Effective encapsulation and biological activity of phosphorylated chemotherapeutics in calcium phosphosilicate nanoparticles for the treatment of pancreatic cancer.
Effective encapsulation and biological activity of phosphorylated chemotherapeutics in calcium phosphosilicate nanoparticles for the treatment of pancreatic cancer.
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DOI：
10.1016/j.nano.2017.06.017
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Adair JH
中科院分区：
文献类型：
--
作者：
Loc WS;Linton SS;Wilczynski ZR;Matters GL;McGovern CO;Abraham T;Fox T;Gigliotti CM;Tang X;Tabakovic A;Martin JA;Clawson GA;Smith JP;Butler PJ;Kester M;Adair JH
胰腺导管腺癌（PDAC）等耐药癌症难以治疗，而纳米颗粒药物输送系统可以克服传统全身化疗的一些局限性。在这项研究中，我们证明 FdUMP 和 dFdCMP（化疗药物 5-FU 和吉西他滨的生物活性磷酸化代谢物）可以封装到磷硅酸钙纳米颗粒 (CPSNP) 中。非磷酸化药物类似物不能被 CPSNP 很好地封装，这表明磷酸盐修饰对于有效封装至关重要。体外增殖测定、细胞周期分析和/或胸苷酸合酶抑制测定证实，CPSNP 封装的磷酸药物保留了生物活性。对用肿瘤靶向 FdUMP-CPSNP 进行系统治疗的小鼠的原位肿瘤进行的分析证实了 PDAC 肿瘤细胞在体内摄取这些颗粒并在细胞内释放活性药物货物。这些发现证明了一种将化疗药物有效封装到 CPSNP 中并将其有效递送至胰腺肿瘤细胞的新方法。通过将化疗剂封装到纳米载体中，例如磷硅酸钙纳米粒子（CPSNP），通常可以避免前药的代谢失活，例如肝酶二氢嘧啶脱氢酶（DPD）引起的5-FU失活。在此，我们证明 5-FU 的生物活性代谢物 FdUMP 可以有效地封装到 CPSNP 中。一旦被肿瘤细胞吸收，mPEG-FdUMP-CPSNP 就会溶解在晚期内体中，释放 FdUMP 货物。在叶酸 (CH2THF) 存在的情况下，FdUMP 不可逆地结合并抑制胸苷酸合酶 (TS)，导致细胞内 dTMP 耗竭、DNA 损伤增加，并最终导致细胞死亡。
Drug resistant cancers like pancreatic ductal adenocarcinoma (PDAC) are difficult to treat, and nanoparticle drug delivery systems can overcome some of the limitations of conventional systemic chemotherapy. In this study, we demonstrate that FdUMP and dFdCMP, the bioactive, phosphorylated metabolites of the chemotherapy drugs 5-FU and gemcitabine, can be encapsulated into calcium phosphosilicate nanoparticles (CPSNPs). The non-phosphorylated drug analogs were not well encapsulated by CPSNPs, suggesting the phosphate modification is essential for effective encapsulation. In vitro proliferation assays, cell cycle analyses and/or thymidylate synthase inhibition assays verified that CPSNP-encapsulated phospho-drugs retained biological activity. Analysis of orthotopic tumors from mice treated systemically with tumor-targeted FdUMP-CPSNPs confirmed the in vivo up take of these particles by PDAC tumor cells and release of active drug cargos intracellularly. These findings demonstrate a novel methodology to efficiently encapsulate chemotherapeutic agents into the CPSNPs and to effectively deliver them to pancreatic tumor cells. By encapsulating chemotherapeutic agents into nanocarriers, such as calcium phosphosilicate nanoparticles (CPSNPs), metabolic inactivation of pro-drugs, for instance the inactivation of 5-FU by the liver enzyme dihydropyrimidine dehydrogenase (DPD), often can be avoided. Herein we demonstrate that the bioactive metabolite of 5-FU, FdUMP, can be effectively encapsulated into CPSNPs. Once taken up by tumor cells, the mPEG-FdUMP-CPSNPs dissolve in the late endosome to release the FdUMP cargo. In the presence of folate (CH2THF), FdUMP irreversibly binds to and inhibits thymidylate synthase (TS), resulting in a cellular depletion of dTMP, increased DNA damage, and ultimately cell death.
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影响因子：
10.8
作者：
Kester M;Heakal Y;Fox T;Sharma A;Robertson GP;Morgan TT;Altinoğlu EI;Tabaković A;Parette MR;Rouse SM;Ruiz-Velasco V;Adair JH
通讯作者：
Adair JH
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2.8
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17.1
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影响因子：
3.9
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影响因子：
2.7
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