Targeted and Oxygen-Enriched Nanoplatform for Enhanced Photodynamic Therapy: In Vitro 2D Cell and 3D Spheroid Model Evaluation.

Abstract

Hypoxic microenvironment and limited penetration of photosensitizers within solid tumors are two crucial factors that restrict the efficacy of photodynamic therapy (PDT). Herein, we developed a new fluorinated mixed micelle (M60@PFC-Ce6) as a tumor-penetrating and oxygen-enriching nanoplatform, which consists of chlorin e6 (Ce6) and perfluorocarbons (PFCs) co-loaded into fluorinated micelles to relieve hypoxia conditions as well as folate as targeting ligand that facilitate the selective biodistribution within tumor solids. Incorporation of fluorinated copolymers into mixed micelles exhibits not only to greatly increase the oxygen-loading capacity, but also improves the stability of liquid PFCs emulsion within micelles without leakage. M60@PFC-Ce6 shows excellent oxygen delivery capability, good intracellular reactive oxygen species (ROS) generation and superior phototoxicity in vitro for both 2D monolayer of cells and 3D multicellular spheroid model. These results indicate the enriched oxygen delivery and increased cellular uptake resulted from folate-targeted ability enhance ROS production and PDT efficacy. The penetration study of M60@PFC-Ce6 into a 3D spheroid confirms the small micellar size and folate conjugation are beneficial for micelles to penetrate and accumulate within spheroids. Thus, we provide a new nanoplatform with enriched oxygen-carrying amount, better drug penetration and stable micellar properties that relieve tumor hypoxia and improve PDT efficacy. This article is protected by copyright. All rights reserved.