Acid Degradable Cross-Linked Micelles for the Delivery of Cisplatin: A Comparison with Nondegradable Cross-Linker

Well-defined and nontoxic cross-linked polymeric micelles, containing either permanent or acid degradable cross-linkers, were employed for efficient intracellular delivery of cisplatin. The self-assembled structures were generated from triblock copolymers of poly(oligo(ethylene glycol) methylether methacrylate)- block -poly( N -hydroxysuccinic methacrylate)- block -poly(1,1-di- tert -butyl 3-(2-(methacryloyloxy)ethyl) butane-1,1,3-tricarboxylate) (POEGMEMA- b -PNHSMA- b -PMAETC) loaded with cisplatinum. The polymeric micelles were subsequently cross-linked via a reaction between pendant activated esters at the nexus core of the triblock copolymer using acid degrdabale ketal diamino cross-linkers. An in vitro study confirmed that both uncross-linked and cross-linked micelles prior to the loading of the platinum drug were nontoxic against OVCAR-3 cells even at high polymer concentration (around 300 μg mL –1 ). The drug loaded cross-linked platinum polymeric micelles were superior to the uncross-linked platinum polymeric micelles in terms of cytotoxicity against OVCAR-3, due to a higher cellular uptake. Although there was no significant difference in cytotoxicity of cross-linked platinum polymeric micelles using different cross-linkers (permanent and acid cleavable) after 72 h of exposure, the difference was noticeable after 24 h of incubation, highlighting a much higher activity for acid degradable cross-linked micelles with conjugated platinum drugs. Moreover, the clonogenic assay suggested that cross-linked micelle loaded platinum drugs, in contrast to uncross-linked micelles, can effectively inhibit the OVCAR-3 cell regrowth for an extended period of time (10 days), even at very low micellar concentrations. In summary, acid degradable linkers ensure high cellular uptake compared to uncross-linked micelles but also lead to a faster drug action in comparison to a permanently cross-linked micelle.