RESUMO
Polyglycerol scaffolds and nanoparticles emerged as prominent material for various biomedical applications including topical drug delivery. The impact of slight structural modifications on the nanoparticles' properties, drug delivery potential, and biocompatibility, however, is still not fully understood.Hence, we explored the influence of structural modifications of five structurally related polyglycerol-based nanoparticles (PG-PEG, SK1-SK5) on dermal drug delivery efficiency and biocompatibility. The PG-PEG particles were synthesized via randomly and controlled alkylated chemo-enzymatic approaches resulting in significantly varying particle sizes and interactions with guest molecules. Furthermore, weobserved considerably improved dermal drug delivery with the smallest particles SK4 and SK5 (11 nm and 14 nm) which also correlated with well-defined surface properties achieved by the controlled alkylated synthesis approach. The consistently good biocompatibility for all PG-PEG particles was mainly attributed to the neutral surface charge. No irritation potential, major cytotoxicity or genotoxicity was observed. Nevertheless, slightly better biocompatibility was again seen for the particles characterized by alkyl chain substitution in the core and not on the particle surface.Despite the high structural similarity of the PG-PEG particles, the synthesis and the functionalization significantly influenced particle properties, biocompatibility, and most significantly the drug delivery efficiency.
Assuntos
Materiais Biocompatíveis/química , Portadores de Fármacos/química , Glicerol/análogos & derivados , Nanopartículas/química , Preparações Farmacêuticas/administração & dosagem , Polietilenoglicóis/química , Pele/metabolismo , Animais , Células 3T3 BALB , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Dano ao DNA , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Glicerol/síntese química , Glicerol/química , Glicerol/toxicidade , Células Endoteliais da Veia Umbilical Humana , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/patologia , Camundongos , Estrutura Molecular , Oxazinas/administração & dosagem , Tamanho da Partícula , Polietilenoglicóis/síntese química , Polietilenoglicóis/toxicidade , Pele/efeitos dos fármacos , Absorção Cutânea/efeitos dos fármacos , Testes de Irritação da Pele , SuínosRESUMO
A growing intended or accidental exposure to nanoparticles asks for the elucidation of potential toxicity linked to the penetration of normal and lesional skin. We studied the skin penetration of dye-tagged dendritic core-multishell (CMS) nanotransporters and of Nile red loaded CMS nanotransporters using fluorescence microscopy. Normal and stripped human skin ex vivo as well as normal reconstructed human skin and in vitro skin disease models served as test platforms. Nile red was delivered rapidly into the viable epidermis and dermis of normal skin, whereas the highly flexible CMS nanotransporters remained solely in the stratum corneum after 6h but penetrated into deeper skin layers after 24h exposure. Fluorescence lifetime imaging microscopy proved a stable dye-tag and revealed striking nanotransporter-skin interactions. The viable layers of stripped skin were penetrated more efficiently by dye-tagged CMS nanotransporters and the cargo compared to normal skin. Normal reconstructed human skin reflected the penetration of Nile red and CMS nanotransporters in human skin and both, the non-hyperkeratotic non-melanoma skin cancer and hyperkeratotic peeling skin disease models come along with altered absorption in the skin diseases.
