3,3'-Diselenodipropionic acid immobilised gelatin gel: a biomimic catalytic nitric oxide generating material for topical wound healing application.

Nitric oxide (NO) plays a pivotal role in the wound healing process and promotes the generation of healthy endothelium. In this work, a simple method has been developed for fabricating a diselenide grafted gelatin gel, which reduces NO donors such as S-nitroso-N-acetylpenicillamine (SNAP) by glutathione peroxidase-like mechanism to produce NO. Briefly, the process involved covalently conjugating 3,3'-diselenodipropionic acid (DSePA) with gelatin via carbodiimide coupling. The resulting gelatin-DSePA conjugate (G-Se-Se-G) demonstrated NO production upon incubation with SNAP and glutathione (GSH) with the flux of 4.8 ± 0.6 nmol cm-2 min-1 and 1.6 ± 0.1 nmol cm-2 min-1 at 10 min and 40 min, respectively. The G-Se-Se-G recovered even after 5 days of incubation with the reaction mixture retaining catalytic activity up to 74%. Subsequently, G-Se-Se-G was suspended (5% w/v) in water with lecithin (6% w/w of gelatin) and F127 (3% w/w of gelatin) to prepare gel through temperature dependant gelation method. The fabricated G-Se-Se-G gel exhibited desirable rheological characteristics and excellent mechanical stability under storage conditions and did not cause any significant toxicity in normal human keratinocytes (HaCaT) and fibroblast cells (WI38) up to 50 µg ml-1 of selenium equivalent. Finally, mice studies confirmed that topically applied G-Se-Se-G gel and SNAP promoted faster epithelization and collagen deposition at the wound site. In conclusion, the development of a biomimetic NO generating gel with sustained activity and biocompatibility was achieved.

Tuning the pharmacokinetics and efficacy of irinotecan (IRI) loaded gelatin nanoparticles through folate conjugation.

Gelatin based nanocarriers have major limitation of shorter circulation half-life (t1/2). Present study addressed this issue by conjugating gelatin with folate followed by nanoprecipitation in presence of polysorbate 80 to form folate attached gelatin nanoparticles (GNP-F). The folic acid was conjugated with gelatin through the formation of amide linkage with a maximum conjugation yield of ~69%. Cryo-SEM analysis indicated that unconjugated gelatin nanoparticles (GNP) and GNP-F were spherical of nearly identical size of ~200 nm. The irinotecan (IRI)-loading efficiency estimated for IRI-GNP and IRI-GNP-F was 6.6 ± 0.42% and 11.2 ± 0.73% respectively and both formulations showed faster release of IRI at acidic pH (~5) than at physiological pH (~7). Further IRI-GNP-F demonstrated significantly higher cytotoxicity in folate receptor (FR)-positive HeLa cells than the unconjugated IRI-GNP nanoparticles confirming active targeting. Subsequently the antitumor activity of above formulations in FR-positive fibrosarcoma (syngeneic) tumor-bearing mice followed the order of IRI-GNP-F > IRI-GNP > free IRI. The pharmacokinetic evaluation of IRI-GNP and IRI-GNP-F revealed that encapsulation of IRI within GNP without folate improved its plasma maximum concentration (Cmax). However, folate conjugation of GNP remarkably improved the t1/2 of IRI. Taken together, folate as a targeting ligand modulates the pharmacokinetic property of IRI loaded GNP to favor active verses passive targeting.

Passive and Active Drug Targeting: Role of Nanocarriers in Rational Design of Anticancer Formulations.

BACKGROUND: Cancer is the major public health problem in developing countries. The treatment of cancer requires a multimodal approach and chemotherapy is one of them. Chemotherapeutic drug is administered to cancer patients in the form of a formulation which is prepared by mixing an active ingredient (drug) with the excipient. The role of excipient in a formulation is to regulate the release, bio-distribution, and selectivity of drug within the body. METHODS: In this context, selectivity of an anticancer formulation is achieved through two mechanisms like passive and active targeting. The passive targeting of a formulation is generally through enhanced permeation retention (EPR) effect which is dictated by physical properties of the carrier such as shape and size. On the contrary, active targeting means surface functionalization of excipient with target-specific ligands and/or receptors to increase its selectivity. RESULTS: Over the past several decades, remarkable progress has been made in the development and application of an engineered excipient or carrier to treat cancer more effectively. Especially nanoparticulate systems composed of metal/liposomes/polymeric material/proteins have received significant attention in the rational design of anticancer drug formulations; for example, therapeutic agents have been integrated with nanoparticles of optimal sizes, shapes and surface properties to improve their solubility, circulation half-life, and bio-distribution. In this review article, recent literature is included to discuss the role of physicochemical properties of excipients in achieving tumour targeting through passive and active approaches. CONCLUSION: The selection of an excipient/carrier and targeting ligand plays a very important role in rational design and development of anticancer drug formulations.