Arvind K. Singh Chandel

Effect of Polyethylene Glycol on Properties and Drug Encapsulation–Release Performance of Biodegradable/Cytocompatible Agarose–Polyethylene Glycol–Polycaprolactone Amphiphilic Co-Network Gels

We synthesized agarose-polycaprolactone (Agr-PCL) bicomponent and Agr-polyethylene glycol-PCL (Agr-PEG-PCL) tricomponent amphiphilic co-network (APCN) gels by the sequential nucleophilic substitution reaction between amine-functionalized Agr and activated halide terminated PCL or PCL-b-PEG-b-PCL copolymer for the sustained and localized delivery of hydrophilic and hydrophobic drugs. The biodegradability of the APCNs was confirmed using lipase and by hydrolytic degradation. These APCN gels displayed good cytocompatibility and blood compatibility. Importantly, these APCN gels exhibited remarkably high drug loading capacity coupled with sustained and triggered release of both hydrophilic and hydrophobic drugs. PEG in the APCNs lowered the degree of phase separation and enhanced the mechanical property of the APCN gels. The drug loading capacity and the release kinetics were also strongly influenced by the presence of PEG, the nature of release medium, and the nature of the drug. Particularly, PEG in the APCN gels significantly enhanced the 5-fluorouracil loading capacity and lowered its release rate and burst release. Release kinetics of highly water-soluble gemcitabine hydrochloride and hydrophobic prednisolone acetate depended on the extent of water swelling of the APCN gels. Cytocompatibility/blood compatibility and pH and enzyme-triggered degradation together with sustained release of drugs show great promise for the use of these APCN gels in localized drug delivery and tissue engineering applications.

Degradable/cytocompatible and pH responsive amphiphilic conetwork gels based on agarose-graft copolymers and polycaprolactone

Amphiphilic conetwork (APCN) gels have emerged as an important class of biomaterials due to their diverse applications. APCN gels based on biocompatible/biodegradable polymers are useful for controlled release and tissue engineering applications. Herein, we report a facile synthesis of APCN gel films by click type sequential nucleophilic substitution reaction between pendent tertiary amine groups of agarose-g-poly(methyl methacrylate)-b(co)-poly(2-dimethylamino)ethyl methacrylate [Agr-g-PMMA-b(co)-PDMA] copolymers and activated benzyl chloride groups of polychloromethyl styrene or benzyl methyl chloride terminated polycaprolactone. A linear triblock copolymer (PDMA-b-PMMA-b-PDMA) containing a central PMMA block and end PDMA blocks was also employed for the synthesis of APCN gels for comparison purposes. These APCN gels exhibit co-continuous nanophase morphology, pH responsive water swelling and pH triggered release of hydrophobic and hydrophilic drugs. These gels are biodegradable/cytocompatible as confirmed by MTT assay and hemolysis experiment. The degraded species undergo micellization in aqueous environment and display a low critical micelle concentration. Milled APCN gel particles are injectable through a hypodermic syringe. This synthesis approach is extremely useful for the preparation of a library of APCN gels of diverse architectures and compositions for biomedical applications.

Multifunctionalization of Poly(vinylidene fluoride)/Reactive Copolymer Blend Membranes for Broad Spectrum Applications

Simultaneous immobilization and cross-linking of antifouling/low toxic polymers, e.g., poly(ethylenimine) (PEI), dextran (Dex), agarose (Agr), poly(ethylene glycol) (PEG), PEI-Dex, and PEI-PEG conjugates, and stimuli-responsive copolymers on a porous membrane surface in mild reaction conditions is desirable for the enhancement of hydrophilicity, antifouling character, cytocompatibility, and inducing stimuli-responsive behavior. Grafting to technique is required since the precursors of most of these macromolecules are not amenable to surface-initiated polymerization. In this work, we report a versatile process for the simultaneous immobilization and cross-linking of a library of macromolecules on and into the blend membrane (PVDF-blend) of poly(vinylidene fluoride) and poly(methyl methacrylate)-co-poly(chloromethylstyrene). Sequential nucleophilic substitution reaction between activated halide moieties of the copolymer and amine groups of different macromolecules readily provided series of modified membranes. These membranes exhibited antifouling property superior to that of the unmodified membrane. The effectiveness of this technique has been demonstrated by the immobilization of pH or both pH- and temperature-responsive copolymer on PVDF-blend membrane for responsive separation of poly(ethylene oxide) and bovine serum albumin. Silver nanoparticles were also anchored on the select modified membranes surfaces for the enhancement of antibiofouling property. Our approach is useful to obtain verities of functional membranes and selection of membrane for a particular application.

Anti-organic fouling and anti-biofouling poly(piperazineamide) thin film nanocomposite membranes for low pressure removal of heavy metal ions

Propensity towards anti-organic fouling, anti-biofouling property and low rejection of multivalent cation (monovalent counter ion) restricts the application of the state-of-art poly(piperazineamide) [poly(PIP)] thin film composite (TFC) nanofiltration (NF) membrane for the treatment of water containing toxic heavy metal ions, organic fouling agents and microbes. Herein, we report the preparation of thin film nanocomposite (TFNC) NF membranes with improved heavy metal ions rejection efficacy, anti-biofouling property, and anti-organic fouling properties compared to that of poly(PIP) TFC NF membrane. The TFNC NF membranes were prepared by the interfacial polymerization (IP) between PIP and trimesoyl chloride followed by post-treatment with polyethyleneimine (PEI) or PEI-polyethylene glycol conjugate and then immobilization of Ag NP. The IP was conducted on a polyethersulfone/poly(methyl methacrylate)-co-poly(vinyl pyrollidone)/silver nanoparticle (Ag NP) blend ultrafiltration membrane support. The TFNC membranes exhibited >99% rejection of Pb2+, 91-97% rejection of Cd2+, 90-96% rejection of Co2+ and 95-99% rejection of Cu2+ with permeate flux ∼40Lm-2h-1 at applied pressure 0.5MPa. The improved heavy metal ions rejection efficacy of the modified NF membranes is attributed to the development of positive surface charge as well as lowering of surface pore size compared to that of unmodified poly(PIP) TFC NF membrane.

Synthesis and Multi-Responsive Self-Assembly of Cationic Poly(caprolactone)-Poly(ethylene glycol) Multiblock Copolymers

Individual dissimilar blocks were combined to obtain well-defined An Bn and (A-B-A)n types of cationic amphiphilic multiblock copolymers (MBCs) through mild sequential nucleophilic substitution without formation of byproducts. MBCs were synthesized by reacting end-functional polymer blocks of poly(caprolactone) (PCL), poly(ethylene glycol) (PEG), and PCL-b-PEG-b-PCL. For selective degradation, acid- and base-labile ester as well as reducible disulfide groups were introduced as linkers between the blocks. The micellar self-assemblies of these MBCs showed exceptional stability under normal physiological conditions with negligible release of the guest molecules. Selective disassembly under mildly acidic and basic conditions or in the presence of reducing agents caused triggered release of the guest molecules. This strategy is versatile and opens an opportunity to obtain a variety of tailor-made MBCs for selective and triggered release of therapeutics.

Self-Assembly of Partially Alkylated Dextran-graft-poly[(2-dimethylamino)ethyl methacrylate] Copolymer Facilitating Hydrophobic/Hydrophilic Drug Delivery and Improving Conetwork Hydrogel Properties

Key issues of injectable hydrogels are incapability of loading hydrophobic drugs due to insolubility of drugs in aqueous prepolymer solution as well as in hydrogel matrix, and high water swelling, which leads to poor mechanical and bioadhesive properties. Herein, we report that self-assembly of partially long-chain alkylated dextran- graft-poly[(2-dimethylamino)ethyl methacrylate] copolymer in aqueous solution could encapsulate pyrene, a hydrophobic probe, griseofulvin, a hydrophobic antifungal drug, and ornidazole, a hydrophilic antibiotic. Addition of activated chloride terminated poly(ethylene glycol) (PEG) into the guest molecules loaded copolymer solution produced an injectable dextran- graft-poly[(2-dimethylamino)ethyl methacrylate]-linked-PEG conetwork hydrogel. The alkylated hydrogels exhibited zero order release kinetics and were mechanically tough (50-54 kPa storage modulus) and bioadhesive (8-9 kPa). The roles of alkyl chains and dextran on the drug loading-release behavior, degradation behavior, gelation time, and the mechanical property of the hydrogels have been studied in details. Additionally, DNA hybrid composite hydrogel was formed owing to the cationic nature of the prepolymer solution and the hydrogel. Controlled alkylation of a prepolymer thus highlights the potential to induce and enhance the hydrogel property.

Nanotechnology Delivery Systems of Coenzyme Q10: Pharmacokinetic and Clinical Implications

Coenzyme Q10 is an antioxidant essential for biochemical reactions in the human body. The deficiency of the coenzyme Q10 in the body leads to several disorders including neurological degeneration, ageing, and cancer. In cell mitochondria, coenzyme Q10 is a cofactor as electron transport system and is responsible for the synthesis of adenosine triphosphate (ATP), a major source of energy. Clinical trials reported the role of coenzyme Q10 in as the drug or dietary supplement. The major issue concerning coenzyme Q10 delivery is its high molecular weight and poor water solubility. This limitation ultimately leads to its poor oral bioavailability. Traditional approaches has been made to overcome poor water solubility, such as size reduction and ionization. New drug delivery carriers include nanoparticles, solid dispersions, liposomes, nanoemulsions, self-emulsifying drug delivery system, nanostructured lipid carrier, cyclodextrins and nanocapsules. These nanocarriers facilitate absorption of coenzyme Q10 from gastrointestinal tract and increase oral bioavailability. Here we review nanotechnology-based drug delivery system for coenzyme Q10 with special emphasis on pharmacokinetic perspective and clinical relevance.

Dually crosslinked injectable hydrogels of poly(ethylene glycol) and poly[(2-dimethylamino)ethyl methacrylate]-b-poly(N-isopropyl acrylamide) as a wound healing promoter

Rapid gelation, low heat generation, biocompatibility, biodegradability, avoiding the use of a small molecular weight gelator and high gel fraction are the essential criteria for the successful biomedical application of an injectable hydrogel. We have developed a series of dually crosslinked injectable hydrogels of PEG and poly[2-(dimethylamino)ethyl methacrylate]-b-poly(N-isopropyl acrylamide) through extremely simple chemistry. The sequential nucleophilic substitution reaction between PEG containing reactive termini and the copolymer provided chemically crosslinked hydrogels with a gel fraction as high as 96-99% with a gelation time of 1-4 min under physiological conditions. The gelation occurred with ca. 1 °C rise in temperature per gram of the injectable solution, avoids formation of by-products and can be performed in the temperature range of 20-37 °C. The hydrogels undergo hardening at a physiological temperature as confirmed by rheological experiments. The gelation time, water swelling, mechanical properties and degradability of the hydrogels depend on the PEG to copolymer ratio in the injectable solution. The rheological behaviour of the fully hydrated hydrogels showed desirable mechanical properties for soft tissue regeneration. The hydrogels exhibited blood compatibility and retained the viability of HepG2 cells with time. Platelet adhesion and aggregation followed by fibrinogen adsorption ability makes these hydrogels suitable for wound healing applications.