Polyphenolic Polymersomes of Temperature-Sensitive\nPoly(<i>N</i>‑vinylcaprolactam)-<i>block</i>-Poly(<i>N</i>‑vinylpyrrolidone) for Anticancer\nTherapy

Abstract

We report a versatile\nsynthesis for polyphenolic polymersomes of\ncontrolled submicron (<500 nm) size for intracellular delivery\nof high and low molecular weight compounds. The nanoparticles are\nsynthesized by stabilizing the vesicular morphology of thermally responsive\npoly­(<i>N</i>-vinylcaprolactam)_<i>n</i>-<i>b</i>-poly­(<i>N</i>-vinylpyrrolidone)_<i>m</i> (PVCL_<i>n</i>–PVPON_<i>m</i>) diblock copolymers with tannic acid (TA),\na hydrolyzable polyphenol, via hydrogen bonding at a temperature above\nthe copolymer’s lower critical solution temperature (LCST).\nThe PVCL₁₇₉–PVPON_<i>m</i> diblock\ncopolymers are produced by controlled reversible addition–fragmentation\nchain transfer (RAFT) polymerization of PVPON using PVCL as a macro-chain\ntransfer agent. The size of the TA-locked (PVCL₁₇₉–PVPON_<i>m</i>) polymersomes at room temperature and upon\ntemperature variations are controlled by the PVPON chain length and\nTA:PVPON molar unit ratio. The particle diameter decreases from 1000\nto 950, 770, and 250 nm with increasing PVPON chain length (<i>m</i> = 107, 166, 205, 234), and it further decreases to 710,\n460, 290, and 190 nm, respectively, upon hydrogen bonding with TA\nat 50 °C. Lowering the solution temperature to 25 °C results\nin a slight size increase for vesicles with longer PVPON. We also\nshow that TA-locked polymersomes can encapsulate and store the anticancer\ndrug doxorubicin (DOX) and higher molecular weight fluorescein isothiocyanate\n(FITC)–dextran in a physiologically relevant pH and temperature\nrange. Encapsulated DOX is released in the nuclei of human alveolar\nadenocarcinoma tumor cells after 6 h incubation via biodegradation\nof the TA shell with the cytotoxicity of DOX-loaded polymersomes being\nconcentration-dependent. Our approach offers biocompatible and intracellular\ndegradable nanovesicles of controllable size for delivery of a variety\nof encapsulated materials. Considering the particle monodispersity,\nhigh loading capacity, and a facile two-step aqueous assembly based\non the reversible temperature-responsiveness of PVCL, these polymeric\nvesicles have significant potential as novel drug nanocarriers and\nprovide a new perspective for fundamental studies on thermo-triggered\npolymer assemblies in solutions.