Aminoglucose-functionalized, redox-responsive polymer nanomicelles for overcoming chemoresistance in lung cancer cells

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.Electronic supplementary materialThe online version of this article (10.1186/s12951-017-0316-z) contains supplementary material, which is available to authorized users.

Advances in redox-responsive drug delivery systems of tumor microenvironment

“…For example, in order to visualize drug delivery and release, combining imaging technique and therapy will facilitate the study of drug distribution and controlled release simultaneously [ 20 ], which is difficult to be achieved currently. Moreover, MDR (multi-drug resistance) leading to low clinical anticancer efficacy remains a complicated problem to be solved [ 34 , 52 , 72 ]. In addition, delivery systems with multiple functions while being simple in structure and delivery systems with specific structures while being less cost are often contradictory.…”

“…1 d) [ 47 ], which is a good strategy to make the structure and function of carriers more abundant [ 48 ]. Linking two polymers which are hydrophilic and hydrophobic respectively via disulfide bonds can form an amphiphilic copolymer and then self-assemble into micelles [ 49 – 52 ], which can deliver hydrophobic drugs and improve their solubility.…”

Preparation, characterization and in vitro–in vivo evaluation of bortezomib supermolecular aggregation nanovehicles

“…The formation mechanisms of the supermolecular nanovehicles BTZ-NP were investigated by 1 H-NMR spectra and thermodynamic study. (23,20,18,19,17). However, in the supermolecular structure of BTZ-NP in D 2 O, none of the BTZ peaks was detectable.…”

“…The drug distribution in the tumor of the BTZ-NP group was statistically higher than the BTZ solution group. The superior enrichment of the BTZ-NP in the malignant tissue was ascribed to the EPR effects of the nano-drug delivery systems and, would promise profound therapeutic effects [16][17][18][19][20][21][22][23][24].…”

Intelligent polymeric micelles for multidrug co-delivery and cancer therapy

“…PMs are definition via the capacity of the co-polymer to selfassemble into nanoscale aggregates that have a hydrophilic shell and hydrophobic core. The hydrophobic core of PMs provided a home for water-insoluble drugs and the hydrophilic shell could be well isolated the external environment and avoid cargo drugs being quickly degraded [19,20]. However, ideal PMs not only co-loaded multidrug but also possessed excellent physical properties such as suitable size distribution, morphology and blood stability.…”