Folate Receptor-Mediated Enhanced and Specific Delivery of Far-Red Light-Activatable Prodrugs of Combretastatin A-4 to FR-Positive Tumor

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• 作者：Gregory Nkepang ; Moses Bio ; Pallavi Rajaputra ; Samuel G. Awuah ; Youngjae You
• 刊名：Bioconjugate Chemistry
• 出版年：2014
• 出版时间：December 17, 2014
• 年：2014
• 卷：25
• 期：12
• 页码：2175-2188
• 全文大小：664K
• ISSN：1520-4812

文摘

We examined the concept of a novel prodrug strategy in which anticancer drug can be locally released by visible/near IR light, taking advantage of the photodynamic process and photo-unclick chemistry. Our most recently formulated prodrug of combretastatin A-4, Pc-(L-CA4)₂, showed multifunctionality for fluorescence imaging, light-activated drug release, and the combined effects of PDT and local chemotherapy. In this formulation, L is a singlet oxygen cleavable linker. Here, we advanced this multifunctional prodrug by adding a tumor-targeting group, folic acid (FA). We designed and prepared four FA-conjugated prodrugs 1鈥?b>4 (CA4-L-Pc-PEG_n-FA: n = 0, 2, 18, 鈭?5) and one non-FA-conjugated prodrug 5 (CA4-L-Pc-PEG₁₈-boc). Prodrugs 3 and 4 had a longer PEG spacer and showed higher hydrophilicity, enhanced uptake to colon 26 cells via FR-mediated mechanisms, and more specific localization to SC colon 26 tumors in Balb/c mice than prodrugs 1 and 2. Prodrug 4 also showed higher and more specific uptake to tumors, resulting in selective tumor damage and more effective antitumor efficacy than non-FA-conjugated prodrug 5. FR-mediated targeting seemed to be an effective strategy to spare normal tissues surrounding tumors in the illuminated area during treatment with this prodrug.