Acetal-linked polymeric prodrug micelles for enhanced curcumin delivery

• Pleiotropic curcumin was conjugated to mPEG-PLA via the acetal linker.
• Upon conjugation, the stability of curcumin prodrug micelles was enhanced.
• The pH-labile curcumin conjugate micelle was superior to the ester-linked control with respect to delivery efficiency.

On-demand curcumin delivery via stimuli-responsive micellar nanocarriers holds promise for addressing its solubility and stability problem. Polymer-curcumin prodrug conjugate micelle is one of such nanosystems. The diversity of linker and conjugation chemistry enabled the generation and optimization of different curcumin micelles with tunable stimuli-responsiveness and delivery efficiency. The aim of the current work was to generate and assess acetal-linked polymeric micelles to enrich the pH-responsive curcumin delivery platforms. Curcumin was slightly modified prior to conjugating to amphiphilic methoxy poly(ethylene glycol)-poly(lactic acid) (mPEG-PLA) copolymer via an acetal bond, whereas an ester bond-linked conjugate was used as the control. The acetal-containing micelles showed a hydrodynamic diameter of 91.1 ± 2.9 (nm) and the accompanying core size of 63.5 ± 7.1 (nm) with a zeta potential of −10.9 ± 0.7 (mV). Both control and pH-labile micelles displayed similar critical micelle concentration at 1.6 μM. The acetal-containing nanocarriers exhibited a pH-dependent drug release behavior, which was faster at lower pH values. The cytotoxicity study in HepG2 cells revealed a significantly lower IC50 at 51.7 ± 9.0 (μM) for acetal-linked micelles in contrast to the control at 103.0 ± 17.8 (μM), but the polymer residue showed no cytotoxicity upon drug release. The acetal-linked micellar nanocarrier could be a useful addition to the spectrum of currently available stimuli-responsive curcumin nano-formulations.

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