ががんん細細胞胞ととががんん幹幹細細胞胞のの双双方方をを標標的的ととすするるボボロロンン酸酸誘誘導導体体をを搭搭載載ししたた ナナノノメメデディィシシンンのの開開発発 東京大学 大学院工学研究科 バイオエンジニアリング専攻准教授 Cabral Horacio 1. Purpose and Background of the Research Altered glycosylation is a hallmark of cancer stimulating severe pathways in tumor biology. Such alteration mainly consists on the hyperactivation of cancer-related sialylated glycans, which promotes immune evasion, migration and apoptosis resistance, with high malignancy and poor prognosis1,2,3. In fact, cancer stem-like cell (CSC)-subpopulations in tumors, which are linked to therapeutic resistance and relapse, present high expression of sialylated variants of CD44 isoforms (CD44v)4. Because sialylated glycan chains on cancer cell surface usually present sialic acid (N-acetylneuraminic acid; SA) as the terminal carbohydrate, ligand molecules binding SA may allow far-reaching tumor-targeted treatments. Ligands directed to SA, such as lectins, antibodies, or glycomimetics blocking SA metabolism have been considered for targeting5,6. Nevertheless, the expression of SA in healthy tissues, such as erythrocytes and endothelial cells, pose a great barrier for developing such targeted agents, limiting these approaches to intratumoral administration. Here, we propose smart ligands activated at intratumoral conditions for promoting effective strategies capable of systemic targeting of SA in tumors7. By taking advantage of the unique selectivity and binding of phenylboronic acid (PBA) to SA at intratumoral pH (pH 7.2-6.5), we could then develop such strategies targeting SA in tumors8. Moreover, because the selectivity and binding affinity of PBA-based ligands to SA at intratumoral pH could be tuned through chemical design, the strategy has the potential for further engineering systems with enhance tumor targeting capability. To show our strategy, we developed nanomedicines with controlled chemical structure of PBA ligands for promoting SA recognition directed to eliciting superior targeting to tumors. We have identified several PBA derivatives with high affinity for SA at acidic pH8, and 5-boronopicolinic acid (5-BPA) showed the sharpest activation of SA binding at intratumoral pH, shifting from glucose complexation at pH 7.4 to selectively binding to SA at pH 6.5, with more than 30-fold higher binding constant for SA than the standard PBA8. Thus, we made nanomedicines having 5-BPA, or standard PBA, installed as ligands on their surface (FFiigguurree 11). These nanomedicines loaded a platinum anticancer drug, i.e. (1,2-diaminocyclohexane)platinum(II) (DACHPt), to exert potent antitumor effects. The capability of the micelles for targeting cancer cells and tumors was compared by using an orthotopic head and neck tumor model, bearing a large fraction of SA-rich CSCs that are resistant to platinum drugs. Our results showed that 5-BPA promoted intracellular delivery and tumor accumulation of DACHPt-loaded micelles (DACHPt/m) to efficaciously eradicate the malignant CSCs, inhibit tumor growth and significantly extend mice survival, demonstrating the potential of engineered PBA-ligands for generating effective therapeutic strategies targeting SA in tumors. FFiigguurree 11.. Preparation of (DACHPt/m). Non-ligand, PBA- and 5-BPA-installed DACHPt/m were self-assembled in water by complexation between DACHPt and poly(ethylene glycol)-b-poly(L-glutamic acid) (PEG-b-PLGA) and PBA- or 5-BPA-installed PEG-b-PLGA. 2. Research Content 2.1 Construction of nanomedicines All the micelles, i.e. DACHPt/m, PBA-DACHPt/m and 5-BPA-DACHPt/m, showed 30 nm size and slightly negative zeta-potentail (-5 to -3 mV) (TTaabbllee 11). The ligands were maintained at 50% of the PEG chains. TTaabbllee 11.. Characteristics of micelles Micelle Size (nm) PDI Drug loading (Pt/polymer wt/wt%) Zeta potential (mV) pH 7.4 pH 6.5 DACHPt/m 28 0.12 30 -5.37 -5.47 PBA-DACHPt/m 35 0.15 31 -2.62 -4.58 5-BPA-DACHPt/m 32 0.09 29 0.062 -2.25 DACHPtClNO330 nm5-BPA-PEG-b-PLAPBA-PEG-b-PLGAMeO-PEG-b-PLGAorDACHPt-loaded micelles(DACHPt/m)2724027240250454037°C, 120h30 nmPBA-installed DACHPt-loaded micelles(PBA-DACHPt/m)30 nm5-BPA-installed DACHPt-loaded micelles(5-BPA-DACHPt/m)Mixed with MeO-PEG-b-PLGA by keeping the total amount of ligand-conjugated copolymer to 50%3 −48−発表番号 24〔中間発表〕
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