Nano carriers of mitoxantrone using natural biopolymer derivatives

Abstract

Drug delivery systems (DDS) have been developed to improve efficacy and reduce toxicities of conventional drugs. Often, low selectivity of anticancer chemotherapeutics cause toxicities against normal tissues, and leads to low therapeutic index. Also, tumor vessels are composed of leaky vessels, and tumor tissues show poor lymphatic recovery. On the other hand, nano carriers could extravasate through the gaps and accumulate in the tumor for longer time period. This phenomenon is called as enhanced permeation and retention effect (EPR effect). Based on EPR effect, we thought our nano carriers could deliver drugs to tumor tissues selectively. Amphiphilic γ-PGA nanoparticles (APGANP) were prepared by introducing phenylalanine ethyl ester to γ-PGA with varying amounts of water soluble carbodiimide (2 mmol and 4 mmol). Mitoxantrone (MTO) was loaded on APGANP (M-APGANP) at various weight ratios of APGA: MTO (w/w) as 10:1, 5:1, and 1:1. Physical properties of nanoparticles were characterized by dynamic light scattering method for particle size measurement. UV-spectroscopy was used to measure loading efficiency (LE) and loading content (LC). The complexation of M-APGANP increased the particle size from APGANP (121.1±3.4 nm) to around 200 nm. Among various M-APGANP groups, 5:1 M-APGANP showed the highest LE and proper LC and used for further experiments. In the in vitro studies, cell viability of KB cells was decreased with increasing M-APGANP, while APGANP showed no cytotoxicity. The increasing cellular uptake of MTO by KB cells was observed with increasing concentrations of MTO in APGANP. The release of MTO from M-APGANP in endolysosome and diffusing out to cytoplasm were confirmed by confocal microscopy. After intravenous administration to tumor-bearing mice, M-APGANP distributed to tumor sites and retained for prolonged period than free MTO. These results suggest the potential of APGANP for delivery of anticancer drugs.