Polymeric micelles are promising nanoscale delivery carriers for a wide range of therapeutic agents. Complexation of hydrophobic anticancer drug (1,2-diaminocyclohexane)platinum(II) (DACHPt) with poly(ethylene glycol)-poly(glutamic acid) block copolymers gives DACHPt-loaded polymeric micelles (DACHPt/m), which exerted high antitumor efficacy against xenograft models of various solid tumors due to its efficient tumor accumulation and are currently investigated under clinical trials. In this study, we demonstrated that α-helix was formed in the DACHPt-conjugated P(Glu) chains, which consists of the core of DACHPt/m, and significantly controlled their size distribution and drug delivery performance. DACHPt/m prepared from PEG-P(Glu) with an ability to form α-helix, <i>i.e.</i> PEG-poly(L-glutamic acid) and PEG-poly(D-glutamic acid), had an average size of 30 nm with low polydispersity, whereas DACHPt/m prepared from PEG-P(Glu) without an ability to adopt regular secondary structures, <i>i.e.</i> PEG-poly(D,L-glutamic acid), showed an average size of 55 nm with relatively high polydispersity. Circular dichroism spectrometry demonstrated that 50% region of the P(Glu) segment in L- and D-DACHPt/m formed α-helix. Considering drug loading of the micelles was independent of the stereoregularity of P(Glu) segment, the size distribution of DACHPt/m could be controlled by α-helix formation. In physiological condition, chloride ions induced DACHPt release from the micelles, leading to micelle dissociation. Interestingly, the DACHPt/m with α-helix showed slow drug release and micelle dissociation at constant rate by keeping their original size, whereas the DACHPt/m without regular secondary structures disintegrated in an accelerated manner while increasing their size. This sustained disintegration process of the DACHPt/m with α-helix was advantageous for avoiding uptake by the liver and spleen and prolonging blood circulation, which eventually augmented tumor accumulation and enhanced antitumor efficacy against pancreatic tumor xenograft models. Introducing secondary structures in the core of polymeric micelles could be a feasible strategy to control their size and stability for desirable tumor targeting performance.

Helical polymer structure provides platinum-loaded polymeric micelles with favorable size and stability for effective tumor-targeting

256th National Meeting (2018)

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