Poly(l-histidine) based copolymers: Effect of the chemically substituted l-histidine on the physio-chemical properties of the micelles and in vivo biodistribution

• DNP group substituted L-histidine could not affect pH sensitivity of the copolymers.
• DNP group substituted copolymer could improve drug loading and stability of micelles.
• DNP group substituted copolymer could improve cellular uptake of micelles.
• Sturated nitrogen of PHis may serve as a valuable site for chemical modification.

Even though the Poly(l-histidine) (PHis) based copolymers have been well studied, the effect of the chemically substituted l-histidine on the physio-chemical and biological properties of the micelles has never been elucidated to date. To address this issue, triblock copolymer of poly(ethylene glycol)-poly(d,l-lactide)-poly(2,4-dinitrophenol-l-histidine)(mPEG-b-PLA-b-DNP-PHis) with DNP group substituted to the saturated nitrogen of l-histidine were synthesized. The pH sensitive properties of the copolymer micelles were characterized using an acid-base titration method, fluorescene probe technique, DLS observation, in vitro drug release and cytotoxicity against MCF-7 cells under different pH conditions, respectively. The results suggest that mPEG-b-PLA-b-DNP-PHis copolymers showed similiar micellar stability for DOX loaded micelles, increased particle size, and similar pH responsive properties with mPEG-b-PLA-b-PHis copolymers. The subcellular distribution observation demonstrated that mPEG-b-PLA-b-DNP-PHis micelles showed a slightly compromised endo-lysosmal escape of doxorubicin as compared to mPEG-b-PLA-b-PHis micelles. The mPEG-b-PLA-b-DNP-PHis micelles showed higher cellular uptake by MCF-7 cells than mPEG-b-PLA-b-PHis micelles due to the different uptake pathways. Effect of DNP substitution on the in vivo distribution of the copolymer micelles was studied using non-invasive near-infrared fluorescence (NIRF) imaging with mPEG-b-PLA-b-PHis micelles as control. The results indicate that the mPEG-b-PLA-b-DNP-PHis micelles showed a reduced passive targeting to the tumor due to the larger particle size. These results suggest that saturated nitrogen of PHis may serve as a valuable site for chemical modification of the PHis based copolymers because of the little effect on the pH responsive properties. However, selection of the substitution group needs to be considered due to the possible increase of micellar particle size of the micelles, leading to compromised passive targeting.

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