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 170nm 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 ~40%. The drug release showed sustained release pattern noted up to 24h. The low hemolysis of 2.39% with short prothrombin time (PT) and activated partial thromboplastin time (APTT) of 14.2 and 35.5s 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 double walled nanogels. Taken together the in vivo and ex vivo results portend promising potential for the utility of the biodegradable nanogels for treating skin cancers.
Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar, MP, India.
Prashant
P
Sahu
Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar, MP, India; Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, 259 Mack Ave, Wayne State University, Detroit, MI 48201, USA. Electronic address: sushil.kashaw@wayne.edu.
Sushil K
SK
Kashaw
Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab, India.
Sanyog
S
Jain
Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, 259 Mack Ave, Wayne State University, Detroit, MI 48201, USA.
Samaresh
S
Sau
Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, 259 Mack Ave, Wayne State University, Detroit, MI 48201, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI 48201, USA. Electronic address: arun.iyer@wayne.edu.
Arun K
AK
Iyer
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000008:administration & dosage / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D065546:Drug Liberation; D005052:Eucalyptus; D005472:Fluorouracil / Q000008:administration & dosage*; D005782:Gels / Q000008:administration & dosage / Q000737:chemistry; D006461:Hemolysis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000008:administration & dosage / Q000737:chemistry; D049329:Nanostructures / Q000008:administration & dosage* / Q000737:chemistry; D010938:Plant Oils / Q000008:administration & dosage* / Q000737:chemistry; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption; D013552:Swine
D000964:Antimetabolites, Antineoplastic; D003692:Delayed-Action Preparations; D005782:Gels; D010938:Plant Oils; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D048271:Chitosan; D005472:Fluorouracil
5-FU; Biodegradable polymeric nanogels; Chitosan; Controlled release; Eucalyptus oil; Nanogels; Nanoparticles; Skin cancer; Sustained release; Topical delivery