membrane, which initiates particledegradation and provides a concentration gradientfor doxorubicin, and diffusion of doxorubicin acrossthe plasma membrane following formation of an ionpair between the positively charged doxorubicin andthe negatively charged cyanoacrylic acid (ananoparticle degradation product). Theseobservations clearly indicate that drug release andnanoparticle degradation must occur simultaneously,yielding an appropriate size complex with correctphysicochemical properties for diffusion across theplasma membrane. Further developments with PACAnanoparticles include preparations that containdoxorubicin within the particle core andNanotechnology for Cancer Therapy.11

General principles of Drug targeting to cancerTherapy

Passive Targeting

Passive targeting refers to the accumulation of drugor drug-carrier system at a particular site due tophysicochemical or pharmacological factors.Permeability of the tumor vasculature increases tothe point where particulate carriers such asnanoparticle can extravagate from blood circulationand localize in the tumor tissue. This occurs becauseas tumors grow and begin to outstrip the availablesupply of oxygen and nutrients, they releasecytokines and other signaling molecules that recruit new blood vessels to the tumor, a process known asangiogenesis. Angiogenic blood vessels, unlike thetight blood vessels in most normal tissues, have gapsas large as 600–800 nm between adjacentendothelial cells. Drug carriers in the nanometer sizerange can extravagate through these gaps into thetumor interstitial space. Because tumors haveimpaired lymphatic drainage, the carriersconcentrate in the tumor, resulting in higher drugconcentration in the tumor tissue (10-fold or higher)than that can be achieved with the same dose of freedrug. This is commonly referred to as enhancedpermeability and retention, or the EPR effect.12

Active Targeting

Active targeting to the tumor can be achieved bymolecular recognition of cancer cells either vialigand–receptor or antibody–antigen interactions.Active targeting may also lead to receptor mediatedcell internalization of drug carrier system.Nanoparticle and other polymer drug conjugatesoffer numerous opportunities for targeting tumorsthrough surface modifications which allow specificbiochemical interactions with the proteins/receptorsexpressed on target cells. For active and passivetargeting of drug carrier systems, it is essential toavoid their uptake by the reticuloendothelial system(RES) so that they remain in the blood circulationand extravagate in the tumor vasculature. Particleswith more hydrophobic surfaces are preferentiallytaken up by the liver, followed by the spleen andlungs. Size of nanoparticle as well as their surfacecharacteristics is the key parameters that can alterthe biodistribution of nanoparticles. Particles smallerthan 100 nm and coated with hydrophilic polymerssuch as amphiphilic polymeric compounds which aremade of polyethylene oxide such as poloxamers,poloxamines, or polyethylene glycol (PEG) are beinginvestigated to avoid their uptake by the RES. Toimprove the efficacy of targeting cancerchemotherapeutics to the tumor, a combination of passive and active targeting strategy is beinginvestigated where long-circulating drug carriers areconjugated to tumor cell specificantibody or peptides. In addition to the aboveapproach, direct intratumoral injection of the carriersystem is feasible if the tumor is localized and can beaccessed for administration of a carrier system.13

Applications of Nanoemulsions in CancerTherapy

The advantages of formulating various lipophilicanti-cancer drugs in submicron O/W emulsion areobvious. The oil phase of the emulsion systems canact as a solubilizer for the lipophilic compound.Therefore, solubility of lipophilic drugs can besignificantly enhanced in an emulsion system,leading to smaller administration volumes comparedto an aqueous solution. In addition, becauselipophilic drugs are incorporated within theinnermost oil phase, they are sequestered from directcontact with body fluids and tissues. Lipid emulsionscan minimize the pain associated with intravenouslyadministered drugs by exposing the tissues to lowerconcentrations of the drug or by avoiding a tissueirritating vehicle.
Furthermore, incorporation of anti-cancer drugs insubmicron emulsions (with droplet size of 50–200nm) with long circulation properties are expected toenhance the tumor accumulation of the drug bypassive targeting through the enhanced permeabilityand retention effect. It possible to enhance the tumoraccumulation of nanoemulsions with appropriatemodification of size or surface functionalization aspreviously discussed. Oil-in-water submicronemulsions appear to be a viable alternative for theintravenous administration of various lipophiliccytotoxic drugs.
Several groups of researchers have reported thesubmicron emulsion formulations of anti-cancerdrugs for improved efficacy and/or reduced toxicity.
Paclitaxel, a highly potent anti-cancer agent initiallyextracted from the bark of the Pacific yew, wasentrapped in lipid emulsion droplets with triolein asoil core and dipalmitoylphosphatidylcholine (DPPC)as the principal emulsifier. The emulsion wasstabilized with polysorbate 80 and PEGdipalmitoylPE. The incorporation of PEG-derivatizedphospholipid is expected to enhance the in vivocirculation half life of the formulation, therebyenhancing the exposure of the drug to the targetedtumor mass.The formulation showed cytotoxicityagainst HeLa cells with an IC50 at 30 nM. An antitumoragent, valinomycin, was formulated in theemulsion form using the commercially-availableIntralipid 10% soybean oil emulsion used inparenteral nutrition.
Evaluation of this formulation in vivo indicated thatthe emulsion formulation produced similarly shapeddose-response curve to that of an aqueoussuspension, but the emulsion formulation required a30-fold lower dose than the suspension to producetherapeutic similar effects.
In formulation of nanoemulsions, selection of theappropriate oil phase is important because most ofthe anti-cancer compounds exhibit poor solubility inthe oil phase, especially those with highly lipophilicoils. Kan et al. determined the solubility of paclitaxelin various oils such as tributyrin, tricaproin,tricaprylin, corn, soyabean, cotton seed, and mineraloil, and they found that triacylglycerols with shortfatty acid chains (tributyrin and tricaproin) weregood solvents for paclitaxel with solubility of morethan 9.00 mg/g as compared to other vegetable oils(range 0.14–0.23 mg/gm).
Another approach to enhance the oil solubility of theanti-cancer compounds is the chemical modificationor prodrug formation. Prodrugs with increased oilsolubility have been obtained with such anti-cancerdrugs as teniposide, etoposide, camptothecin, and paclitaxel, whereas amphiphilic derivatives have beenprepared from fluorodeoxyuridine. Esterificationwith long-chain fatty acids (i.e., oleic acid) has alsobeen reported to increase the oil solubility of manyanti-cancer drugs.15

Positively charged nanoemulsions in cancertherapy

Positively charged nanoemulsions systems areexpected to interact with negatively charged cellsurfaces more efficiently, and this aspect of thepositively charged nanoemulsions has been exploredfor possibility of oligonucleotide delivery to cancercells.50–53 Because oligonucleotides moleculesdisplay a polyanioinc character and present a largemolecular structure, their ability to cross cellmembranes remains very low.. The fate of both thepdT and the marker of the oil phase (cholesteryloleate) were determined in the fluid (devoid of cancercells) and in the P388/ ADR cell pellet. The resultsindicated that pdT in solution remained only in thefluid and did not associate at all with the tumor cells.However, pdT injected as an emulsion formulationwas detectable in the cancer cells pellet even after 24h and in very high proportions (up to 18% of theinjected dose). When the area-under-the-curvevalues of the concentration versus time profiles fordifferent formulations were compared, it wasobserved that RPR C18 formulations favored anincreased association of pdT to the tumor cellscompared to SA Because the distribution of the oilmarker in the tumor fluid and the P388/ADR cellpellet could not be correlated with that of pdT, theauthors postulated that pdT was probably not takenthrough the endocytosis of the oil droplets but bypositive charges of the emulsion that probablyincreased membrane permeability and allowed thepdT molecules to more efficiently enter the cells..
Furthermore, the use of chitosan as a condensingagent (for DNA) and subsequent complexation withcationic emulsion composed of DC-chol enhanced thetransfection efficiency in vitro compared toDNA/emulsion complexes with the same formulationwith chitosan. In vivo study in mice showed that withchitosan enhanced emulsion complexes, the GFPmRNA expression was prolonged in liver and lung.16

Neutron Capture Therapy of Cancer

Neutron Capture Therapy (NCT) is a binary radiationtherapy modality that brings together twocomponents that when kept separate, have onlyminor effects on the cells. The first component is astable isotope of boron or gadolinium (Gd) that canbe concentrated in tumor cells by a suitable deliveryvehicle. The second is a beam of low-energyneutrons. Boron or Gd in or adjacent to the tumorcells disintegrates after capturing a neutron, and thehigh energy heavy charged particles producedthrough this interaction destroy only the cancer cellsin close proximity to it, leaving adjacent normal cellslargely unaffected.66 The success of NCT relies onthe targeting of boron and Gd-based compounds tothe tumor mass and to achieve desirable intracellularconcentrations of these agents. At the present time,there are two targets with NCT, namely glioblastoma(malignant brain tumor) and malignant melanoma.
The formulation was designed based on the fact thatLDL and high-density lipoproteins (HDL) are naturalcarriers of cholesteryl esters in the body, and certainhuman and animal tumor types have been shown to have elevated LDL-receptor activity primarilybecause the rapidly dividing cancer cells requirehigher amounts of cholesterol to build new cellmembranes. It is expected that VLDL-resemblingformulation may mimic the VLDL–LDL biologicalprocess for targeted drug delivery to cancer cells. Cellculture data showed sufficient uptake of BCH in rat 9glioma cells (O50 mg boron/g cells).17

Dendrimer-Related Delivery Agents

Dendrimers are synthetic polymers with a welldefinedglobular structure. They are composed of acore molecule, repeat units that have three or morefunctionalities, and reactive surface groups.Twotechniques have been used to synthesize thesemacromolecules:divergent growth outwards from thecore,37 or convergent growth from the terminalgroups inwards towards the core. Regular andrepeated branching at each monomer group givesrise to a symmetric structure and pattern to theentire globular dendrimers. Dendrimers are anattractive platform for macromolecular imaging andgene delivery because of their low cytotoxicity andtheir multiple types of reactive terminal groups.

Boronated Dendrimers Linked to MonoclonalAntibodies

Boron Clusters Directly Linked to mAb

Monoclonal antibodies (mAb) have been attractivetargeting agents for delivering radionuclides, drugs,toxins, and boron to tumors.Prior to the introductionof dendrimers as boron carriers, boron compoundswere directly attached to mAbs.

Liposomes As Boron Delivery Agents

Liposomes are biodegradable, nontoxic vesicles thathave been used to deliver both hydrophilic andhydrophobic agents . Both classical and PEGylated(“stealth”) liposomes can increase the amounts ofanti-cancer drugs that can be delivered to solid tumors by passive targeting. Rapidly growing solidtumors have increased permeability to nanoparticlesdue to increased capillary pore size. These can rangefrom 100 to 800 nm. In comparison, endothelial poresize of normal tissues, which are impermeable toliposomes, can range in size from 60 to 80 nm. Inaddition, tumors lack efficient lymphatic drainage,and consequently, clearance of extravasatedliposomes is slow.
Modification of the liposomal surface by PEGylationor attachment of antibodies or receptor ligands, willimprove their selective targeting and increase theircirculation time. 6,7

Boron Delivery By Dextrans

Dextrans are glucose polymers that consist mainly ofa linear a-1,6-glucosidic linkage with some degree ofbranching via a 1,3-linkage. Dextrans have been usedextensively as drug and protein carriers to increasedrug circulation time. In addition, native orchemically-modified dextrans have been used forpassive targeting to tumors, the RES or activereceptor-specific cellular targeting.
To link boron compounds to dextrans, b-decachloroo-carborane derivatives, in which one of the carbonatoms was substituted by –CH2CHOHCH2–O–CH2CHaCH2, were epoxidized and thensubsequently bound to dextran with a resultingboron content of 4.3% (w/w). The modified dextranthen could be attached to tumor-specific antibodies.–150 BSH was covalently coupled to dextranderivatives by two methods. In the first method,dextran was activated with 1-cyano-4-(dimethylamino)pyridine (CDAP) and subsequentlycoupled with 2-aminoethyl pyridyl disulfide. Then,thiolated dextran was linked to BSH in a disulfideexchange reaction. A total of 10– 20 boron cageswere attached to each dextran chain.
In the second method, dextran was derivatized to amultiallyl derivative , which was reacted with BSH in a free-radical-initiated addition reaction. Using thismethod, 100–125 boron cages could be attached perdextran chain, suggesting that this derivative mightbe a promising template for the development of otherHMW delivery agents.

Long-Circulating nanoparticles

Long-circulating nanoparticles can be createdthrough surface modification of conventionalnanoparticles with water-soluble polymers such aspolyethylene glycol (PEG) or polyethylene oxide(PEO) .The hydrophilic nature of these surfacemodifiers minimizes the interactions between thenanoparticles and plasma proteins (opsonins),resulting in reduced uptake by the reticuloendothelialsystem (RES). The major outcome ofmodification with PEG or other hydrophilic flexiblepolymers is a significant increase in circulation time,the advantages of which include maintenance ofoptimal therapeutic concentration of the drug in theblood after a single administration of the drugcarrier, increased probability of extravasation andretention of the colloidal carrier in areas ofdiscontinuous endothelium, and enhancement intargetability of the system by use of a target-specificligand.
The protective action of PEG is mainly due to theformation of a dense, hydrophilic cloud of longpolyethylene chains on the surface of the colloidalparticle that reduces the hydrophobic interactionswith the RES. The tethered or chemically anchoredPEG chains undergo spatial conformations, therebypreventing the opsonization of particles by the RESof the liver and spleen and improving the circulationtime of molecules and particles in the blood. Thegreater the flexibility of the polymer, the greater thetotal number of possible conformations andtransitions from one conformation to another. Watermolecules form a structured shell through hydrogenbonding to the ether oxygens of PEG. The tightly bound water around PEG chains forms a hydratedfilm around the particle and prevents proteininteractions.
PEGylation may also increase the hydrodynamic sizeof the particles, decreasing their clearance throughthe kidneys, renal filtration being dependent onmolecular mass and volume. This would ultimatelyresult in an increase in the circulation half-life of theparticles.
The size, molecular weight, and shape of the PEGfraction and the linkage used to connect it to theentity of interest determine the consequences ofPEGylation in relation to protein adsorption andpharmacokinetics such as volume of distribution,circulation time, and renal clearance.
When formulated into colloidal particles, the PEGdensity on the colloidal surface can be changed byusing PEG of appropriate molecular weight (PEGchain length) and molar ratio (the graftingefficiency). Longer PEG chains offer greater stericinfluence around the colloidal entity, similar toincreased grafting density with shorter PEG chains.Longer PEG chains may also collapse onto thenanoparticle surface, providing a hydrophilic shield.Besides PEG, other hydrophilic polymers, includingpolyvinyl alcohol, polyacryl amide, polyvinylpyrrolidone, poly-[N-(2-hydroxypropylmethacrylamide], polysorbate, and block copolymerssuch as poloxomer (Pluronicw) andpoloxamine (Tetronicw), are also being used tomodify the physicochemical properties of thecolloidal carriers.18
image
A representative biodegradable, hydrophobic poly(baminoester) (PBAE) with pH sensitive solubility properties was synthesized by conjugate addition of4,4’-trimethylenedipiperidine with1,4-butanedioldiacrylate, developed in Professor Robert Langer’slab at Massachusetts Institute of Technology. Thepaclitaxel-loaded nanoparticles (150–200 nm)prepared from PBAE were modified with PluronicwF-108 (poloxamer 407), a triblock copolymer ofpolyethylene oxide/polypropyleneoxide/polyethylene oxide (PEO/PPO/PEO).
The PPO segment of the triblock polymer attaches tothe hydrophobic surface of the nanoparticles, and thehydrophilic PEO segment contributes to the stealthproperties of the polymeric nanoparticles. The pHsensitivenature of the particles prepared from PBAEhas already been shown by in vitro release studiescarried out in the presence of buffers of pH rangingfrom 5.0 to 7.4 and was found to rapidly degrade in amedium of pH less than 6.5. Therefore, thesenanoparticles were expected to readily release theircontents within the acidic tumor microenvironmentand in the endosomes and lysosomes of the cellsupon internalization. This was confirmed by the invitro cellular uptake of the PEO–PBAE nanoparticlesencapsulated with tritiated [3H]-paclitaxel by humanbreast adenocarcinoma cells .
The biodistribution of these PEO-modified PBAEnanoparticles was carried out by encapsulating alipophilic form of the radionuclide indium-111(111indium oxine). Following tail vein injection innude mice bearing a human ovarian xenograft, theradiolabeled PEO-modified PBAE nanoparticles werefound to accumulate in the highly perfused organssuch as the liver, spleen, and lungs with greaterentrapment in the microvasculature of the lungsduring the initial time points. The increasingconcentrations in the kidney also indicate that thenanoparticles, once internalized, were disintegratedand eliminated through the kidney. The plasma halflifeof the unmodified nanoparticles was reported tobe one to ten minutes. By virtue of surface modification with PEO, the PBAE nanoparticles wereshown to have improved circulation times, resultingin a mean residence time in the systemic circulationof 21 h. The paclitaxel-encapsulated PEO–PBAEnanocarriers were found to deliver the drugefficiently to solid tumors, resulting in a 5.2-fold and23-fold higher concentration of the drug at one hourand five hours post-administration relative to thesolution form of the drug.From the tumoraccumulation of the paclitaxel-loaded (3H-labeled)nanoparticles, it is evident that the pH-sensitivePEO–PBAE nanoparticle formulations can deliversignificantly higher concentrations of the drug intothe tumor than the solution form.18,19

Poly (ethylene oxide)-modified poly (3-Caprolactone) Nanoparticles

Poly (3-caprolactone) (PCL) is another biodegradablepolymer that has been used to encapsulatehydrophobic drugs. Using this polymer,nanoparticles were prepared by solvent displacementin an acetone-water system in the presence ofPluronicw. The solvent displacement technique usedfor the preparation of PCL nanoparticles facilitatesinstant adsorption of PPO–PEO groups whentheorganic solution of the polymer is introduced intoaqueous solution containing the stabilizer. Inaddition, it also favors the encapsulation ofhydrophobic drugs such as tamoxifen that could bedissolved along with the polymer in the organicphase, resulting in a high entrapment efficiency ofgreater than 90% at loading levels of 20% of theweight of the drug. The intracellular uptake of thesenanoparticles in MCF-7 estrogen receptor-positivebreast cancer cells and MDA-MB231 human breastadenocarcinoma cells was monitored at differenttime points using tritiated [3H]- tamoxifen. Theresults showed that the cell uptake followed saturablekinetics with most of the nanoparticles beinginternalized within the first 30 min of incubation.
The in vivo disposition of these PEO-modified PCLnanoparticles was completed in mice bearing MDAMB231xenograft breast cancer tumors as it is a wellcharacterizedand simpler model compared to MCF-7that requires estrogen priming for growth. and drug-loaded, unmodified nanoparticles. At earlytime points (one hour), the nanoparticles modifiedwith Pluronicw F-108 had greater concentration inthe tumor with no significant difference in theconcentration of the Pluronicw-modifiedformulations at six hours post-injection.
In a parallel study, the PEO-modified PCLnanoparticles were radiolabeled by a similarprocedure specific to PEO–PBAE nanoparticles. Thenanoparticles, encapsulated with [3H] tritiumlabeledpaclitaxel, were used to understand thechange in concentration and localization of the drugin ovarian tumors (SKOV3). From the biodistributionstudies, it was shown that the modification of PCLnanoparticles with PEO had extended the meanresidence time to up to 25 h.
Hydrophobic drugs such as paclitaxel were found tohave high plasma concentrations as a result of theirprotein binding capacity; however, they were clearedfrom the blood within 24 h. The circulation time ofsuch drugs has been enhanced by encapsulating themin PEO–PCL nanoparticles that, in turn, has resultedin higher concentrations of the drug in the tumors.The PEO–PCL nanoparticles have resulted in an 8.7-fold increase in drug concentration at five-hour timepoints when compared to the solution form of thedrug.
To potentially overcome MDR in ovarian cancer celllines, C6-ceramide has been encapsulated along withpaclitaxel into PEO-modified PCL nanoparticles.Upon treatment of the cells with paclitaxel, the MDRcell line SKOV3/TR exhibited 65.65G2. 16% viabilityat 1 mM dose; the the sensitive cell line SKOV3showed 16.37G0. 41% viability at 100 nM dose. Cotreatmentof these cells along with 20 mM C6- ceramide in addition to paclitaxel (1 mM in the caseof a resistant cell line and 100 nM in a sensitive cellline) resulted in a cell viability of 2.69G0.51% withthe resistant cells and 7.38G1.25% with the sensitivecell lines, indicating a significant increase in celldeath when compared to the paclitaxel treatmentalone. Furthermore, the co-encapsulation of thesedrugs within PEO–PCL nanoparticles resulted inenhanced cell kill compared to the drugs alone.10,18,20
A 10 nM dose of paclitaxel, delivered in combinationwith ceramide in PEO–PCL nanoparticles, resulted in63.98G4.9% viability, and the free drugs in solutionat these doses did not provoke any cell kill in theresistant cell line. The use of these drug-loadednanoparticles resulted in a 100-fold increase inchemosensitivity of the MDR cells. These resultsdemonstrate the clinical use of PEO–PCLnanoparticles in overcoming MDR by combinationtherapy.20

PLGA as a Polymer for Nanoparticles

A number of different polymers, both synthetic andnatural, have been utilized in formulatingbiodegradable nanoparticles. Synthetic polymershave the advantage of sustaining the release of theencapsulated therapeutic agent over a period of daysto several weeks as compared to natural polymerswhich, in general, have a relatively short duration ofdrug release. The polymers used for the formulationof nanoparticles include synthetic polymers such aspolylactide–polyglycolide copolymers, polyacrylates,and polycaprolactones, or natural polymers such asalbumin, gelatin, alginate, collagen, and chitosan. Ofthese polymers, polylactides (PLA) and poly (D,Llactide-coglycolide)(PLGA) have been mostextensively investigated for drug deliveryapplications.
PLGA/PLA-based polymers have a number ofadvantages over other polymers used in drug and gene delivery, such as their biodegradability,biocompatibility, and approval by the FDA for humanuse. PLGA/PLA polymers degrade in the bodythrough hydrolytic cleavage of the ester linkage tolactic and glycolic acid, although there are reports ofinvolvement of enzymes in their biodegradation.
These monomers are easily metabolized in the bodyvia Krebs’ cycle and eliminated as carbon dioxide andwater. Biodegradation products of PLGA and PLApolymers are formed at a very slow rate, and theytherefore do not affect normal cell function.Furthermore, these polymers have been tested fortoxicity and safety in extensive animal studies andare currently used in humans for resorbable sutures,bone implants and screws, contraceptive implants,and also as graft materials for artificial organs andsupporting scaffolds in tissue engineering research.Long-term biocompatibility of these polymers wasdemonstrated by the absence of any untoward effectson intravascular administration of nanoparticlesformulated using these polymers to the arterial tissuein pig and rat models of restenosis.21

Application Of PLGA/PLA Nanoparticles AsDrug delivery Vehicles To Cancer Tissues

There are several studies regarding PLGA/PLAnanoparticles or some modification of thesepolymers for delivery of anti-cancer agents and othertherapeutic agents.We have recently demonstratedincreased efficacy of transferrin conjugatedpaclitaxel-loaded PLGA nanoparticles both in vitroand in an animal model of prostatecarcinoma.Transferrin receptors are over-expressedin most cancer cells by two to tenfold more than innormal cells. We have demonstrated thattransferring-conjugated nanoparticles have enhancedcellular uptake and retention than unconjugatednanoparticles. A single-dose intratumoral injection oftransferrin conjugated nanoparticles in animalmodels of prostate carcinoma demonstrated complete tumor regression and higher survival ratethan animals that received either drug in solution orunconjugated nanoparticles.
The IC50 for paclitaxel with transferrin conjugatednanoparticles was fivefold lower than that withunconjugated nanoparticles or with drug in solutionin PC3 24 and in MCF-7 cells. Kim et al. havedemonstrated enhanced intracellular delivery ofPLGA nanoparticles, which were surface-coated withcationic di-block copolymer, poly(L-lysine)–poly(ethylene glycol)–folate (PLL–PEG–FOL), in KBcells that overexpress folate receptors.In anotherstudy, paclitaxel-loaded PLGA nanoparticles, whichwere conjugated to wheat germ agglutinin (WGA),demonstrated greater anti-proliferation activity inA549 and H1299 cells as compared to theconventional paclitaxel formulations.
This enhanced activity of WGA-conjugatednanoparticles was attributed to greater intracellularaccumulation of drug via WGA-receptor-mediatedendocytosis of conjugated nanoparticles.33 Cegnar etal. have developed cystatin-loaded PLGAnanoparticles with the strategy of inhibiting thetumor-associated activity of intracellular cysteineproteases cathepsins B and L. In an in vitro study,cystatin-loaded PLGA nanoparticles demonstrated160-fold greater cytotoxic effect in MCF-10A neoTcells than free cystatin. Similarly, interferon-alpha(IFN-alpha) loaded PLGA nanoparticles are beingdeveloped to improve the therapeutic efficacy of IFNalphawhile reducing its dose-related sideeffects.18,21,22

Polymer-Based Nuclear Imaging andRadiotherapy

With the appropriate delivery system, radioisotopeshave a significant advantage over other therapyagents, namely, the emission of energy that can kill ata distance from the point of radioisotope localization.
This diameter of effectiveness helps to overcome theproblem of tumor heterogeneity because, unlikeother molecular therapy (cell toxins, chemotherapy,etc.), not all tumor cells need to take up theradioisotope to eradicate a tumor.
There are also physical characteristics (type ofparticle emission, emission energy, half-life) ofdifferent radioisotopes that may be selected toenhance therapeutic effectiveness. For example,different isotopes deliver beta particulate ionizationover millimeters (131I) to centimeters (90Y). Longlivedisotopes such as 131I that remain within thetumor target may provide extended radiationexposure and high radiation dose, especially if thereis progressive renal clearance and high target to nontargetratios. RGD peptides labeled withtherapeutically relevant isotopes such as b-particleemitters have been investigated as potentialangiogenesis targeted radiotherapy .
The chelation conditions for 90Y and lutetium-177(177Lu) labeled RGD have revealed that time,temperature, pH, presence of trace metalcontaminants, and stoichiometric ratio of chelator toisotope all have significant effects on the rate ofchelation and radiolabeling efficiency. A majorchallenge in development of therapeuticradiopharmaceuticals is radiolytic degradation ofradiolabeled products because of production of freeradicals in the presence of a large amount of highenergy ß-particles.
These conjugates may be particularly advantageousfor cancer radiotherapy because the combination ofpolyvalent interaction and EPR effect would help toretain the conjugate in the tumor, enhancing theradiation dose.
The use of a water-soluble polymer (HPMA)-basedconjugate of RGD peptide and the acyclic chelator cyclohexyl-diethylenetriamine penta acetic acid forangiogenesis directed (90Y) radiotherapy has beenstudied. After intravenous injection in prostatecarcinoma . xenograft bearing SCID mice, the tumoraccumulation of the conjugate peaked at 72 h postinjection,whereas the accumulation in other majororgans significantly decreased during that period. Asingle injection of the 90Y labeled conjugate at doselevels of 100 and 250 Ci caused significant reductionof tumor volume as compared to the untreatedcontrol that was evident from day 7 post-injection.18,23

Solid Lipid Nanoparticles fo Anti-Tumor DrugDelivery

Solid lipid nanoparticles (SLN) are colloidal particlesof a lipid matrix that is solid at body temperature. Since their first introduction by Mulleret al. SLN have attracted increasing interest as acarrier system for therapeutic and cosmeticapplications. As a drug delivery system, SLN havebeen investigated in the last ten years forpharmacological and dermatological formulationdevelopment. They can be administered through anumber of routes including parenteral, peroral,dermal and rectal.Improved bioavailability andtargeting capacity have been observed and enhancedcytotoxicity against multidrug resistant cancer cellshave been evidenced when SLN are used as thedelivery vehicles.
SLN have been proposed as an alternative to othercontrolled drug delivery systems (CDDS) such aslipid emulsion, liposome, and polymericnanoparticles as a result of their several advantages.For instance, in comparison to lipid emulsion, thesolid lipid matrix of SLN makes sustained drugrelease possible. The solid lipids also immobilizedrug molecules, thereby protecting the labile andsensitive drugs from coalescence and degradation,and reduce drug leakage that are commonly seen inmany other CDDS such as liposomes. Compared with some polymeric nanoparticles, SLN are generally lesstoxic because physiological and biocompatible lipidsare utilized. Meanwhile, all of the less toxicsurfactants that have been applied to other CDDS areequally applicable for SLN preparation. Otherappealing features of SLN include the feasibility formass production, flexibility in sterilization, andavoidance of organic solvents in a typical SLNpreparation process. It should be noted that SLN arealso a versatile formulation. Both lipophilic andhydrophilic compounds can be encapsulated anddelivered by SLN with modification in theformulation.24
The aforementioned useful qualities of SLN makethem particularly attractive for the deliveryof cancer chemotherapeutic agents. Anti-tumordrugs, especially the cytotoxic compounds that areused in conventional chemotherapy, are unique whencompared to other classes of drugs in a number ofareas such as the strong toxicity that is typical ofcytotoxic drugs often compromises their therapeuticeffects; poor specificity of their drug action ingeneral; and the frequent occurrence of drugresistance during chemotherapeutic treatment. Theseissues may all at least be partly tackled by deliveringanti-tumor compounds with a suitable drug carriersystem. SLN is potentially a valuable choice for thispurpose. SLN may also be used for the delivery ofthese compounds to further improve theeffectiveness of chemotherapy of cancer normallyresistant to cytotoxic drugs.25

Conclusion

The amount of research in targeted, polymericnanoparticles for cancer imaging and therapy hasincreased dramatically in the past 5–10 years. Seeingactual products using targeted therapies has nodoubt fueled that work. In the next decade, we willcertainly see products, whether with polymericnanoparticles or some other type of delivery system, using folate receptors and carrying imaging agents.All of these technologies, driven by the fields offundamental immunology, biochemistry, polymerchemistry, and biomedical engineering, are bringingus closer to the time when cancer may be treated onan individual basis. One patient’s diagnosis andtreatment will be unique to her condition and will bethe most effective treatment possible for her.
There are multiple factors affecting the delivery ofdrugs and genes to tumors. Factors such as bloodflow, angiogenesis, microvessel density, interstitialpressure, macrophage activity, extracellular andintracellular components, and, most importantly, thephysicochemical properties of the drug carrier playan important role in the transport of drugs andmacromolecules to tumors.
Polymeric carriers could be modified usinghydrophilic polymers such as PEG and PEO. Thistherapeutic strategy could be used to alter thepassive/active targeting ability of the drug and genecarriers. However, the delivery of these newer agentsis still a challenge, highlighting the necessity ofadditional research in this area.
 

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