Self-targeted polymersomal co-formulation of doxorubicin, camptothecin and FOXM1 aptamer for efficient treatment of non-small cell lung cancer.

Abstract

In spite of huge developments in cancer treatment, versatile combinational formulations of different chemotherapeutic agents to enhance anticancer activity while reducing systemic toxicity still remains a challenge. In this regard, in the current study, an amphiphilic hyaluronic acid-b-polycaprolactone diblock copolymer was synthesized using click chemistry . The synthesized copolymer was self-assembled to form polymersomal structures for co-encapsulation of hydrophilic doxorubicin (DOX) and hydrophobic camptothecin (CPT) in their interior aqueous compartment and their bilayer, respectively with 1:10 and 1:1 ratios. The prepared polymersomal combinational formulation surrounded by hyaluronic acid brush as hydrophilic segment, could provide active targeting of the system against CD44 marker expressed on the surface of cancerous cells. The hyaluronic acid shell could also provide flexible chemistry for the conjugation of therapeutic FOXM1-specific DNA aptamer (Forkhead Box M1; against transcription factor FOXM1) on the surface of polymersomes in order to further suppress cancerous cell proliferation. The obtained results demonstrated that the prepared co-formulation provided sustained, controlled release of the entrapped drugs during 200\u202fh. In vitro cytotoxicity experiments on non-small cell lung cancer, A549 and SK-MES-1 cell lines, demonstrated that the co-formulation of DOX and CPT provided synergistic effect and significantly higher cytotoxicity in comparison with free drugs. The cytotoxicity experiment also indicated that the aptamer conjugation on the co-formulations surface could significantly increase the cytotoxicity and induce apoptosis in combination therapy on both A549 and SK-MES-1 cell lines while aptamer-conjugated blank NPs did not show any cytotoxicity which emphasizes on the sensitization capability of the FOXM1 DNA aptamer against non-small cell lung cancer. Furthermore, it was shown that the co-formulation with or without aptamer renders the formulation specific tumor accumulation in vivo 24\u202fh post-administration, assisting the combination synergy observed in vitro to be translated to in vivo antitumor efficacy. This combinatorial delivery platform strongly offers a novel approach for the synergistic controlled transportation of several chemotherapeutics for the treatment of non-small cell lung cancer.