RESUMO
We propose a polymeric nanovehicles (PNVs)-based enhanced transdermal delivery platform. A technical advance can be found in that delivery efficiency is significantly enhanced by effective adhesion of PNVs to the cell membrane, which is characterized noninvasively by using a confocal laser scanning microscopy (CLSM)-based skin visualization technique. To this end, the PNVs with a soft core phase were fabricated through co-assembly of two amphiphilic triblock copolymers, poly(ethylene oxide)-b-poly(ε-caprolactone)-b-poly(ethylene oxide) (PEO-b-PCL-b-PEO) and poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO-b-PPO-b-PEO). The softness of PNVs was tuned successfully, while maintaining the particle size at â¼110â¯nm, by incorporation of PEO-b-PPO-b-PEO into the PNVs to a volume fraction of 0.3. Through an ex vivo skin penetration test, we showed that transactivating transcriptional activator (TAT)-decorated soft PNVs could not only exert strong adhesion to skin but also increase cellular uptake, leading to a transdermal delivery efficiency that is twice that of a hard PNV control. Moreover, CLSM-based noninvasive visualization of a fluorescent drug probe in the skin showed that the adhesiveness and softness of the PNVs contributed directly to the enhancement of transdermal delivery.
Assuntos
Membrana Celular , Sistemas de Liberação de Medicamentos , Fragmentos de Peptídeos/administração & dosagem , Poliésteres/administração & dosagem , Polietilenoglicóis/administração & dosagem , Propilenoglicóis/administração & dosagem , Produtos do Gene tat do Vírus da Imunodeficiência Humana/administração & dosagem , Adesividade , Administração Cutânea , Animais , Linhagem Celular Tumoral , Humanos , Microscopia Confocal , Tamanho da Partícula , Poliésteres/química , Polietilenoglicóis/química , Propilenoglicóis/química , Pele/metabolismo , Absorção Cutânea , SuínosRESUMO
We herein propose a polymeric nanovehicle system that has the ability to remarkably improve cellular uptake and transdermal delivery. Cell-penetrating peptide-patchy deformable polymeric nanovehicles were fabricated by tailored coassembly of amphiphilic poly(ethylene oxide)- block-poly(ε-caprolactone) (PEO- b-PCL), mannosylerythritol lipid (MEL), and YGRKKRRQRRR-cysteamine (TAT)-linked MEL. Using X-ray diffraction, differential scanning calorimetry, and nuclear magnetic resonance analyses, we revealed that the incorporation of MEL having an asymmetric alkyl chain configuration was responsible for the deformable phase property of the vehicles. We also discovered that the nanovehicles were mutually attracted, exhibiting a gel-like fluid characteristic due to the dipole-dipole interaction between the hydroxyl group of MEL and the methoxy group of PEO- b-PCL. Coassembly of TAT-linked MEL with the deformable nanovehicles significantly enhanced cellular uptake due to macropinocytosis and caveolae-/lipid raft-mediated endocytosis. Furthermore, the in vivo skin penetration test revealed that our TAT-patchy deformable nanovehicles remarkably improved transdermal delivery efficiency.