Carboplatin‐Complexed and cRGD‐Conjugated Unimolecular Nanoparticles for Targeted Ovarian Cancer Therapy

Abstract

Platinum-based chemotherapy has been widely used to treat cancers including ovarian cancer; however, it suffers from dose-limiting toxicity. Judiciously designed drug nanocarriers can enhance the anticancer efficacy of platinum-based chemotherapy while reducing its systemic toxicity. Herein the authors report a stable and water-soluble unimolecular nanoparticle constructed from a hydrophilic multi-arm star block copolymer poly(amidoamine)-b-poly(aspartic acid)-b-poly(ethylene glycol) (PAMAM-PAsp-PEG) conjugated with both cRGD (cyclo(Arg-Gly-Asp-D-Phe-Cys) peptide and cyanine5 (Cy5) fluorescent dye as a platinum-based drug nanocarrier for targeted ovarian cancer therapy. Carboplatin is complexed to the poly(aspartic acid) inner shell via pH-responsive ion–dipole interactions between carboplatin and the carboxylate groups of poly(aspartic acid). Based on flow cytometry and confocal laser scanning microscopy analyses, cRGD-conjugated unimolecular nanoparticles exhibit much higher cellular uptake by ovarian cancer cells overexpressing αvβ3 integrin than nontargeted (i.e., cRGD-lacking) ones. Carboplatin-complexed cRGD-conjugated nanoparticles also exhibit higher cytotoxicity than nontargeted nanoparticles as well as free carboplatin, while empty unimolecular nanoparticles show no cytotoxicity. These results indicate that stable unimolecular nanoparticles made of individual hydrophilic multi-arm star block copolymer molecules conjugate with tumor-targeting ligands and dyes (i.e., PAMAM-PAsp-PEG-cRGD/Cy5) are promising nanocarriers for platinum-based anticancer drugs for targeted cancer therapy.

Conjugates of Cell Adhesion Peptides for Therapeutics and Diagnostics Against Cancer and Autoimmune Diseases

“…One way to overcome drug resistance is by formulating carboplatin in unimolecular nanoparticles with the idea that the targeted carboplatin can be released in a pH-sensitive manner [93]. In this case, a block copolymer poly(amidoamine)- b -poly(aspartic acid)- b -poly(ethylene glycol) (PAMAM-PAsp-PEG) was used as a core nanoparticle with multiple linkable arms.…”

“…In this case, a block copolymer poly(amidoamine)- b -poly(aspartic acid)- b -poly(ethylene glycol) (PAMAM-PAsp-PEG) was used as a core nanoparticle with multiple linkable arms. cRGDfC peptide was one of the linked moieties used to target the nanoparticles to cancer cells [93]. The core arm was connected to poly-aspartic acid chains in order to coordinate carboplatin on the nanoparticle through two carboxylic acid side chains of the series of Asp residues [93].…”

“…cRGDfC peptide was one of the linked moieties used to target the nanoparticles to cancer cells [93]. The core arm was connected to poly-aspartic acid chains in order to coordinate carboplatin on the nanoparticle through two carboxylic acid side chains of the series of Asp residues [93]. Additional arms that extend from the PAMAM core were conjugated to fluorescent dye cyanin5 (Cy5) in order to follow cell or tissue deposition of the nanoparticles.…”

“…Additional arms that extend from the PAMAM core were conjugated to fluorescent dye cyanin5 (Cy5) in order to follow cell or tissue deposition of the nanoparticles. The uptake of RGD-containing nanoparticles was 3–4 fold more than nanoparticles without RGD peptide in ovarian cancer-3 (OVCAR-3) cells, indicating the role of RGD peptide and overexpression of α V β 3 integrins in the targeted nanoparticle delivery [93]. Furthermore, nanoparticles were internalized into lysosomes of the cancer cells.…”

“…Furthermore, nanoparticles were internalized into lysosomes of the cancer cells. The pH drop resulting from the inherently acidic environment of the cancerous lysosomes protonates the carboxylic side-chains of the carboplatin-complexed poly-Asp network and releases the cytotoxic payload to its target [93]. In vitro , the carboplatin is released up to 88% at pH 5.5, while it is only released up to 18% at pH 7.4 by the 50-hour time point, showing that carboplatin can be released in a targeted and controlled way in lysosomes of cancer cells.…”