Abstract
BackgroundChemotherapeutic drugs used for cancer therapy frequently encounter multiple-drug resistance (MDR). Nanoscale carriers that can target tumors to accumulate and release drugs intracellularly have the greatest potential for overcoming MDR. Glucose transporter-1 (GLUT-1) and glutathione (GSH) overexpression in cancer cells was exploited to assemble aminoglucose (AG)-conjugated, redox-responsive nanomicelles from a single disulfide bond-bridged block polymer of polyethylene glycol and polylactic acid (AG-PEG-SS-PLA). However, whether this dual functional vector can overcome MDR in lung cancer is unknown.ResultsIn this experiment, AG-PEG-SS-PLA was synthetized successfully, and paclitaxel (PTX)-loaded AG-PEG-SS-PLA (AG-PEG-SS-PLA/PTX) nanomicelles exhibited excellent physical properties. These nanomicelles show enhanced tumor targeting as well as drug accumulation and retention in MDR cancer cells. Caveolin-dependent endocytosis is mainly responsible for nanomicelle internalization. After internalization, the disulfide bond of AG-PEG-SS-PLA is cleaved in the presence of high intracellular glutathione levels, causing the hydrophobic core to become a polar aqueous solution, which subsequently results in nanomicelle disassembly and the rapid release of encapsulated PTX. Reduced drug resistance was observed in cancer cells in vitro. The caspase-9 and caspase-3 cascade was activated by the AG-PEG-SS-PLA/PTX nanomicelles through upregulation of the pro-apoptotic proteins Bax and Bid and suppression of the anti-apoptotic protein Bcl-2, thereby increasing apoptosis. Furthermore, significantly enhanced tumor growth inhibition was observed in nude mice bearing A549/ADR xenograft tumors after the administration of AG-PEG-SS-PLA/PTX nanomicelles via tail injection.ConclusionsThese promising results indicate that AG-PEG-SS-PLA/PTX nanomicelles could provide the foundation for a paradigm shift in MDR cancer therapy.
Highlights
Chemotherapeutic drugs used for cancer therapy frequently encounter multiple-drug resistance (MDR)
Synthesis and characterization of AG‐P‐SS‐P The structure of the diblock copolymer P-SS-P of AGP-SS-P consists of polyethylene glycol (PEG) and PLA blocks bridged by a disulfide bond, and the selective cleavable property of this disulfide bond in response to a redox environment allows structural control of the diblock copolymer
allyloxy polyethylene glycol (APEG)-SS-NH2 was synthesized by activating APEG with p-nitrophenyl chloroformate (p-NPC) and cystamine·2HCl
Summary
Chemotherapeutic drugs used for cancer therapy frequently encounter multiple-drug resistance (MDR). Glucose transporter-1 (GLUT-1) and glutathione (GSH) overexpression in cancer cells was exploited to assemble aminoglucose (AG)-conjugated, redox-responsive nanomicelles from a single disulfide bond-bridged block polymer of polyethylene glycol and polylactic acid (AG-PEG-SS-PLA). Whether this dual functional vector can overcome MDR in lung cancer is unknown. P-glycoprotein (P-gp) is often overexpressed in the plasma membrane of many MDR cells, and it mediates drug efflux, which might represent an important mechanism of the resistance of these cells to various anticancer drugs [3]. The overexpression of GLUT-1, which has been verified in a variety of cancer cells, including lung cancer cells [8], has been a target of drug treatment
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