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Background: The alkaloid camptothecin analog SN38 is a potent antineoplastic agent, but cannot be used directly for clinical application due to its poor water solubility. Currently, the prodrug approach on SN38 has resulted in 3 FDA-approved cancer therapeutics, irinotecan, ONIVYDE, and Trodelvy. However, only 2–8% of irinotecan can be transformed enzymatically in vivo into the active metabolite SN38, which severely limits the drug's efficacy. While numerous drug delivery systems have been attempted to achieve effective SN38 delivery, none have produced drug products with antitumor efficacy better than irinotecan in clinical trials. Therefore, novel approaches are urgently needed for effectively delivering SN38 to cancer cells with better efficacy and lower toxicity. Methods: Based on the unique properties of human serum albumin (HSA), we have developed a novel single protein encapsulation (SPE) technology to formulate cancer therapeutics for improving their pharmacokinetics (PK) and antitumor efficacy and reducing their side effects. Previous application of SPE technology to doxorubicin (DOX) formulation has led to a promising drug candidate SPEDOX-6 (FDA IND #, 152154), which will undergo a human phase I clinical trial. Using the same SPE platform on SN38, we have now produced two SPESN38 complexes, SPESN38-5 and SPESN38-8. We conducted their pharmacological evaluations with respect to maximum tolerated dose, PK, and in vivo efficacy against colorectal cancer (CRC) and soft tissue sarcoma (STS) in mouse models. Results: The lyophilized SPESN38 complexes can dissolve in aqueous media to form clear and stable solutions. Maximum tolerated dose (MTD) of SPESN38-5 is 250 mg/kg by oral route (PO) and 55 mg/kg by intravenous route (IV) in CD-1 mice. SPESN38-8 has the MTD of 45 mg/kg by IV in the same mouse model. PK of SPESN38-5 by PO at 250 mg/kg gave mouse plasma AUC0-∞ of 0.05 and 4.5 nmol × h/mL for SN38 and SN38 glucuronidate (SN38G), respectively, with a surprisingly high molar ratio of SN38G:SN38 = 90:1. However, PK of SPESN38-5 by IV at 55 mg/kg yielded much higher mouse plasma AUC0-∞ of 19 and 28 nmol × h/mL for SN38 and SN38G, producing a much lower molar ratio of SN38G:SN38 = 1.5:1. Antitumor efficacy of SPESN38-5 and irinotecan (control) was evaluated against HCT-116 CRC xenograft tumors. The data indicates that SPESN38-5 by IV at 55 mg/kg is more effective in suppressing HCT-116 tumor growth with lower systemic toxicity compared to irinotecan at 50 mg/kg. Additionally, SPESN38-8 and DOX (control) by IV were evaluated in the SK-LMS-1 STS mouse model. The results show that SPESN38-8 at 33 mg/kg is highly effective for inhibiting SK-LMS-1 tumor growth with low toxicity, in contrast to DOX's insensitivity to SK-LMS-1 with high toxicity. Conclusion: SPESN38 complexes provide a water soluble SN38 formulation. SPESN38-5 and SPESN38-8 demonstrate better PK values, lower toxicity, and superior antitumor efficacy in mouse models, compared with irinotecan and DOX. [ABSTRACT FROM AUTHOR]

Background: Macrophage infiltration in the tumor microenvironment participates in the regulation of tumor progression. Previous studies have found that Notch signaling pathway is involved in regulating the progression of colorectal cancer (CRC), however, the specific mechanism is still unclear. Methods: The correlation between Notch signaling pathway and macrophage infiltration was investigated in TCGA database and verified in clinical samples of patients with CRC using immunohistochemistry. Gene Set Enrichment Analysis was used to find out genes related to Notch3 expression. Colony formation assay, and flow cytometry were utilized to test tumor growth and immune cell infiltration in vitro and in vivo. Results: Using bioinformatics analysis and clinical sample validation, we found that Notch3 was highly expressed in colon tumor tissues compared to adjacent normal tissues, and it participated in regulating the recruitment of macrophages to the tumor microenvironment. Furthermore, we found that the Notch3 expression was positively correlated with the expression of macrophage recruitment-related cytokines in colon tumor tissues. Finally, we demonstrated that depletion of Notch3 had no significant effect on the growth of colon tumor cells in vitro, while, attenuated the growth of colon cancer tumors in vivo. Simultaneous, immunosuppressive cells, macrophages and myeloid-derived suppressor cell (MDSC) infiltration were dramatically reduced in the tumor microenvironment. Conclusion: Our study illustrated that Notch3 could facilitate the progression of CRC by increasing the infiltration of macrophages and MDSCs to promote the immunosuppressive tumor microenvironment. Targeting Notch3 specifically is a potentially effective treatment for CRC. [ABSTRACT FROM AUTHOR]