Toolbox of Biodegradable Dendritic (Poly glycerol sulfate)–SS-poly(ester) Micelles for Cancer Treatment: Stability, Drug Release, and Tumor Targeting

Abstract

In this paper, we present well-defined dPGS-SS-PCL/PLGA/PLA micellar systems demonstrating excellent capabilities as a drug delivery platform in light of high stability and precise <i>in vitro</i> and <i>in vivo</i> drug release combined with active targetability to tumors. These six amphiphilic block copolymers were each targeted in two different molecular weights (8 or 16 kDa) and characterized using ¹H NMR, gel permeation chromatography (GPC), and elemental analysis. The block copolymer micelles showed monodispersed size distributions of 81-187 nm, strong negative charges between -52 and -41 mV, and low critical micelle concentrations (CMCs) of up to 1.13-3.58 mg/L (134-527 nM). The serum stability was determined as 94% after 24 h. The drug-loading efficiency for Sunitinib ranges from 38 to 83% (8-17 wt %). The release was selectively triggered by glutathione (GSH) and lipase, reaching 85% after 5 days, while only 20% leaching was observed under physiological conditions. Both the <i>in vitro</i> and <i>in vivo</i> studies showed sustained release of Sunitinib over 1 week. CCK-8 assays on HeLa lines demonstrated the high cell compatibility (1 mg/mL, 94% cell viability, 48 h) and the high cancer cell toxicity of Sunitinib-loaded micelles (IC₅₀ 2.5 μg/mL). By <i>in vivo</i> fluorescence imaging studies on HT-29 tumor-bearing mice, the targetability of dPGS_7.8-SS-PCL_7.8 enabled substantial accumulation in tumor tissue compared to nonsulfated dPG_3.9-SS-PCL_7.8. As a proof of concept, Sunitinib-loaded dPGS-SS-poly(ester) micelles improved the antitumor efficacy of the chemotherapeutic. A tenfold lower dosage of loaded Sunitinib led to an even higher tumor growth inhibition compared to the free drug, as demonstrated in a HeLa human cervical tumor-bearing mice model. No toxicity for the organism was observed, confirming the good biocompatibility of the system.