Assessment of penetration potential of pH responsive double walled biodegradable nanogels coated with eucalyptus oil for the controlled delivery of 5-fluorouracil: In vitro and ex vivo studies

Penetration enhancers coated biodegradable polymeric nanogels loaded with cytotoxic drugs applied via the topical route, can be a promising strategy for improving the chemotherapeutic efficiency of skin cancers. The major objective of proposed research was to investigate the in vitro and ex vivo chemotherapeutic potential of double walled PLGA-chitosan biodegradable nanogel entrapped with 5-fluororuacil (5-FU) coated with eucalyptus oil, topically applied onto the skin. 5-FU was first entrapped in PLGA core by solvent evaporation technique followed by coating with cationic chitosan for ionic interaction with anionic skin cancer cell membrane. A surface coating of eucalyptus oil (1%) was employed to improve the penetration efficacy of the nanogel into stratum corneum. The surface modified biodegradable double walled nanogel was characterized for particle size, charge and thermal properties followed by pH dependent in vitro analysis. Human keratinocyte (HaCaT) cell line was employed for the bio- and cyto-compatibility testing prior to the hemolysis assay and coagulation assessment. A porcine skin ex vivo screening was performed for assessing the penetration potential of the nanogels. DLS and TEM revealed a particle size about 170 nm for the double walled nanogels. The nanogels also exhibited high thermal stability as analyzed by thermogravimetry (TG) and differential thermal analysis (DTA). The drug entrapment efficacy was about similar to 40%. The drug release showed sustained release pattern noted up to 24 h. The low hemolysis of 2.39% with short prothrombin time (PT) and activated partial thromboplastin time (APTT) of 14.2 and 35.5 s respectively, revealed high biocompatibility of the nanogels. The cellular uptake and localization was assessed by confocal microscopy. The cytotoxicity (MTT assay) on HaCaT cell line demonstrated high cytocompatibilty of the nanogels. An ex vivo evaluation using porcine skin displayed efficient and steady state flux of 5-FU from the biodegradable nanogles into the skin, while the histology of the porcine skin revealed enhanced penetration potential of eucalyptus oil coated PLGA-chitosan doublewalled nanogels. Taken together the in vivo and ex vivo results portend promising potential for the utility of the biodegradable nanogels for treating skin cancers. (C) 2017 Published by Elsevier B.V.