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)-<i>block</i>-poly­(<i>N</i>-hydroxysuccinic methacrylate)-<i>block</i>-poly­(1,1-di-<i>tert</i>-butyl 3-(2-(methacryloyloxy)­ethyl) butane-1,1,3-tricarboxylate) (POEGMEMA-<i>b</i>-PNHSMA-<i>b</i>-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

Block Copolymer Micelles with Pendant Bifunctional Chelator for Platinum Drugs: Effect of Spacer Length on the Viability of Tumor Cells

Three monomers with 1,3-dicarboxylate functional groups but varying spacer lengths were synthesized via carbon Michael addition using malonate esters and ethylene- (MAETC), butylene- (MABTC), and hexylene (MAHTC) glycol dimethacrylate, respectively. Poly­[oligo-(ethylene glycol) methylether methacrylate] (POEGMEMA) was prepared in the presence of a RAFT (reversible addition–fragmentation chain transfer) agent, followed by chain extension with the prepared monomers to generate three different block copolymers (BP-E80, BP-B82, and BP-H79) with similar numbers of repeating units, but various spacer lengths as distinguishing features. Conjugation with platinum drugs created macromolecular platinum drugs resembling carboplatin. The amphiphilic natures of these Pt-containing block copolymers led to the formation micelles in solution. The rate of drug release of all micelles was similar, but a noticeable difference was the increasing stability of the micelle against dissociation with increasing spacer length. The platinum conjugated polymer showed high activity against A549, OVCAR3, and SKOV3 cancer cell lines exceeding the activity of carboplatin, but only the micelle based on the longest spacer had IC₅₀ values as low as cisplatin. Cellular uptake studies identified a better micelle uptake with increasing micelle stability as a possible reason for lower IC₅₀ values. The clonogenic assay revealed that micelles loaded with platinum drugs, in contrast to low molecular weight carboplatin, have not only better activity within the frame of a 72 h cell viability study, but also display a longer lasting effect by preventing the colony formation A549 for more than 10 days