Tumor-Activatable Nanoparticles Target Low-Density Lipoprotein Receptor to Enhance Drug Delivery and Antitumor Efficacy.
Tumor-Activatable Nanoparticles Target Low-Density Lipoprotein Receptor to Enhance Drug Delivery and Antitumor Efficacy.
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DOI：
10.1002/advs.202201614
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发表时间：
2022-08
期刊：
影响因子：
15.1
通讯作者：
Lin, Wenbin
中科院分区：
文献类型：
--
作者：
Jiang, Xiaomin;Han, Wenbo;Liu, Jianqiao;Mao, Jianming;Lee, Morten J.;Rodriguez, Megan;Li, Youyou;Luo, Taokun;Xu, Ziwan;Yang, Kaiting;Bissonnette, Marc;Weichselbaum, Ralph R.;Lin, Wenbin
血浆蛋白与纳米药物的结合被广泛认为不利于它们向肿瘤的递送。在此，报道了用于主动肿瘤靶向的OxPt/SN 38纳米颗粒的设计，该纳米颗粒在配位聚合物核中含有亲水性奥沙利铂（OxPt）前药，在脂质壳上含有疏水性胆固醇缀合的SN 38前药。OxPt/SN 38在低密度脂蛋白（LDL）颗粒上搭便车，通过LDL受体介导的内吞作用在肿瘤中浓缩，并在酸性、富含酯酶和还原性肿瘤微环境中选择性释放SN 38和OxPt，导致肿瘤中的累积比游离药物高6.0和4.9倍。通过同时交联DNA和抑制拓扑异构酶I，OxPt/SN 38在五种结直肠癌肿瘤模型中实现了92-98%的肿瘤生长抑制，并且在三种人类结直肠癌肿瘤模型中与游离药物对照相比延长了小鼠存活58-80天，而没有引起严重的副作用。该研究揭示了一种新的纳米医学策略，通过主动靶向LDL受体共同向肿瘤提供联合化疗。开发了在配位聚合物核中含有亲水性奥沙利铂前药和在脂质壳上含有疏水性胆固醇缀合的SN 38前药的核壳纳米粒，用于主动肿瘤靶向。这种肿瘤可活化纳米颗粒搭低密度脂蛋白的便车，通过LDL受体介导的内吞作用在肿瘤中浓缩，并在溶酶体中选择性释放奥沙利铂和SN 38，从而产生上级抗肿瘤作用。
The binding of plasma proteins to nanomedicines is widely considered detrimental to their delivery to tumors. Here, the design of OxPt/SN38 nanoparticle containing a hydrophilic oxaliplatin (OxPt) prodrug in a coordination polymer core and a hydrophobic cholesterol‐conjugated SN38 prodrug on the lipid shell for active tumor targeting is reported. OxPt/SN38 hitchhikes on low‐density lipoprotein (LDL) particles, concentrates in tumors via LDL receptor‐mediated endocytosis, and selectively releases SN38 and OxPt in acidic, esterase‐rich, and reducing tumor microenvironments, leading to 6.0‐ and 4.9‐times higher accumulations in tumors over free drugs. By simultaneously crosslinking DNA and inhibiting topoisomerase I, OxPt/SN38 achieved 92–98% tumor growth inhibition in five colorectal cancer tumor models and prolonged mouse survival by 58–80 days compared to free drug controls in three human colorectal cancer tumor models without causing serious side effects. The study has uncovered a novel nanomedicine strategy to co‐deliver combination chemotherapies to tumors via active targeting of the LDL receptor. The core‐shell nanoparticle that containing a hydrophilic oxaliplatin prodrug in a coordination polymer core and a hydrophobic cholesterol‐conjugated SN38 prodrug on the lipid shell for active tumor targeting is developed. This tumor‐activable nanoparticle hitchhikes on low‐density lipoproteins, concentrates in tumors via LDL receptor‐mediated endocytosis, and selectively releases oxaliplatin and SN38 in lysosome, resulting superior antitumor effects.
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