Abstract
BackgroundCombinatorial systemic chemotherapy is a powerful treatment paradigm against cancer, but it is fraught with problems due to the emergence of chemoresistance and additive systemic toxicity. In addition, coadministration of individual drugs suffers from uncontrollable pharmacokinetics and biodistribution, resulting in suboptimal combination synergy.MethodsToward the goal of addressing these unmet medical issues, we describe a unique strategy to integrate multiple structurally disparate drugs into a self-assembling nanococktail platform. Conjugation of a polyunsaturated fatty acid (e.g., linoleic acid) with two chemotherapies generated prodrug entities that were miscible with tunable drug ratios for aqueous self-assembly. In vitro and in vivo assays were performed to investigate the mechanism of combinatorial nanococktails in mitigating chemoresistance and the efficacy of nanotherapy.ResultsThe coassembled nanoparticle cocktails were feasibly fabricated and further refined with an amphiphilic matrix to form a systemically injectable and PEGylated nanomedicine with minimal excipients. The drug ratio incorporated into the nanococktails was optimized and carefully examined in lung cancer cells to maximize therapeutic synergy. Mechanistically, subjugated resistance by nanococktail therapy was achieved through the altered cellular uptake pathway and compromised DNA repair via the ATM/Chk2/p53 cascade. In mice harboring cisplatin-resistant lung tumor xenografts, administration of the nanococktail outperformed free drug combinations in terms of antitumor efficacy and drug tolerability.ConclusionOverall, our study provides a facile and cost-effective approach for the generation of cytotoxic nanoparticles to synergistically treat chemoresistant cancers.
Highlights
Systemic chemotherapy remains the mainstay therapeutic modality for advanced and metastatic cancers and has shown efficacy in extending patient survival
Subjugated resistance by nanococktail therapy was achieved through the altered cellular uptake pathway and compromised DNA repair via the ataxia telangiectasia mutated (ATM)/checkpoint kinase 2 (Chk2)/p53 cascade
We report the development of a therapeutic nanococktail (NC) platform constructed from self-assembling small molecular lipid prodrugs and test it against cisplatin-resistant non-small cell lung cancer (NSCLC)
Summary
Systemic chemotherapy remains the mainstay therapeutic modality for advanced and metastatic cancers and has shown efficacy in extending patient survival. The emergence of de novo or acquired chemoresistance discounts the clinical response and represents one of the formidable obstacles for effective cancer chemotherapy [1, 2] To tackle these challenges, combinatorial regimens that integrate multimodal therapies have been extensively explored and have been remarkably successful in the clinic. Coencapsulation within a single nanoparticle platform has been extensively explored in numerous preclinical models [14,15,16] These codelivery strategies help minimize off-target dissemination of toxic agents and maximize the treatment synergism by codelivery to the same target cells [17]. Coadministration of individual drugs suffers from uncontrollable pharmacokinetics and biodistribution, resulting in suboptimal combination synergy
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