Abstract
Polymer-based nanomedicines are extensively investigated in the field of cancer therapy to improve the poor aqueous solubility, limited therapeutic efficacy and off-target side-effects of chemotherapeutic agents. Particularly polymeric micelles, self-assembled nanostructures consisting of a core and a shell with a diameter between 10-100 nm have attracted a lot of attention.
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Generally, the hydrophobic core of the micelles can accommodate hydrophobic drugs, while the hydrophilic shell renders colloidal stability and protection against the immune system. Sufficient stability and drug retention of the nanoformulations in the blood circulation are prerequisites for achieving a favorable anticancer outcome. As previously demonstrated by our colleagues, polymeric micelles based on poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide) (mPEG-b-p(HPMA-Bz)), stabilized by π–π stacking interaction between the aromatic groups, are associated with excellent particle stability and good drug retention, thereby significantly improved the circulation kinetics and therapeutic efficacy of the loaded drug compared to the unformulated drug. In this project, nanoformulations based on mPEG-b-p(HPMA-Bz) polymer were further developed and optimized to obtain a manufacturing process that is potentially suitable for upscale production and subsequent clinical translation. Micelles were prepared by nanoprecipitation technique. The formulation and processing parameters influencing the nanostructures in both batch mode and microfluidics system were studied to tune the sizes in the range suitable for drug delivery (25-100 nm). The block copolymer properties (e.g, molecular weight, their hydrophilic-to-hydrophobic ratio, homopolymer content), organic solvents, aqueous phases, polymer concentrations and addition rates were varied. Interestingly, the continuous flow process demonstrated excellent control over the size and morphology with the possibility of large continuous production. Curcumin, a hydrophobic compound with a potential anticancer activity, was selected to encapsulate in these micelles. Stability studies in plasma showed no change in micelle size during 24 h incubation at 37 °C. While curcumin was released over time and the release rate was inversely dependent on the size of the hydrophobic block. In vivo studies in mice using the most stable formulation showed that the circulation time of curcumin was significantly shorter than that of the micelles. In contrast, the circulation time was around 5 times longer than has been reported for free curcumin. Therefore, mPEG-b-p(HPMA-Bz) micelles only marginally improved the circulation kinetics of the loaded curcumin compared to the free form and essentially performed as a solubilizer. Despite the solubilizing effect of these micelles, therapeutic efficacy was not observed in the experimental mice model, which might be related to the relatively low sensitivity of the tumor cells for curcumin. Further research is still required to show the potential of these curcumin-loaded micelles in cancer treatment.
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