Nuclear Localizing Peptide-Conjugated, Redox-Sensitive Polymersomes for Delivering Curcumin and Doxorubicin to Pancreatic Cancer Microtumors
Nuclear Localizing Peptide-Conjugated, Redox-Sensitive Polymersomes for Delivering Curcumin and Doxorubicin to Pancreatic Cancer Microtumors
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DOI：
10.1021/acs.molpharmaceut.7b00014
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发表时间：
2017-06-01
影响因子：
4.9
通讯作者：
Mallik, Sanku
中科院分区：
文献类型：
--
作者：
Anajafi, Tayebeh;Yu, Junru;Mallik, Sanku
提高抗癌剂的治疗指数是一个巨大的挑战。靶向通过将药物递送至预期目的地来减少治疗剂的副作用。含有核定位肽序列（NLS）的纳米载体易位至细胞核。然而，核定位肽是非选择性的，不能区分恶性细胞和健康细胞。在这项研究中，我们设计了一个“掩蔽”的NLS肽，只有在胰腺癌微环境中过表达的基质金属蛋白酶-7（MMP-7）酶的存在下才被激活。该肽与氧化还原响应聚合物囊泡的表面缀合，以将阿霉素和姜黄素递送至胰腺癌细胞核。我们已经在胰腺癌和正常细胞的二维和三维培养物中测试了该制剂。我们的研究表明，药物包封的聚合物囊泡对癌细胞的毒性明显高于正常细胞（球状体收缩高达24%）（球状体收缩高达49%）。这项研究可能导致其他细胞器靶向药物输送系统的发展，为各种人类恶性肿瘤。
Improving the therapeutic index of anticancer agents is an enormous challenge. Targeting decreases the side effects of the therapeutic agents by delivering the drugs to the intended destination. Nanocarriers containing the nuclear localizing peptide sequences (NLS) translocate to the cell nuclei. However, the nuclear localization peptides are nonselective and cannot distinguish the malignant cells from the healthy counterparts. In this study, we designed a "masked" NLS peptide which is activated only in the presence of overexpressed matrix metallo-proteinase-7 (MMP-7) enzyme in the pancreatic cancer micro environment. This peptide is conjugated to the surface of redox responsive polymersomes to deliver doxorubicin and curcumin to the pancreatic cancer cell nucleus. We have tested the formulation in both two- and three-dimensional cultures of pancreatic cancer and normal cells. Our studies revealed that the drug-encapsulated polymeric vesicles are significantly more toxic toward the cancer cells (shrinking the spheroids up to 49%) compared to the normal cells (shrinking the spheroids up to 24%). This study can lead to the development of other organelle targeted drug delivery systems for various human malignancies.