000005378 001__ 5378
000005378 005__ 20240523043255.0
000005378 02470 $$ahttps://doi.org/10.1021/acsnano.2c09788$$2doi
000005378 037__ $$aTEXTUAL$$bArticle
000005378 041__ $$aeng
000005378 245__ $$aTwo-Stage SN38 Release from a Core–Shell Nanoparticle Enhances Tumor Deposition and Antitumor Efficacy for Synergistic Combination with Immune Checkpoint Blockade
000005378 269__ $$a2022-11-16
000005378 336__ $$aArticle
000005378 520__ $$aLong-circulating nanomedicines efficiently deliver chemotherapies to tumors to reduce general toxicity. However, extended blood circulation of nanomedicines can increase drug exposure to leukocytes and lead to hematological toxicity. Here, we report a two-stage release strategy to enhance the drug deposition and antitumor efficacy of OxPt/SN38 core–shell nanoparticles with a hydrophilic oxaliplatin (OxPt) prodrug coordination polymer core and a lipid shell containing a hydrophobic cholesterol-conjugated SN38 prodrug (Chol-SN38). By conjugating cholesterol to the phenol group of SN38 via an acetal linkage and protecting the 20-hydroxy position with a trimethylsilyl (TMS) group, Chol-SN38 releases SN38 in two stages via esterase-catalyzed cleavage of the acetal linkage in the liver followed by acid-mediated hydrolysis of the TMS group to preferentially release SN38 in tumors. Compared to irinotecan, OxPt/SN38 reduces SN38 blood exposure by 9.0 times and increases SN38 tumor exposure by 4.7 times. As a result, OxPt/SN38 inhibits tumor growth on subcutaneous, spontaneous, and metastatic tumor models by causing apoptotic and immunogenic cell death. OxPt/SN38 exhibits strong synergy with the immune checkpoint blockade to regress subcutaneous colorectal and pancreatic tumors with 33–50% cure rates and greatly inhibits tumor growth and invasion in a spontaneous prostate cancer model and a liver metastasis model of colorectal cancer without causing side effects. Mechanistic studies revealed important roles of enhanced immunogenic cell death and upregulated PD-L1 expression by OxPt/SN38 in activating the tumor immune microenvironment to elicit potent antitumor immunity. This work highlights the potential of combining innovative prodrug design and nanomedicine formulation to address unmet needs in cancer therapy.
000005378 536__ $$oNational Cancer Institute$$c1R01CA223184
000005378 536__ $$oNational Cancer Institute$$c1R01CA216436
000005378 540__ $$a<p>Copyright © 2022 American Chemical Society</p> <p>This work is licensed under the <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License</a>.</p>
000005378 542__ $$fCC BY
000005378 594__ $$aThe authors declare that all the data supporting the findings of this study are available within the article and its Supporting Information files or from the corresponding author upon reasonable request.
000005378 6531_ $$aPD-L1
000005378 6531_ $$aantitumor immunity
000005378 6531_ $$achemoimmunotherapy
000005378 6531_ $$acore−shell nanoparticle
000005378 6531_ $$aimmunogenic cell death
000005378 6531_ $$aprodrug
000005378 6531_ $$atumor microenvironment
000005378 690__ $$aBiological Sciences Division
000005378 691__ $$aRadiation and Cellular Oncology
000005378 691__ $$aRadiology
000005378 692__ $$aLudwig Center for Metastasis Research
000005378 7001_ $$1https://orcid.org/0000-0001-8304-4938$$2ORCID$$aJiang, Xiaomin$$uUniversity of Chicago
000005378 7001_ $$1https://orcid.org/0000-0003-0069-7541$$2ORCID$$aLee, Morten$$uUniversity of Chicago
000005378 7001_ $$aXia, Junjie$$uUniversity of Chicago
000005378 7001_ $$1https://orcid.org/0000-0001-5894-0490$$2ORCID$$aLuo, Taokun$$uUniversity of Chicago
000005378 7001_ $$aLiu, Jianqiao$$uUniversity of Chicago
000005378 7001_ $$aRodriguez, Megan$$uUniversity of Chicago
000005378 7001_ $$1https://orcid.org/0000-0001-7035-7759$$2ORCID$$aLin, Wenbin$$uUniversity of Chicago
000005378 773__ $$tACS Nano
000005378 8564_ $$yArticle$$936dd28bc-5166-4672-a3ad-f89b54b0eb23$$s12793379$$uhttps://knowledge.uchicago.edu/record/5378/files/Two-Stage-SN38-Release-from-a-Core-Shell-Nanoparticle.pdf$$ePublic
000005378 8564_ $$ySupporting information$$9d4ea73f4-3b29-4ea7-b69b-c4c688ce215e$$s4466715$$uhttps://knowledge.uchicago.edu/record/5378/files/nn2c09788_si_001.pdf$$ePublic
000005378 908__ $$aI agree
000005378 909CO $$ooai:uchicago.tind.io:5378$$pGLOBAL_SET
000005378 983__ $$aArticle