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

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 in vitro and in vivo 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 H-1 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 in vitro and in vivo 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 mu g/mL). By in vivo fluorescence imaging studies on HT-29 tumor-bearing mice, the targetability of dPGS(7.8)-SS-PCL7.8 enabled substantial accumulation in tumor tissue compared to nonsulfated dPG(3.9)-SS-PCL7.8. 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.

Automated summary

Six well-defined amphiphilic block copolymers were synthesized and characterized for their excellent drug delivery capabilities, showing monodispersed size distributions, strong negative charges, and low critical micelle concentrations. These micelles exhibited high serum stability and efficient drug-loading efficiency, with selective release triggered by specific stimuli. In vitro and in vivo studies demonstrated sustained release of the drug, high cell compatibility, and improved antitumor efficacy at a lower dosage. Targetability to tumor tissue was confirmed through fluorescence imaging studies. The system showed good biocompatibility with no observed toxicity.