Many coupled with the complexity and diversity of

Many drugs fail duringpreclinical evaluations due to poor efficacy, limited bioavailability and otherchallenges associated with effective drug delivery. These challenges, coupledwith the complexity and diversity of new pharmaceuticals are fuelling the evolutionof novel drug delivery systems that overcome bioavailability and deliveryobstacles.

The objective of effective drug delivery is improving thepharmacokinetics and pharmacodynamics of each therapeutic to enable drugdelivery to the right place. Polymer carriers loaded with therapeutics enablecontrolled temporal and spatial release of a drug by controlling drugdiffusion, the rate of dissolution and degradation of the carrier.Targeted Delivery Drug efficacy can be enhanced, and toxicity minimized bylocalization at the target site. Targeting can be achieved by coating orconjugating the carrier with affinity reagents such as nucleic acids, peptides,antibodies, or others that bind specific cell receptor proteins, nucleic acids,or polysaccharides.

Reservoir-Based Polymer Drug Delivery Systems:Polymer selection greatly influences the performance of thedrug delivery system. Polymer selection will determine the mechanism for drug releaseand the choice of polymer properties will influence release rate and impactpharmacokinetics.in This system the drug is surrounded by polymers anddepending on the properties of these polymers and the physiochemical propertiesof the drug such as solubility, particle size and molecular weight affect therate at which the drug is released. These reservoir-based systems are mostbeneficial if the long-term administration of a medication is toxic (cancertreatments). the reservoir based system can be classified as the followingcategories:Polymeric Microspheres & Nanoparticles:microsphere and nanospheres are small size drug particlethat are coated with.

Microspheres reduce the dosing frequency, they canrelease a drug continuously over time, thereby providing a prolongedtherapeutic, microspheres allow for the targeted drug delivery of potent drugsat reduced concentrations, thereby minimizing systemic exposure and adverseside effects. Finally, polymeric microspheres facilitate manipulation of invivo behaviour, pharmacokinetic profile, tissue distribution, and cellular interactionof the drug.2 Microspheres are typically comprised of biodegradablepolymers. These polymers degrade in vivo by hydrolysis of their ester backboneinto non-toxic products, which are excreted by the kidneys. PLGA microsphereshave been widely used to encapsulate drug molecules and have been used aslong-acting, sustained-release pharmaceutical formulations.Polymeric nanospheres the use ofAPI-loaded polymeric nanoparticles for intravenous administration is apromising approach for achieving the controlled release and site-specificdelivery of drugs.

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The nanoparticle delivery system can be designed to maintainappropriate therapeutic concentration in the bloodstream (controlled release)or to target a specific cell type (e.g., bone marrow, blood cells).

Varioustypes of APIs, including small molecule drugs and biologic compounds, can beincorporated into PLGA polymer nanoparticles by either microencapsulation orsurface conjugation. Nanoencapsulation can protect the API from earlydegradation, facilitate cell entry, and increase solubility andbioavailability. The surface properties of intravenously injected particles areimportant factors determining in vivo organ distribution and fate. Furthermore,surface modification can be an effective approach to targeting specifictissues. Surface modification of nanoparticles with polyethylene glycol (PEG)can be used to prolong the in vivo circulation lifetime of drug-loadednanoparticles. PEGylation of the nanoparticle can be accomplished by adding acopolymer containing PEG chains during the nanoparticle fabrication process.For example, the addition of an ethylene glycol monomer during lactide andglycolide copolymerization can lead to a PEGylated PLGA polymer.

PEGylation canincrease nanoparticle hydrophilicity and improve degradation rate andcrystallization.3 In addition to being biocompatible, PEG is resistant toimmunological recognition. PEG units on the NP surface prevent opsonin-NPbinding, thus preventing the nanoparticles from being recognized by monocytesand macrophages and, therefore, increasing circulation time in the body.4 Insome circumstances nanoparticles have been shown to remain in circulation 40×longer when coated with PEG compared to uncoated nanoparticles.5 Otheradvantages of PEGylated nanoparticles include increased drug loading ofhydrophilic drugs, reduced initial burst and improved bioavailability.6PEGylated nanoparticles have been used as carriers for vaccine and protein APIsand are particularly useful in both sustained/controlled release and targeteddrug delivery systems. Currently, there are more than 35 U.

S. FDA-approvedproducts utilizing PEG in their biomedical applications.4 Nanoparticles canalso facilitate the crossing of the blood brain barrier (BBB). Surfactants suchas Polysorbate 80 and Poloxamer 188 have been shown to facilitate the BBBcrossing of drug molecules encapsulated in polybutyl cyanoacrylatenanoparticles or solid lipid nanoparticles.7 In some nanoparticle formulations,the API is attached to the surface instead of being encapsulated inside theparticle. For example, a peptide for ocular delivery (POD) and a humanimmunodeficiency virus trans-activator were conjugated to the surface of PLGAnanoparticles, and the conjugate was found to improve ocular drugbioavailability.8 The conjugation can be done by reacting the terminalfunctional group (e.g.

, terminal COOH) on the PLGA molecule with a reactivegroup (e.g., amino) on the peptide, API or protein. Finally, in some cases,PLGA nanoparticles themselves can have therapeutic effects againstcertain diseases. luprolide acetate is a PLGApolymeric microspheres that’s approved by the FDA used for the treatment ofprostate cancer and endometriosis, luprolide is subcutaneously administeredover long intervals at 1month, 3month, or 6month intervalsThe first Food and DrugAdministration (FDA)–approved controlled-release system was Lupron Depot,injectable microspheres composed of lactic acid–glycolic acid copolymer andleuprolide acetate.

This system was introduced in 1989 to treat prostatecancer, and the drug release lasted for 30 days.3 Other microsphere ornanosphere drug delivery systems subsequently approved by the FDA includeAmBisome (liposomal amphotericin B for fungal infection treatment),16 Adagen(PEG-adenosine deaminase for severe combined immunodeficiency disease),17Doxil/Caelyx (Stealth PEG-stabilized liposomal doxorubicin for refractoryovarian and breast cancer),18 DepoCyt (liposomal cytosine arabinoside formeningitis),19 ONTAK (denileukin diftitox for cutaneous T-cell lymphoma),20Mylotarg (gemtuzumab ozogamicin for CD33+ relapsed acute myeloid leukemia),21PEG-Intron (PEG-interferon ?-2b for hepatitis C),22 and Neulasta (pegfilgrastimfor reduction of febrile neutropenia associated with chemotherapy).23Hydrogels: Hydrogel consist of crosslinkednetworks of hydrophilic polymer chains that form colloidal gels. They are madefrom either natural (chitosan and alginate) or synthetic polymeric (poly vinylalcohol (PVA), poly ethylene glycol (PEG), poly ethyleneimine (PEI), poly vinylpyrrolidone, and poly-N-isopropylacrylamide) networks. The highly porous natureof hydrogels makes the drug release rate significantly depend on the diffusion coefficientof the drug molecules through the gel network. Through controlling the degreeof cross-linking The porosity of hydrogels can be adjusted, which will affectthe release rate of the entrapped drug particles.

5,24,25 Crosslinkingbetween polymer chains can be triggered chemically or physically. Physicalcross-linking can be triggered by the change of pH, temperature, and ionicstrength and a variety of physicochemical interactions, chemical cross-linkinginvolves adding additional cross-linking entities to covalently bond tohydrogels, leading to the chemical modification of the system. Since Hydrogelsare highly absorbent (up to 99.9% water) they can encapsulate water-soluble,small molecule APIs that are difficult to encapsulate using traditional biodegradablepolymeric particles comprised of PLGA and PCL. As a result, these gels areparticularly suitable for the sustained release of water-soluble drugs orproteins. Other advantages of hydrogel particles include their high drugloading and activity, biocompatibility, and biodegradability. Also, themanufacturing of hydrogels does not require organic solvents. Hydrogel systemshave various applications including oral, transdermal, nasal, rectal, andocular drug delivery.

Embolization therapy is another application of hydrogelmicrospheres. It is typically used to prevent the growth of cancer cells byblocking the blood supply to the feeding artery.Hydrogels provide a suitablevehicle for localized administration of APIs such as proteins and small moleculesby maintaining a high local concentration of a drug. Hydrogels can also bypassthe need for systemic drug administration and provide a reservoir of the drugto be released slowly over time. Poly ethylene glycol (PEG) have been studiedextensively for drug delivery because of its favourable characteristics:non-toxic, biocompatible and are non-biodegradable that made PEG hydrogels anideal drug delivery vehicle.1 also the mechanical properties of PEGhydrogels are well-defined and can be tuned for application, including the drugdelivery site and drug diffusion kinetics, by modifying PEG molecular weightand crosslink density.

2 PEG can be end-functionalized with a variety ofother groups, including methoxy, hydroxy, maleimide, thiol, and azide The diversityof functional groups allows unique crosslinkers with different crosslinkingchemistry, such as Michael-type additions, thiolene and Diels-Alder clickreactions, enzymatic reactions, and carbonyl additions.3 Drug deliveryfrom a hydrogel involves the diffusion of an encapsulated pharmaceutical agentthrough the bulk of the gel into the immediate microenvironment surrounding thedelivery site. Depending on the porosity, hydrophilicity, and otherphysicochemical properties of the hydrogel and the drug, the loaded drug canelute slowly over time in a pharmacokinetically controlled manner that prolongscirculation time.

5 Implants:Implants are less commonly used, they consist of a core drugmolecule surrounded by a permeable polymer membrane, the permeability and thethickness of the polymer membrane determine the extent at which the drug isreleased. Implants have been utilized in ophthalmology. The driving force ofthe drug release is constant diffusion through the polymer coating, andzero-order release kinetics can be achieved. Depending on the polymer used, theimplant systems can be classified into nonbiodegradable (silicone, polyvinylalcohol (PVA) and ethylene vinyl acetate (EVA) and biodegradable (PLA, PGA andpolylactic-co-glycolic PLGA copolymer).

 Polymer based-drug conjugated:Polymer based conjugate improve the aqueous solubility of drugmolecules and hence increasing the bioavailability. This is of significantrelevance as it has been estimated that 40–60% of drugs in development exhibitpoor bioavailability due to low aqueous solubility. In addition, polymer-drugconjugates reduce the flocculation with periodic dosing and administrationdecreasing the undesired side effects and the possible organ toxicity due tohigh concentration of the drug.

Polymer conjugation also increases thecirculation time in plasma This is particularly useful for drugs which exhibita short blood plasma half-life due to rapid metabolism or clearance or fordrugs which exhibit off target toxicities (i.e. anticancer agents).

As previously mentioned, anothermajor advantage that can be realized through drug-polymer conjugation is theinclusion of targeting moieties, which function to carry the drug to the siteof pharmacological action. Poly ethylene glycol (PEG) and N-(2-hydroxypropyl)methacrylamide (HPMA) are the most investigated polymers into drug conjugated Larson and Ghandehari 2013. Poly ethylene glycol (PEG) gained importance due to its ability toprotect proteins, when proteins are conjugated with (PEG) it prevents proteindegradation by enzymes and reduces uptake by reticuloendothelial system Pasut 2008. Protein PEGylation has ledto the development of numerous therapeutics, including PEG-asparaginase(Oncaspar), PEG-adensoine deaminase (Adagen), PEG-interferon ?-2a (Pegasys),PEG-interferon ?-2b (PEG-Intron), PEG-granulocyte colony-stimulating factor(Neulasta), and PEG-growth hormone receptor antagonist (Somavert). The biocompatibilityof PEG has led to this development in PEG drug conjugates, but since PEG non-biodegradablethis might lead for conjugate accumulation and toxic side effects another disadvantageof PEG-drug conjugates is the low drug loading that is achieved due toconjugation at only the end chains of PEG. To overcome these limitations, branched andmultiarm PEGs have been investigated which can be excreted more easilyfollowing biodegradation Larson andGhandehari 2013.

N-(2-hydroxypropyl) methacrylamide(HPMA) copolymers showed great hydrolytic stability upon the Substitution ?-carbonand the presence of an amide linkage in the side. In addition, side chainswhich include drugs, targeting moieties, imaging agents, or reactive groups canbe combined with relative synthetic ease. The development of oligopeptidesequences drug linkers greatly pushed for further of HPMA as drug.

They weredesigned to ensure hydrolytic stability during systemic transport because oftheir ability to be enzymatically cleaved by lysosomal enzymes followingcellular internalization Larson and Ghandehari2013. PK1 polymer-drug conjugate for cancer therapy consists ofthe anticancer anthracycline antibiotic doxorubicin (8.7% of weight) attachedto a HPMA copolymer backbone via the lysosomally degradable sequence GFLG. PK1demonstrated higher tumor accumulation of doxorubicin by 17–70 fold than freedoxorubicin in melanoma tumor bearing mice. These promising results led to thefurther clinical development of PK1.

Also, PK1 was generally well toleratedwith and no anthracycline related cardiotoxicity until doses greater than 1680mg/m2 Seymour LW 2009.