Transparent Tumor Microenvironment: Are Liposomal Nanoparticles Sufficient for Drug Delivery to Hypoxic Regions and Clonogenic Cells?

Passive targeting of nanoparticles (NPs) mediated by Enhanced Permeability and Retention effect is essential to NP delivery to tumors. However, clinically, only limited success has been found due to inadequate intratumoral delivery. Herein, for the first time, we present direct a demonstration visualizing the spatial distribution of liposomal nanoparticles (NP1: Lip-Ru (similar to 126 nm), NP2: Lip-Ru (similar to 164 nm) and NP3: Lip-Ru (similar to 234 nm)) in relation to hypoxic (HIFI alpha) and clonogenic (CD44) cells in intact transparent tumor tissues. Quantitative verification indicated that NP1, NP2, and NP3 did not diffuse into the intratumoral region over 100 mu m away from the blood vessel. However, the liposomal nanoparticles represented slight difference in the three dimensional distribution within 100 tim around the blood vessel. Spatial distribution of HIF1 alpha cells in tumors ranged from 62 to similar to 460 mu m. By contrast, CD44 expressing cells were observed in regions adjacent and away from the vessels. However, the maximum distribution of CD44 was observed similar to 300 mu m from the nearest vessels. Thus, the transparent tumor model reveals the penetration limits of Lip-Ru, and beyond the maximum diffusion of Lip-Ru, tumors contain hypoxic and clonogenic cells that are viable. (C) 2020 Elsevier Ltd. All rights reserved.