Abstract
Development of stimuli-responsive supramolecular micelles that enable high levels of well-controlled drug release in cancer cells remains a grand challenge. Here, we encapsulated the antitumor drug doxorubicin (DOX) and pro-photosensitizer 5-aminolevulinic acid (5-ALA) within adenine-functionalized supramolecular micelles (A-PPG), in order to achieve effective drug delivery combined with photo-chemotherapy. The resulting DOX/5-ALA-loaded micelles exhibited excellent light and pH-responsive behavior in aqueous solution and high drug-entrapment stability in serum-rich media. A short duration (1–2 min) of laser irradiation with visible light induced the dissociation of the DOX/5-ALA complexes within the micelles, which disrupted micellular stability and resulted in rapid, immediate release of the physically entrapped drug from the micelles. In addition, in vitro assays of cellular reactive oxygen species generation and cellular internalization confirmed the drug-loaded micelles exhibited significantly enhanced cellular uptake after visible light irradiation, and that the light-triggered disassembly of micellar structures rapidly increased the production of reactive oxygen species within the cells. Importantly, flow cytometric analysis demonstrated that laser irradiation of cancer cells incubated with DOX/5-ALA-loaded A-PPG micelles effectively induced apoptotic cell death via endocytosis. Thus, this newly developed supramolecular system may offer a potential route towards improving the efficacy of synergistic chemotherapeutic approaches for cancer.
Highlights
Cancer—remains a significant cause of death, with an unprecedented 9.6 million cancer deaths in 2018 [1]
The hydrodynamic size and morphology of double-cargo DOX/5-aminolevulinic acid (5-ALA)-loaded A-polypropylene glycol (PPG) micelles were determined by dynamic laser scattering (DLS) and atomic force microscopy (AFM) to optimize the photo-regulated micelles
DOX/5-ALA-loaded A-PPG micelles were added to PBS containing 10 v% fetal bovine serum (FBS), which functions as an effective nanoparticle-destabilizing agent, and subjected to DLS at 25 ◦C [15,51]
Summary
Cancer—remains a significant cause of death, with an unprecedented 9.6 million cancer deaths in 2018 [1]. The treatment outcomes of chemotherapy are substantially compromised by non-specific product delivery, low bioavailability and poor target precision [4,5] To resolve these issues, a number of soft materials including lipids, polymers and liposomes have been actively used as drug delivery carriers to improve the blood circulation time and improve the bioavailability of anticancer drugs. A number of soft materials including lipids, polymers and liposomes have been actively used as drug delivery carriers to improve the blood circulation time and improve the bioavailability of anticancer drugs These strategies take advantage of the enhanced permeability and retention (EPR) effect, which leads to accumulation of drugs at tumor sites [6]. Nanoparticles have limited ability to effectively deliver therapeutic agents into tumors, as most nanoparticles become entrapped in the basement membrane of the cells [9,10]
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