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

Abstract

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 IC(50) values as low as cisplatin. Cellular uptake studies identified a better micelle uptake with increasing micelle stability as a possible reason for lower IC(50) 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.

Doxorubicin-loaded amphiphilic polypeptide-based nanoparticles as an efficient drug delivery system for cancer therapy

“…630 The stability of nanocarriers was found to be the key to a suc-631 cessful drug delivery system. The uptake of the drug carrier by tu-632 mor cells can be significantly enhanced with increasing stability, 633 which further leads to a substantial increase in antitumor activity 634 [28,29]. Previously, the present authors prepared a DOX-loaded of DOX under physiological conditions (Fig.…”

Anti-inflammatory and antitumour activity of various extracts and compounds from the fruits of Piper longum L.

“…Colony formation assay was performed on SKOV-3 cells as described previously with some modifications. [22] Cells were treated with samples for 24 h. Then, fresh drug-free medium was replaced for additional 10 days. Cells were fixed with methanol and stained with 0.1% crystal violet.…”

Nano-Based Systems and Biomacromolecules as Carriers for Metallodrugs in Anticancer Therapy

“…One strategy involved the covalent attachment of the drug directly to the micelle to avoid its premature release in the circulation [55][56][57][58][59]. Sentzel's group has developed micelles to deliver Pt(II) and Ru(II) complexes to cancer cells [61][62][63][64]. They used various lengths of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMEMA) and 1,1-di-tert-butyl 3-(2-(methacryloyloxy)ethyl) butane-1,1,3-tricarboxylate (PMAETC) block copolymers with pendant bidentate carboxylate ligands to form a carboplatin-like complex directly on the polymer [62].…”