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.