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Calcium Phosphate-cured Nanocluster of Poly(L-glutamic acid)-Cisplatin and Arsenic Trioxide for Synergistic Chemotherapy of Peritoneal Metastasis of Ovarian Cancer
- Acta Polymerica Sinica Vol. 51, Issue 8, Pages: 901-910(2020)
- 作者机构：
1.中国科学院长春应用化学研究所 中国科学院生态环境高分子材料重点实验室 长春 130022
2.中国科学技术大学应用化学与工程学院 合肥 230026
- 作者简介：
- 基金信息：
DOI：10.11777/j.issn1000-3304.2020.20053
CLC：Published：2020-8，
Published Online：22 July 2020，
Received：4 March 2020，
Revised：30 April 2020，
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Zhong-yu Jiang, Xiang-ru Feng, Wei-guo Xu, Xiu-li Zhuang, Jian-xun Ding, Xue-si Chen. Calcium Phosphate-cured Nanocluster of Poly(L-glutamic acid)-Cisplatin and Arsenic Trioxide for Synergistic Chemotherapy of Peritoneal Metastasis of Ovarian Cancer. [J]. Acta Polymerica Sinica 51(8):901-910(2020)
Zhong-yu Jiang, Xiang-ru Feng, Wei-guo Xu, Xiu-li Zhuang, Jian-xun Ding, Xue-si Chen. Calcium Phosphate-cured Nanocluster of Poly(L-glutamic acid)-Cisplatin and Arsenic Trioxide for Synergistic Chemotherapy of Peritoneal Metastasis of Ovarian Cancer. [J]. Acta Polymerica Sinica 51(8):901-910(2020) DOI： 10.11777/j.issn1000-3304.2020.20053.
摘要
在临床上，顺铂(CDDP)作为一线化疗药物被广泛应用于治疗各种实体肿瘤. 然而，肿瘤细胞内的还原微环境会降低CDDP的疗效. 在本研究中，通过磷酸钙固化技术将聚(L-谷氨酸)-CDDP纳米粒子(PGN-Pt)与三氧化二砷(ATO)结合，构建细胞内酸敏感的纳米团簇NC
PGN-Pt+ATO
，以提高肿瘤治疗效果. NC
PGN-Pt+ATO
为粒径在129.8 nm的纳米球，能够在血液中长循环并通过增强渗透与滞留效应在肿瘤组织富集. NC
PGN-Pt+ATO
被细胞摄取后在细胞内酸性环境中释放PGN-Pt和ATO. PGN-Pt在细胞内持续释放CDDP以保持其有效杀伤浓度. CDDP和ATO共同提高细胞内活性氧的水平杀死肿瘤细胞，同时提升CDDP的疗效协同抑制肿瘤进展. 鉴于良好的有效性和安全性，NC
PGN-Pt+ATO
为CDDP纳米药物的设计提供了新的有效策略.
Abstract
Cisplatin (CDDP)
as a traditional first-line chemotherapeutic drug
has been broadly used for the treatment of numerous solid cancers in the clinic. However
the treatment efficacy of CDDP is limited by a variety of issues
including enhanced efflux
increased detoxification capability
and improved ability of DNA damage repair of cancer cells. For example
the high level of intracellular glutathione (GSH) significantly decreases the cytotoxicity of CDDP through the formation of stable GS-Pt complex
which can be rapidly extracted from the tumor cells through an adenosine triphosphate-dependent glutathione S-conjugate export pump (GS-X pump). Therefore
the antitumor efficacy of CDDP can be upregulated by inhibiting the synthesis of GSH with drugs
directly depleting GSH with organic or inorganic nanoparticles
or neutralizing GSH through upregulating the level of reactive oxygens species (ROS) in the cells. Herein
the intracellular acidity-sensitive nanocluster (NC
PGN-Pt+As
) was developed to improve the antitumor efficacy
which was fabricated by the calcium phosphate (Ca
3
(PO
4
)
2
)-curing of CDDP-loaded poly(L-glutamic acid) nanoparticle (PGN-Pt) and arsenic trioxide (ATO). The optimal mass ratio of CDDP and ATO in NC
PGN-Pt+As
was determined to be 2:1 by the coefficient of drug interaction (CDI) between CDDP and ATO. NC
PGN-Pt+As
exhibited a nanosphere structure with a diameter of 129.8 nm. NC
PGN-Pt+As
showed prolonged blood circulation
evidenced by the increased half-life (
t
1/2
β
) and the area under the drug concentration-time curve (AUC
0-
t
). Moreover
NC
PGN-Pt+As
demonstrated the reduced accumulation in the normal tissues and improved accumulation in the tumor. The intratumoral accumulations of CDDP and ATO were 5.7 and 3.9 times higher than those of the free CDDP+ATO group
respectively
which should be attributed to the enhanced permeability and retention effect. Upon entering the endosome
NC
PGN-Pt+As
decomposed and released PGN-Pt and ATO under the acidic conditions. CDDP was sustainedly released from PGN-Pt in the cells and maintained effective concentration. CDDP and ATO synergistically upregulated the level of intracellular ROS
which could kill tumor cells or enhance the efficacy of CDDP and synergistically inhibit peritoneal metastasis of ovarian cancer. At the same time
NC
PGN-Pt+As
was proved safe by the remained body weights of mice during the treatment period and normal levels of the liver- and kidney-related parameters after all treatments relative to free CDDP+ATO. Given its excellent efficacy and safety
this platform provided a uniquely effective strategy for the design of CDDP nanomedicines.
关键词
高分子纳米药物三氧化二砷磷酸钙纳米团簇细胞内药物递送癌症协同化疗
Keywords
Polymer nanomedicineArsenic trioxideCalcium phosphate nanoclusterIntracellular drug deliverySynergistic chemotherapy of cancer
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