PH-responsive Polymeric Micelles For Co-delivery Of Curcumin And Doxorubicin

Intelligent amphiphilic block copolymer micelles exhibit the benefits of enhanced aqueous solubility of hydrophobic drugs and passive tumor targeting, and thus have been widely used for anticancer drug delivery. Co-delivery of therapeutic agents can achieve the enhanced efficacy as well as reduced toxicity in terms of chemotherapy. Stimuli-responsive drug release can realize the rapid onset of drug action. The current study aimed to generate two types of pH-labile polymeric micelles for co-delivery of two model agents, curcumin(Cur) and doxorubicin(Dox), and both can be released in the acidic microenvironment inside cells for synergism and rapid therapeutical effect.Amphiphilic methoxy poly(ethylene glycol)-co-poly(lactide)(mPEG-PLA) was selected as the model copolymer. Curcumin was modified by levulinic acid and glutaric acid, respectively to obtain two derivatives for ease of conjugation with the copolymer. These two derivatives were chemically linked to mPEG-PLA, forming two pH-labile conjugates, i.e. hydrazone-linked mPEG-PLA-hydrazone-Cur and ester-linked mPEG-PLA-Cur. Upon dialysis in an aqueous medium, doxorubicin was physically loaded with the nano-micelles, i.e. m PEG-PLA-hydrazone-Cur/Dox and mPEG-PLA-Cur/Dox. The successful synthesis of both conjugates were verified 1H-NMR. Based on the same method, the percentage of curcumin conjugation was 39%(mPEG-PLA-Cur) and 88%(mPEG-PLA-hydrazone-Cur), respectively.With pyrene as a fluorescent probe, the critical micelle concentration(CMC) of the hydrazone-linked nanomicelles was determined at 7.7 ± 0.1(?g/mL), indicating a good physical stability of micelles. The dynamic light scattering(DLS) analysis gave a average hydrodynamic diameter of ca. 90 nm. Future transmission electron microscopy images showed spherical micelle morphology. Both agents were quantified by a validated high performance liquid chromatography(HPLC) method with a gradient elution. The in vitro release from both micelles exhibited a pH-dependent profile with faster release at lower pH. The cell cytotoxicity and cellular uptake experiments were conducted on HepG2 cells. The results showed that mPEG-PLA-hydrazone-Cur/Dox micelles had a greater cytotoxicity in contrast to mPEG-PLA-Cur/Dox. The cellular uptake study demonstrated a co-localization of both agents inside cells.In summary, pH-labile conjugate micelles achieved the co-delivery of doxorubicin and curcumin. Such nanomicelle could be a versatile platform for co-administration of multiple hydrophobic anti-cancer agents to realize the synergistic effect to the tumor cells, showing promise for efficacy enhancement and side-effects reduction in tumor chemotherapy.