Triggered drug release from anti-tumor nanomedicine is an efficient approach to address the dilemma of systemic nanocarrier stability and on-demand drug liberation in tumor sites. Combinational drug delivery has been a useful means to enhance antitumor efficacy and reduce adverse effects. We report a multifunctional micelle for dually hypoxia- and singlet oxygen-responsive integration of chemotherapy and photodynamic therapy. The micelles were made of a nitroimidazole (NI)-bearing polymer; doxorubicin (Dox) and chlorin e6 (Ce6) were selected as the model chemodrug and photosensitizer, respectively. The co-delivery micelles displayed a hydrodynamic size of 138.5 ± 3.6 nm with the cargo loading at 2.5 ± 0.2% w/w (Dox) and 1.8 ± 0.3% w/w (Ce6), respectively. Under hypoxia (e.g. tumor microenvironment), the NI moiety was bio-reduced to aminoimidazole, resulting in micelle disassembly, rapid cargo release, and glutathione (GSH) depletion. Upon laser irradiation, the singlet oxygen produced by Ce6 caused the oxidation of NI, leading to micelle collapse, facilitated payload release, and the production of aldehyde end-products. Rapid drug release enabled the fast onset of the therapeutic action. GSH depletion and aldehyde production would provide a supplementary effect to enhance the anti-tumor efficacy of co-delivery micelles. This proof-of-concept was demonstrated in a murine mammary carcinoma cell line (4T1) in vitro as well as in a 4T1 tumor-bearing mouse model in vivo. This study expanded the function of traditional stimuli-responsive nanomedicines by utilizing the multifunctional NI moiety that could realize both triggered release and the amplified anti-tumor effect via the auxiliary action of GSH depletion and aldehyde production.

Nanoscale drug delivery platforms have been developed over the past four decades that have shown promising clinical results in several types of cancer and inflammatory disorders. These nanocarriers carrying therapeutic payloads are maximizing the therapeutic outcomes while minimizing adverse effects. Yet one of the major challenges facing drug developers is the dilemma of premature versus on-demand drug release, which influences the therapeutic regiment, efficacy and potential toxicity. Herein, we report on redox-sensitive polymer-drug conjugate micelles for on-demand intracellular delivery of a model active agent, curcumin. Biodegradable methoxy poly(ethylene glycol)-poly(lactic acid) copolymer (mPEG-PLA) was conjugated with curcumin via a disulfide bond or ester bond (control), respectively. The self-assembled redox-sensitive micelles exhibited a hydrodynamic size of 115.6 ± 5.9 (nm) with a zeta potential of −10.6 ± 0.7 (mV). The critical micelle concentration was determined at 6.7 ± 0.4 ( μ g mL ⁻¹ ). Under sink conditions with a mimicked redox environment (10 mM dithiothreitol), the extent of curcumin release at 48 h from disulfide bond-linked micelles was nearly three times higher compared to the control micelles. Such rapid release led to a lower half maximal inhibitory concentration (IC ₅₀ ) in HeLa cells at 18.5 ± 1.4 ( μ g mL ⁻¹ ), whereas the IC ₅₀ of control micelles was 41.0 ± 2.4 ( μ g mL ⁻¹ ). The cellular uptake study also revealed higher fluorescence intensity for redox-sensitive micelles. In conclusion, the redox-sensitive polymeric conjugate micelles could enhance curcumin delivery while avoiding premature release, and achieving on-demand release under the high glutathione concentration in the cell cytoplasm. This strategy opens new avenues for on-demand drug release of nanoscale intracellular delivery platforms that ultimately might be translated into pre-clinical and future clinical practice.