Two-Stage SN38 Release from a Core-Shell Nanoparticle Enhances Tumor Deposition and Antitumor Efficacy for Synergistic Combination with Immune Checkpoint Blockade.
Two-Stage SN38 Release from a Core-Shell Nanoparticle Enhances Tumor Deposition and Antitumor Efficacy for Synergistic Combination with Immune Checkpoint Blockade.
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DOI：
10.1021/acsnano.2c09788
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发表时间：
2022-12-27
期刊：
影响因子：
17.1
通讯作者：
Lin, Wenbin
中科院分区：
文献类型：
--
作者：
Jiang, Xiaomin;Lee, Morten;Xia, Junjie;Luo, Taokun;Liu, Jianqiao;Rodriguez, Megan;Lin, Wenbin
关键词：
长期循环的纳米药物有效地为肿瘤提供化疗药物，以减少全身毒性。然而，延长纳米药物的血液循环会增加药物对白细胞的暴露，并导致血液毒性。在这里，我们报告了一种两阶段释放策略，以增强OxPT/SN38核壳纳米粒的药物沉积和抗肿瘤效果。该纳米粒具有亲水性奥沙利铂(Oxpt)前药配位聚合物核和含有疏水胆固醇偶联SN38前药的脂壳(Chol-SN38)。Chol-SN38通过缩醛基团将胆固醇偶联到SN38的苯酚基团上，并用三甲基硅基(TMS)保护20-羟基位置，通过酯酶催化肝脏缩醛基团的裂解和TMS基团的酸介导的水解分两步释放SN38，从而在肿瘤中优先释放SN38。与伊立替康相比，Oxpt/SN38将SN38血液暴露减少9.0倍，将SN38肿瘤暴露增加4.7倍。因此，Oxpt/SN38通过导致细胞凋亡和免疫原性细胞死亡来抑制皮下、自发性和转移性肿瘤模型中的肿瘤生长。在自发性前列腺癌模型和结直肠癌肝转移模型中，Oxpt/SN38与免疫检查点阻断显示出很强的协同作用，可消退皮下结直肠癌和胰腺癌，治愈率为33%-50%，并极大地抑制了肿瘤的生长和侵袭，且无副作用。机制研究揭示了Oxpt/SN38促进免疫原性细胞死亡和上调PD-L1表达在激活肿瘤免疫微环境以诱导强大的抗肿瘤免疫中的重要作用。这项工作突出了创新的前药设计和纳米药物配方相结合的潜力，以解决癌症治疗中未得到满足的需求。
Long-circulating nanomedicines efficiently deliver chemotherapies to tumors to reduce general toxicity. However, extended blood circulation of nanomedicines can increase drug exposure to leukocytes and lead to hematological toxicity. Here, we report a two-stage release strategy to enhance the drug deposition and antitumor efficacy of OxPt/SN38 core–shell nanoparticles with a hydrophilic oxaliplatin (OxPt) prodrug coordination polymer core and a lipid shell containing a hydrophobic cholesterol-conjugated SN38 prodrug (Chol-SN38). By conjugating cholesterol to the phenol group of SN38 via an acetal linkage and protecting the 20-hydroxy position with a trimethylsilyl (TMS) group, Chol-SN38 releases SN38 in two stages via esterase-catalyzed cleavage of the acetal linkage in the liver followed by acid-mediated hydrolysis of the TMS group to preferentially release SN38 in tumors. Compared to irinotecan, OxPt/SN38 reduces SN38 blood exposure by 9.0 times and increases SN38 tumor exposure by 4.7 times. As a result, OxPt/SN38 inhibits tumor growth on subcutaneous, spontaneous, and metastatic tumor models by causing apoptotic and immunogenic cell death. OxPt/SN38 exhibits strong synergy with the immune checkpoint blockade to regress subcutaneous colorectal and pancreatic tumors with 33–50% cure rates and greatly inhibits tumor growth and invasion in a spontaneous prostate cancer model and a liver metastasis model of colorectal cancer without causing side effects. Mechanistic studies revealed important roles of enhanced immunogenic cell death and upregulated PD-L1 expression by OxPt/SN38 in activating the tumor immune microenvironment to elicit potent antitumor immunity. This work highlights the potential of combining innovative prodrug design and nanomedicine formulation to address unmet needs in cancer therapy.
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影响因子：
5.6
作者：
Espino Y Sosa S;Flores-Pliego A;Espejel-Nuñez A;Medina-Bastidas D;Vadillo-Ortega F;Zaga-Clavellina V;Estrada-Gutierrez G
通讯作者：
Estrada-Gutierrez G
用于药物输送和癌症治疗的超分子金属纳米颗粒。
影响因子：
7.8
作者：
Jiang X;He C;Lin W
通讯作者：
Lin W
影响因子：
16.6
作者：
Liu, Demin;Poon, Christopher;Lu, Kuangda;He, Chunbai;Lin, Wenbin
通讯作者：
Lin, Wenbin
影响因子：
46.9
作者：
Lehar, Joseph;Krueger, Andrew S.;Avery, William;Heilbut, Adrian M.;Johansen, Lisa M.;Price, E. Roydon;Rickles, Richard J.;Short, Glenn F., III;Staunton, Jane E.;Jin, Xiaowei;Lee, Margaret S.;Zimmermann, Grant R.;Borisy, Alexis A.
通讯作者：
Borisy, Alexis A.
影响因子：
16.6
作者：
He C;Duan X;Guo N;Chan C;Poon C;Weichselbaum RR;Lin W
通讯作者：
Lin W