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European Journal of Nanomedicine

Editor-in-Chief: Hunziker, Patrick / Mollenhauer, Jan

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A contemporary review on – polymer stereocomplexes and its biomedical application

Muthupandian Saravanan
  • Corresponding author
  • Institute of Biomedical Sciences, College of Health Science, Mekelle University, Mekelle 1871, Federal Democratic Republic of Ethiopia
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  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Abraham J. Domb
  • Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
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  • De Gruyter OnlineGoogle Scholar
Published Online: 2013-04-04 | DOI: https://doi.org/10.1515/ejnm-2012-0017

Abstract

Nanomedicine is the most emerging, multidisciplinary field of research that is gaining popularity in recent years. Nanomedicine encompasses medical applications of nanomaterials, nanoelectronic biosensors including future applications of molecular nanotechnology. Nanomedical approaches to drug delivery, wound healing and treatment of certain diseases center on developing nanoscale particles such as sterocomplexed polymers and hydrogels or similar molecules to improve drug bioavailability. These polymers are biodegradable, bioactive, biocompatible and their strong interactions with the drug help in sustained release of the drug for longer periods. The formulation of these drugs and sterocomplexed polymers to be used as controlled drug delivery system are discussed in this tutorial review. Polymer stereocomplexes have a great promise in sustained delivery of human growth hormone, insulin, Leuprolide, Bupivacaine, Dexamethanosone, Doxorubicin, Haloperidol and vaccines. Various novel ideas of drug delivery into eye, uterus (birth control), targeted cancer therapy and brain diseases (Parkinson’s and Alzheimer’s diseases).

Keywords: biocompatible; biodegradable polymer; controlled drug delivery; nanomedicine; polymer stereocomplex

Introduction

Nanotechnology is a multidisciplinary field which is gaining enormous developments in science frontiers there by developing a novel science and puzzling out the problems with accuracy. Quite number of researchers is focusing on nanoscience to overcome the residing problems in the fields of science and technology. The interdisciplinary oriented hypothesis should have the sound knowledge of the nanotechnology to resolve the upcoming problems. Nanoscience, concerned with the size of the synthesized products with brilliant properties, plays a vital role in this modernized era.

Biopolymers have been intensively studied and used for various applications owing to its exclusive properties such as biodegradability (polymer degrades either chemically or enzymatically and are excreted naturally through kidney or by degrading into smaller metabolites of the body), biocompatibility and bioactiveness and thus synthetic polymers are replaced with biopolymers (1–10). These are applied as drug carriers, in wound dressing, medical devices in biomedical applications and as cell scaffold in tissue engineering (11–14). The proper choice of the polymer plays an important role in successful biomedical application.

Polymers which are held by interactions possess different tacticities and configuration prevails over that one with same tacticity or configuration, so that a stereoselective association of the prior polymer takes place, such association is said to be as stereocomplexation. Fox et al. reported an example for stereocomplex association i.e., the one between isotactic and syndiotactic poly(methyl methacrylate) (15). Pauling and Corey first reported stereocomplexation for enantiomeric polymers between R- and S-configured polymer chains in a polypeptide (16). Slager and Domb reported that polymers with identical and non-identical chemical structures are called as homostereocomplexes and heterostereocomplexes, respectively (17). Stereocomplexation occurs between the polymers with isotactic and syndiotactic properties or with R- and S-configured polymer chains with distinguished chemical structures. Stereocomplexes have different physiochemical behavior when compared to their parent polymers.

Stereocomplexed polymers are mainly focused on drug delivery mechanism (18). Polymer stereocomplexes mainly include polyesters, polyanhydrides, polyamides, polyethers, polyketones and are used for many biomedical applications. Among these, polyesters and polyanhydrides are mainly used for drug delivery mechanism. Sterocomplexed polymers were advantageous especially used in controlled release of the drug. The drug release depends on the polymer backbone and polymer isomer which is purely dependant on molecular interactions and slightly dependant on rate of diffusion. Drug delivery particles are spontaneously generated in the absence of specific surfactants or additives, by ignoring the microsphere preparation process (19).

Proteins have a three-dimensional helical structure that naturally twists in a counter-clockwise direction (“L-Configured”). The biodegradable material, poly(lactic acid) (“PLA”), has both clockwise (D-Configured) and counter-clockwise types that have a structural similarity in terms of torsion angles and bond-lengths to the “backbone” of the protein helix structure. Slager and Domb (19) discovered that D-PLA forms stereocomplexes with naturally occurring L-configured proteins along the protein backbone. The discovery of this three-dimensional molecular “wrapping” has tremendous implications in the sustained release of protein drugs. The concept uses D-PLA to form a complex with therapeutic proteins. Over time the D-PLA molecule degrades and is eliminated from the body. As the D-PLA/protein complex breaks down, the therapeutic protein is released at a rate which can be engineered to provide optimal dosage (Figure 1).

Illustration of polymer stereocomplexation of DL-PLA, D-PLA and L-Peptide.
Figure 1

Illustration of polymer stereocomplexation of DL-PLA, D-PLA and L-Peptide.

Hydrogels are three dimensional, hydrophilic and polymeric networks. These are capable of imbibing huge amount of water or biological fluids within networks but can retain their three dimensional structure even in the swollen state and thus these are being used as contact lenses, in protein separation, as matrices for cell encapsulation, in several pharmaceutical applications and also in biomedical applications as biomedical devices for controlled drug delivery (20–25). The water content in the hydrogels is at least 20% of its total weight (26). So there is very low interfacial tension between the hydrogel surface and aqueous solution which is one of the factors why protein adsorption and cell adhesion is diminished. Hydrogels can be classified into various groups based on its physical structure (i.e., amorphous, semicrystallinity, hydrogen bonded or supramolecular), electric charge (i.e., ionic or neutral) and Crosslink (i.e., physical). In physical gels, the polymer networks are cross linked by non-covalent interactions such as hydrogen bonds, hydrophobic interactions, sterocomplex formations, ionic complexation and crystallized domains, and chemical. The polymer which is covalently cross linked is referred to as chemical gel (27, 28).

Methods of stereocomplexation

Solid mediated stereocomplexation

Polymerization

Spinu et al. have recently reported a new method for the formation of stereocomplex between two enantiomeric polymers. Polymerization of L and D forms of stereoisomer in the presence of D and L polymeric enatiomers, respectively, gives L-stereoisomer with D form of polymeric enantiomer (29–31). They also stated that the polymerized chains prepared in this method have strong interaction with the template chains and thus it gives well stereocomplexed materials (32).

Compression

Bourque et al., Pelletier and Pezolet reported that stereocomplex formation takes place when subjected to compression. Monolayers of D/L polymeric enantiomers were compressed in the mixture films. Stereocomplexed bi-layers were formed in the equilibrium with the monolayer at the air-water interface (33, 34).

Orientation

Tsuji et al. demonstrated that stereocomplex crystallization of the equimolar L and D polymeric enantiomers were enhanced by heat, where this process causes expanded chain length or increased surface area per unit molecule (35). As a result there is an increased probability of interactions between L and D enantiomers causing increase in the Tm and Xc which promotes tensile properties (36).

Hydrolytic degradation

Li et al. proposed that stereocomplex formation occurs by hydrolytic degradation in copolymers with mm thickness for longer periods and those having <200 μm thickness cannot form stereocomplex (37–41). Hydrolytic degradation promotes decreasing molecular weight and upon addition of plasticizer there is mobility of the polymeric chains i.e., removing atactic sequences selecting and leaving isotactic chains.

In solutions mediated stereocomplexation

If once the polymer stereocomplexed crystallites are formed, they are insoluble in solvents like chloroform, dioxane while parent enantiomers are soluble. The stereocomplex crystallites are soluble in good solvents at elevated temperatures near the boiling point or at extremely good solvents at room temperature, yet the stereocomplex may not dissolve in the good solvents even at high temperature if the thickness of the polymer is high.

Fixed polymer concentration

When polymer concentration exceeds critical level then polymer crystals are formed. The critical concentration of stereocomplex crystallization is much lower than that of parent enantiomeric homocrystallization. It is said that good solvents of the enantiomers might be poor solvents or non-solvents for the stereocomplexes of the respective enantiomers. Thus, the initial polymer concentration will be less than the critical level for homocrystallizate formation and higher than that of stereocomplex formation. So, the separate solutions of the two enantiomers are mixed for stereocomplex crystallization. Such stereocomplexation induces particulate precipitates or single crystals in dilute solutions or gels in concentrated solutions (42, 43). Murdoch and Loomis first observed gel formation in PLA stereocomplexation in 1960s (36). In this, stereocomplexed crystalline regions act as physical crosslinks between the PLA chains where D and L lactyl units are insoluble in water and thus hydrogels are formed in aqueous media upon mixing (44).

Casting

By solvent evaporation, the polymer concentration is increased from initial to infinite concentration. During the process of solvent evaporation, first the polymer concentration exceeds the critical level of stereocomplexation and then reaches the homocrystallization. Stereocomplexation occurs when there is equimolar concentration of enantiomers and low solvent evaporation. Rapid solvent evaporation will not form stereocomplexation instead polymer concentration may reach homocrystallization.

Precipitation into non-solvent

When mixed solutions of enantiomers suspended in non-solvent or a precipitant causes removal of the solvent from the solution and diffusion of non-solvent into solvent resulting in fast crystallization. The high shear rate of the non-solvent and low polymer concentration favors stereocomplex crystallization (45).

Controlled drug delivery mechanisms

The most upcoming trends in pharmacological applications during the past two decades deal with controlled release devices (46–48). The main aim of the controlled release of the drug is to improve the effectiveness of drug therapy and thereby increasing patient compliance (46, 49). The controlled release of the drug is based on the detachment of stereocomplex and diffusion rate, i.e., the rate at which the peptide is diffused from the matrix which is assisted by polymer degradation (50). The drug encapsulated in the matrix allows the drug to be maintained at a required optimum level which not only increases therapeutic activity but also decreases its side effects. Besides such formulations are made to target the drug to the active site and to protect the active component from environmental enzymatic degradation (18). Biodegradable polymer mainly includes polyether and polyanhydrides. They are favoured for controlled drug delivery systems as they have hydrophobic backbone and hydrolytical labile anhydride and/or ester bonds which hydrolyse to give decarboxylic acids and hydroxyl acids monomers when placed in aqueous medium.

In vitro release of the drug is influenced by the properties of the polymer and nanoparticles, such as polymer hydrophobocity, particle size and particle location. Increase in the polymer hydrophobicity diminishes the initial burst and there by extends the releasing period. Increase in the particle size depromotes the initial burst and promotes the release rate.

Temporal

The drug is delivered over an extended period or at a specific time during the treatment. Controlled release over an extended duration is advantageous for those drugs which are metabolized rapidly and eliminated soon after the administration into the body (18).

Delayed dissolution

Drug molecules should be dissolved in aqueous surroundings within the body so that the drug can easily diffuse before they act on the target. This drug molecules are protected from aqueous environment by using polymers so that they cannot diffuse out from the polymer there by controlling the drug flow (51). The delayed drug delivery can be achieved by controlling the rate of dissolution at which drug delivery vehicle (polymer matrix) are exposed to water in the aqueous environment.

Diffusion controlled

Within the aqueous solution, the diffusion of drug molecules is inhibited by polymer matrix, and thus these drug molecules should pass through different pathways to diffuse out of the matrix. There are polymer chains as in hydrogel which are cross linked to form barrier. The barrier can be reduced by swelling the hydrogel so that the drug passes through the voids. Polymers used in diffusion controlled release can either be fabricated as matrices; where drug is distributed uniformly or as membranes; that protects the drug reservoir from environment.

Osmotic gradient

Sometimes drug solutions utilize osmotic potential gradients across semi permeable polymer barriers to generate pressurized chambers containing aqueous solutions of the drug. This pressure is relieved by the flow of the solution out of the delivery device. The rate of flow is controlled because flow is restricted to fluid transport through a micrometer scale to large diameter pore or pores. By using the above mechanisms many temporal controlled release devices release the drug at a constant rate. The other form of these mechanisms is that, the drug can be released only when the body is in pulsatile manner (52).

Solvent activated: drug entrapped in the polymer is released when an external solvent either swells the polymer or initiates water imbibement there by creating osmotic pressure. This osmotically controlled system contains an osmotic agent (tablet) which posses semi permeable membrane with laser drilled hole. When an external solvent enters the osmotic agent, then the drug is released out at a constant rate.

Distribution controlled

The most efficient method of achieving drug delivery is to directly deliver the drug to the target site. Majority of diseases require distribution controlled release of drug, where targeting mechanism allows the drug delivery system to find the desired target (53). Two types of polymers are used for this application, (1) colloidal carriers, where polymer encapsulates the drug within nano or microcapsules (54); and (2) polymer drug conjugates, both polymer and drug are held by covalent interactions. In both the types polymer acts only as a carrier but not as a targeting device (55). In these systems, biological molecules are frequently used as a targeting moieties which include immunoglobulin’s and carbohydrates. Polymer surfactants such as block copolymer of poly(ethylene glycol) and poly(propylene oxide) (which are also called as Pluronics) are used, which fluctuate the distribution control around the body (56–58). Change in distribution control is dependent on the ability of the surfact polymer to change the protein adsorption on the particle surfaces. The polymer drug conjugates contain spacer molecule which gets cleaved at the specific site.

Diffusion

In reservoir systems, drug is encapsulated by a polymer membrane such as capsule or microcapsule. In matrix systems, drug is distributed uniformly throughout the polymer. In both the cases, diffusion of drug takes place through the polymer backbone or pores in the polymer membrane, which is a rate limiting mechanism. The release rate of the drug from membrane is depended on steady state Ficks law of diffusion. In case of matrices, the diffusion takes place through solution-diffusion mechanism.

Chemical reaction

Water and enzymes cause the degradation of the polymer (bioerodible system) thus releasing the drug from the encapsulated polymer. In chemical point of view, bioerodible systems can be divided into three dissolution mechanisms: (1) water soluble polymers insolubilized by degradable crosslinks; (2) water insoluble polymers solubilized by hydrolysis, ionization/protonation of pendant side groups; and (3) water insoluble polymers solubilized by backbone chain cleavage to small water soluble molecules (Figure 2).

Mechanisms of controlled polymer-based drug release systems. (A) Delayed dissolution of drug mediated by a stereocomplexed polymer which dissolves slowly. (B) Delayed diffusion and controlled discharge of drug through stereocomplexed polymeric devices. (C) Controlled expulsion of the drug solution employed an osmotic potential gradient across a semi-permeable polymer network.
Figure 2

Mechanisms of controlled polymer-based drug release systems. (A) Delayed dissolution of drug mediated by a stereocomplexed polymer which dissolves slowly. (B) Delayed diffusion and controlled discharge of drug through stereocomplexed polymeric devices. (C) Controlled expulsion of the drug solution employed an osmotic potential gradient across a semi-permeable polymer network.

Biomedical application of polymer stereocomplexes

The strong interactions between the stereo regular polymers result in stereocomplexation. The stereocomplexed polymers holding good mechanical properties, thermal resistance, hydrolysis resistance gives the right platform for the development of novel biodegradable materials such as hydrogels and drug delivery particles. The stereocomplexed particles have wide range of applications in biomedicine.

Bupivacaine loaded in poly(DL: lactic acid co castor oil 3:7) for in vivo studies

Prolonged action of bupivacaine will extend the postoperative analgesia, reducing the post surgery complications (58, 59). Poly(DL: lactic acid co castor oil) 3:7 was loaded with 10% Bupivacaine in mice model. It was confirmed that this formulation blocks sensory and motorsignals and thus it is said to be toxic and also decreases burst release effect. Comparatively with 7.5% and 10% of the drug loaded in the polymer there is decrease in the toxicity and increase in the drug delivery activity. To obtain less toxicity and increased drug delivery system 15% of the drug was loaded in the polymer. It is said that 200-fold higher concentration is required for the humans compared to rats, but presently only 5–10-fold higher is prescribed as dosage. In clinical studies, a dosage of 150–250mg showed no significant side effects (60).

Somatostatin analogue

Apart from common delivery systems, one of novel concepts used for the delivery of peptides and proteins is heterosterocomplexation. Ashganand Abraham demonstrated that stereocomplexation occurs between D-PLA and peptides which is applied to control drug delivery systems (50, 61–63). Accordingly, somatostatin analogue was delivered as Octreotide mimicing naturally occurring somatostatin. Hetero-sterocomplexes of poly(D-Lactide) and L-octreotide were obtained by spray freezing the solution of PLA and octreotide. L-PLA is added to reduce the release rate initially. The release system was assayed in vitro in phosphate buffer which was determined by HPLC. It was reported that the stable stereocomplexes synthesized in the form of spherical porous microparticles gradually release the stereocomplexed peptide while D-PLA being degraded when placed in physiological medium (64).

Release of insulin

Slager and Domb reported L-peptide forms of diasteriomeric complex with isotactic D-PLA. In accordingly, D-PLA and L-insulin were suspended in acetonitrile solution forming microparticulate, diasteriomeric complexes spontaneously which was confirmed by SEM micrographs. Besides sterocomplexes of DPLA/LPLA entrapped insulin can be synthesized by blending in acetonitrile solution. The reaction of PLA enantiomers and insulin lead to the microparticelate complexes, where the release patterns were analyzed with HPLC. From the results it was observed that there was sustained release of PLA from the polymers without burst effect (61).

Delivery of dexamethanosone with stereocomplexes of triblock copolymers

Poly(lactide)-poly(ethylene glycol)-poly(lactide) (PLA-PEG-PLA) triblock copolymer were synthesized by ring open polymerization of lactide and PEG2000 diol as cocatalyst. Stereocomplexes were formed by blending (PLA-PEG-PLA) and homopoly(lactide) enantiomers in acetonitrile solutions yielding stereocomplexes of micro or nano particles stereocomplexes.

These stereocomplexes are applied for dexomethasone phosphate which is corticosteroid anti-inflammatory drug. In-vitro release of drug was analyzed, where it was found that the stereocomplexes encapsulate the drug in high yield and dexomethasone phosphate was gradually released and polymer was degraded rapidly which was shown by IR spectra because of its large surface area and also due to greater water accessibility causing splitting of the polymer chains of triblock copolymer stereocomplex (65, 66).

Wound healing

PLA holding good mechanical properties made itself useful for various applications such as scaffolds for tissue regeneration implants, wound dressing materials etc. (67–70). Yet there is a limitation that PLA for prolonged storage under physiological conditions results in high hydrolytic sensitivity. To overcome this, one of the approaches is the stereocomplexation between enantiomeric PLLA and PDLA synthesis by electrospinning which is an effective method for the synthesis of micro and nano fibrous materials (71). The formation of stereocomplexed crytallites is boosted by high degree of orientation during electrospinning and repressed when high molecular weight PDLA and PLLA are used (72).

Amphiphilic PLA based copolymer containing immunogenic block are extremely attractive for the preparation of materials with improved physiochemical properties and targeted behavior on contact cells and tissues as well. Poly(N,N-dimethylamino-Z-ethylmethacrylate) (PDMAEMA) possessing inherent hemostatic and antibacterial activity (73–78). There by using PLA-b-PDMAEMA block copolymer, novel PLA-sterocomplex fibres materials are prepared by electro spinning knowing that the surface of the fibers ‘SC’ PLA-b-PDMAEMA/MMPLA and HM (high molecular weight PLA) mats are enriched in tertiary amino groups of PDMAEMA.

These fibrous mats of both stereocomplex that is PDLA-b-PDMAEMA/HMPLLA and stereocomplex PLLA-b-PDMAEMA/HMDPLA are placed in contact with blood and analysed for blood counting by using SEM. Then it was observed that there was a decrease in RBC and thrombocytes count. The mats are intensively red because RBC is adhered and thrombocytes formation is observed. The RBC is aggregated, agglutinated and highly deformed and this is the indication that surface of stereocomplexes fibers are enriched with tertiary groups and PDMAEMA imparts the haemostatic properties. In the same manner they had observed for anti bacterial activity with S. aureus cells. Thus from this it was said that the stereocomplexes can be potentially used as wound healing materials as well as devices adhered with harmful micro organisms (79).

Inhibit growth of cancer cells

In 1931, Warburg reported that glycolysis is the primary source of anaerobic glucose metabolism within cancer cells and he was awarded Nobel Prize in medicine (80). It is not that all the cancer utilizes glycolysis for generation of ATP, but some undergo oxidative phosphorylation (Krebs cycle) to generate energy (81). Goldberg demonstrated that oligomers of polymer D-lactic acid (PDLA) will form a stereocomplex with L-lactate in vivo, resulting lactate deficiency in tumor cells. Those cancer cells that utilize the transport of lactate to maintain electrical neutrality may cease to multiply or die because of lactate trapping and these cancer cells that benefit from utilization of extra cellular lactate may be impaired. Neither of the concepts were conclusively proven, that is stereocomplexation and trapping lactate inhibit the tumor cell growth. But the concepts were supported by experiments with inefficient (high) concentrations of PDLA that are very likely to contain biologically active oligomer(s) that trap lactate as well as inactive oligomers (82).

Controlled release of Leuprolide using heterostereocomplexes of D-PLA and DL-PLA

Reversible stereoselective complexes can be formed between D-PLA and L-Peptide (61, 63). Reversible heterostereoselective complexes can be produced between enantiomeric D-PLA and L-Leuprolide (LHRH analogue) in acetonitrile solutions. The sterocomplexation between peptide and polymer were studied under several conditions with a focus to know whether they can be used for controlled drug delivery. In vivo system, the polymer loaded with peptide is administered through subcutaneous route and it was observed that the release of the drug from sterocomplex can be estimated by testosterone blood levels in rats. Leuprolide follows negative feedback mechanism where the drug initially enhances testosterone synthesis and later the synthesis is blocked to control testosterone levels.

Low testosterone blood levels were reported for 25days and after 4 weeks the suppressed testosterone level was slowly restored to its control levels. Besides in vitro studies revealed the release profile of the drug is depended on the molecular weight of the polymer and leuprolide content where high molecular weight of the polymer and increase in the drug content increases the amount of the release. Addition of additives like PEG and water also enhances the release of the drug for prolonged period and it was observed a logarithmic fit in all cases (19).

Reversible steroselective complexes were obtained spontaneously by enantiomeric D-PLA, L-PLA, L-leuprolide in acetonitrile solutions. Addition of L-PLA to the complex reaction mixture of D-PLA and L-leuprolide is done to observe the change in peptide release. The peptide release system is almost same as that of DPLA and L-peptide reaction mixture (Figure 3). However, there is a slight variation that low testosterone levels were reported for at least five weeks (50).

(A) Illustration of chain stereocomplexation. (B) Scanning electron microscopy. Image of Leuprolide/D-PLA hetero-stereocomplex, obtained by spontaneous precipitation from a solution of D-PLA (120 kDa) and Leuprolide (2%, w/w) in acetonitrile at 60°C. (C) D-PLA/L-PLA/octreotide 5% w/w obtained by spontanous precipitation from an acetonitrile (62, 64).
Figure 3

(A) Illustration of chain stereocomplexation. (B) Scanning electron microscopy. Image of Leuprolide/D-PLA hetero-stereocomplex, obtained by spontaneous precipitation from a solution of D-PLA (120 kDa) and Leuprolide (2%, w/w) in acetonitrile at 60°C. (C) D-PLA/L-PLA/octreotide 5% w/w obtained by spontanous precipitation from an acetonitrile (62, 64).

Delivery of anticancer drug doxorubicin with polyacetal

Though many polymer anticancer drug conjugates have been proposed only eleven of them are being used for clinical trials (83, 84). Tumor targeting by polymer conjugates for prolonged period occur by enhanced permeability and retention effect (85, 86). The magnitude of EPR effect by polymer conjugates significantly depend on plasma concentrations (87, 88). Aminopendantpolyacetals (APEG-DOX) has long circulating in plasma and improved tumor targeting when it is observed in C57 mice bearing a SC B16f10 tumor. An HPLC assay was used to quantitative the total dox content of plasma and tissue. Administration of APEG-DOX led to low deposition of dox in liver and spleen. PEG is hydrophilic polymers which are used to prolong the plasma circulation of proteins and liposomal drug carriers (89, 90). The high PEG content within APEG backbone is responsible for low uptake APEG-DOX by reticuloendothelial system. In kidney, high level of uptake was observed only for 1 h, after that there is no progressive accumulation (91).

PEG – Doxorubicin conjugates

PEG are being used so as to modify proteins and peptides to attain increased solubility, reduced immunogenic and increased resistance to proteolysis and to be means of pharmacokinetics and modulations (89, 92). PEG-DOX conjugates are produced by conjugating polymers, which can be either linear or branced structures and peptide linkers. Peptide linkers like GLG, GLFG, GFLG, Nle-RGLG, Nle-GGRR are used. Peptidyl linkers form covalent interaction between drug and polymer. In the present study, PEG is linked to GLFG. The antitumor activity was studied in male mice injected with tumor SC B16f10 murine melanoma cells (DOX resistant model) and ip L1210 (DOX sensitive model). The former model did not show significant antitumor activity where it appeared to correlate with increased rate of DOX release in the presence of lysosomal enzymes which is due to the presence of peptide linker. The later model PEG-DOX showed antitumor activity and has reduced survival compared to DOX. Thus, PEG-DOX conjugates possess EPR mediated targeting. With the substantiation of lesser effect on animal weight loss PEG-DOX are fewer toxic (93).

In-vitro release of Haloperidol loaded with PLGA

Bala et al., reported that by using PLGA, time controlled drug delivery can be achieved via polymer systems (94). By using homogenization and sonication, organic phase was prepared consisting of polymer poly(D,L-lactic-co-glycolic acid)/poly(lactic acid) (PLGA/PLA) and drug (Haloperidol) dissolved in organic solvent, dichloromethane (DCM). This organic phase was added to aqueous phase with surfactant polyvinyl alcohol (PVA) to form an emulsion. By using external energy on this emulsion, it breaks down to form nano droplets and when subjected to solvent evaporation, nano particles were formed.

In vitro release of this PLGA loaded drug was assayed by HPLC in PBS buffer solution. The amount of haloperidol released to the drug content depends on the volume of the sample. The effect of the various properties including polymer hydrophobicity, particle drug content and surface coating on the release behavior was also studied. Polymer hydrophobocity reduces the initial burst and prolongs the time period of the release rate. Coating the particle surface with chitosan considerably reduce the initial burst. Increasing the size of the particle reduces the initial burst and increases release rate. The predominant release mechanism is by diffusion (95).

Vaccine delivery

The vaccine containing adjuvant such as tyrosine encapsulated with lactic acid/glycolic acid copolymers can be released slowly for about one year from a single injection which occasionally promote higher antibody titers (96, 97). Various microcapsule injectable approaches showed different antigenic response such as, when administered orally, they become trapped in the peyer patches to release antigen and stimulate the production of secretory immunoglobulin A2, and the specific antigens which entered into the gastrointestinal track is destroyed (98).

Delivery of drug in eye

In between two ethylene vinyl acetate copolymer membranes pilocarpine (ocusert) is placed. The release rate depends on the thickness of the membranes. The drug is delivered at a slow steady rate so that the side effects will be withheld by eye drops; i.e., double vision can be reduced. It is beneficial to go with ocusert system which can be inserted within a week rather than having 28 eye drops (99).

Birth control

Ethylene vinyl acetate copolymer (reservoir system) slowly releases progesterone through diffusion over a year. This copolymer system is placed in the uterus as it delivers the drug to its target. Vaginal rings made up of silicone rubber are designed to release the birth control drugs slowly. These are generally used once in six months where this system is placed in the vagina for three weeks and then removed before one week from menstrual bleeding (100). A three day oral supplement of drug for a year is better and also that this system reduces bleeding.

Brain diseases

Parkinson’s disease: in animal models, ethylene vinylacetate copolymer discs loaded with dopamine are placed in brain to treat this disease (101). Alzheimer’s disease: in animal models, Bathenecol placed in poly(anhydride) microsperes are placed in hippocampus to treat this disease (102).

Hydrogel applications

Wichterle and Lim pioneered the novel hydrogels are the emerging, exciting material in the research field due to its soft, hydrophilic nature and biodegradability. These properties have drawn its applications in biomedical and delivery systems mainly in protein delivery with promising strategies (103).

Amphiphilic multiblock copolymers in wound healing

Hydrogels have many significant benefits for wound dressing because of its homogenous adhesion to the injured parts, free from wrinkles in the wound bed, easy removal and rapid reconstruction of the injured site without impairment and improved patient compliance (104).

Multiblock copolymers are composed of alternative short blocks of PEO poly(ethylene oxide) and PCL poly(ε-caprolactone) or PLLA poly(L-lactic acid) etc. The copolymers with high molecular weight forms physically crosslinked, thermoplastic biodegradable hydrogel while low molecular weight polymers are water soluble. PEO/PLLA multiblock copolymers loaded with basic fibroblast growth factor (bFGF) is applied for wound healing where, the bFGF possess significant wound healing properties, a promoter of angiogenesis, a mitogen and a chemoattractant for endothelial cells, fibroblasts and also a stimulator of the collagenase and plasminogen activator production (105–108). The bFGF triggers the degradation of extracellular matrix which facilitates the migration of cells to the wound site. In mice model, when bFGF loaded polymer matrix was applied to the wound, the healing rate is faster than the other control sites treated with commercially available ointments (fucidic acid) (109).

In-situ crosslinked biodegradable hydrogels loaded with IL-2

Several delivery systems have been reported earlier like polymer based release systems and liposomal formulations where the controlled delivery is very complicated to attain. However, controlled delivery of rhIL-2 has been attained by chemically crosslinked dextran based hydrogel with low cure rate (110–121).

Stereocomplexation between polymers with oppositely chirality were used as a novel method to synthesize physically crosslinked hydrogels (122–124). In this approach, dextran is changed by oligo(lactic acid) to obtain hydrogel by stereocomplexation in all aqueous environment. In this study, physical crosslinking was obtained, by stereocomplexation between L-lactic acid and D-lactic acid oligomers which can be grafted separately to dextran.

In mice models, physically crosslinked dextran hydrogels are loaded with rhIL-2 and investigated against SL-2 lymphoma. The loading of the rhIL-2 should be either by single shot or for five consecutive days (125–127). The therapeutic efficacy of physically cross linked dex-lactate is very good and its 100% curable (128).

Pluronic/Heparin composites enhance sustained release of bFGF

In-situ forming hydrogels are highly beneficial compared to conventional devices as they can be administered through a minimal invasive protocol to achieve controlled sustained release of the drug molecules. Heparin, well noticed natural polysaccharide from extracellular matrix, possesses specific binding affinity to certain growth factors which includes basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β) (129). For sustained delivery system, heparin is incorporated into injectable hydrogels along with growth factors which enhances the stability of growth factors. In-situ forming gels composed of star shaped PEG with heparin at the terminal ends were synthesized by using peptides as crosslinker for binding to the heparin (130). These hydrogels showed erosion dependent mechanism for release profile of bFGF. Hydrogels are formed by photopolymerization of di-acryl pluronic copolymer and vinyl conjugated heparin for bFGF delivery system (131). The Pluronic/Heparin composite hydrogels showed sustained release of bFGF in a bioactive form inducing neovascularization in vivo (132).

Insulin delivery

Insulin was encapsulated in poly(MMA-g-PEG) hydrogels crosslinked with tetraethylene glycol dimethacrylate (TEGDMA) that protects the drug from degradation by intestinal and gastric enzyme (133). Lowman et al. tested the delivery of insulin through oral route in vivo (134). If administered orally, insulin absorption and blood glucose reduction was observed and thereby enhancing the effect on insulin (135, 136). Madsen and Peppas reported that these hydrogels will bind to Ca+2 at the PH of the small intestine inhibiting the activity of Ca+2 dependent intestinal pump and thus protecting the drug from degradation (137).

Sustained delivery of human growth hormone using pluronic copolymer hydrogels

A novel hydrogel holds distinctive characters such as injectability, thermosensitivity, biocompatibility, bioerodability for in situ sustained delivery of human growth hormones composed of an equimolar mixture of oligo(D-lactic acid) and Oligo(L-Lactic acid) conjugated triblock co-polymers poly ethylene oxide-poly propylene oxide-poly ethylene oxide (PEO-PPO-PEO) or pluronic (PL) solutions. To improve the mechanical properties, the copolymer mixture was intermixed with PL solutions leading to alteration in the nanoscale internal networks resulting in modified PL hydrogel systems (138).

In the same manner Chung et al. used a series of multiblockpluronic copolymer linked with oligo(D-Lactic acid) and oligo(L-Lactic acid) conjugated with different spacers to synthesize stereocomplexed hydrogel which assists sustained delivery of human growth hormone by diffusion/erosion coupled mechanism (139). The release profiles of hGH by triblock copolymers as well as multiblock pluronic copolymer follow zero-order fashion, but there is a variation in sustained release periods that is multiblock pluronic copolymer release the drug for 13days while triblock copolymers release for 5 days.

Supramolecular hydrogels for controlled drug delivery

The new supramolecular hydrogel are fine tuned with composition, molecular weight and chemical structures of the copolymer. These are self assembled between poly(ethylene)-poly(R)-3-hydroxy-butyrate-poly (ethylene oxide) (PEO-PHB-PEO) triblock copolymer and α-cyclodextrin. These supramolecular hydrogels have dragged a keen observation on themselves as they serve as models to understand molecular recognition and also act as precursor for many new materials which are used for biomedical applications (140–142).

In-vitro studies were demonstrated by using this triblock copolymer and α-cyclodextrin with flurosceinisothiocyanate labeled dextran (dextran FITC) as a molecular drug. It was observed that the disappearance of the hydrogel occurs only after the complete release of dextran-FITC where the hydrogels gradually disappear by dissolution and dissociation of complex hydrogels. This supramolecular hydrogels are preferably used for delivery of drugs for longer periods (143).

Dextran hydrogels for protein release

It was reported that there is loss of activity of the proteins when they are released from polymeric materials (144–148). De Jong et al. reported that dextran-lactate hydrogels act as devices for protein delivery with full preservation of its enzymatic activity (123). L-lactic acid and D-lactic acid oligomers were grafted to dextran, forming dex-L-lactate and dex-D-lactate. Upon blending the solutions of dex-L-lactate and dex-D-lactate, a hydrogel which was crosslinked physically was formed by sterocomplexation between enantiomers (122, 124). Lysozyme and IgG are encapsulated within dextran hydrogel due to attractive properties of protein release. There is no need of reactive or protein incompatible crosslinking agents, organic solvents for the preparation of protein loaded gel. The release profile of the proteins is based on diffusion and the degradation depends on polydispersity lactate grafts. Low polydespersity of lactate grafts has longer degradation periods than the high polydispersity hydrogels.

Gene therapy

A variety of synthetic vectors were developed for gene transfer. Among these, cationic polymer based gene therapy methods have been the most extensively studied and more efficient in condensing DNA and RNA. Moreover further accuracy of the delivery system will constantly rely on a better understanding of the in vitro and in vivo barriers in gene transfer. Since the last two decades considerable improvements in the application of polymeric gene delivery systems are witnessed. Many types of polymers have been evaluated as gene delivery vehicles, among which polyethylenimines (PEI) are confirmed to have the most potential (149–151). Cationic polymer/DNA/RNA complexes (polyplexes) have been used in a number of experimental trails for the healing of cystic fibrosis and cancer (152–154). Recent studies have shown polymers can also form a stable nano-devices upon mixing with DNA/RNA and it was confirmed to the improved gene expression (155–157). As a result of these studies it would be great to validate the concept of human gene therapy.

Conclusion

Polymer stereocomplexes have a bright vision in sustained delivery of human growth hormone, insulin, Leuprolide, Bupivacaine Dexamethanosome, Doxorubicin, Haloperidol and vaccine. Various novel ideas like delivers the drugs into eye, uterus (birth control), targeted cancer therapy and brain diseases (Parkinson’s and Alzheimer’s diseases). It might result in an associated enhancement in the quality, efficiency, and safety profile of the polymer stereocomplexes.

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About the article

Muthupandian Saravanan

M. Saravanan completed his Post Graduation in Microbiology in 2000 at Madurai Kamaraj University, M.Phil, in Biotechnology in 2004 at Bharathidasan University, India and completed his PhD under the guidance of Dr. Anima Nanda at the Sathyabama University, Chennai, India, in 2010. Thereafter, he was done 1 year Post Doctoral Research through Israel Government research fellowship with Prof. Abraham J. Domb at The Hebrew University of Jerusalem, Israel 2011, worked on biodegradable polymers controlled drug delivery. He worked at SRM University, India as Assistant Professor (SG) of Department of Biotechnology from August 2005 to September 2012. He is currently working as Assistant Professor, Institute of Biomedical Sciences, College of Health Science, Mekelle University, Mekelle, Federal Democratic Republic of Ethiopia and has 15 publications to his credit that include research articles, reviews and book chapters. His current research interests are in Medical Microbiology, Nano-biotechnology and Nanomedicine.

Abraham J. Domb

Abraham J. Domb is the head of the Department of Identification and Forensic Sciences (DIFS), Israel police since 2007. He is a Professor for Medicinal Chemistry and Biopolymers at the Faculty of Medicine of the Hebrew University, Jerusalem, Israel. He earned Bachelor’s Degrees in Chemistry, Pharmaceutics and Law studies and PhD. Degree in Chemistry from Hebrew University. He did his postdoctoral training at MIT and Harvard University, USA, and was R&D Manager at Nova Pharm. Co. Baltimore, USA during 1988–1992. Since 1992 he is a faculty member at the Hebrew University of Jerusalem and has more than 200 publications to his credit that include research articles, reviews and book chapters with interests in biopolymers, medicinal chemistry and forensic sciences.


Corresponding author: Muthupandian Saravanan, Institute of Biomedical Sciences, College of Health Science, Mekelle University, Mekelle 1871, Federal Democratic Republic of Ethiopia, Phone: +251-344416678, Fax: +251-344416681


Received: 2013-12-14

Accepted: 2013-03-05

Published Online: 2013-04-04

Published in Print: 2013-07-01


Citation Information: European Journal of Nanomedicine, ISSN (Online) 1662-596X, ISSN (Print) 1662-5986, DOI: https://doi.org/10.1515/ejnm-2012-0017.

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