Abstract
Colon carcinomas comprise over two-thirds of all colorectal cancers with an overall 5-year survival rate of 64%, which rapidly decreases to 14% when the cancer becomes metastatic. Depending on the stage of colon carcinoma at diagnosis, patients can undergo surgery to attempt complete tumor resection or move directly to chemotherapy with one or a combination of drugs. As with most cancers, colon carcinomas do not always respond to chemotherapies, so targeted therapies and immunotherapies have been developed to aid chemotherapy. We report the development of a local combination therapy for colon carcinoma whereby chemo- and immunotherapeutic entities are delivered intratumorally to maximize efficacy and minimize off-target side effects. A hydrophobic chemotherapeutic agent, docetaxel (DTX), and cholesterol-modified Toll-like receptor 9 (TLR9) agonist CpG (cho-CpG) oligonucleotide are co-loaded in synthetic HDL (sHDL) nanodiscs. In vivo survival analysis of MC-38 tumor-bearing mice treated intratumorally with DTX-sHDL/CpG (median survival; MS = 43 days) showed significant improvement in overall survival compared to mice treated with single agents, free DTX (MS = 23 days, p < 0.0001) or DTX-sHDL (MS = 28 days, p < 0.0001). Two of seven mice treated with DTX-sHDL/CpG experienced complete tumor regression. None of the mice experienced any systemic toxicity as indicated by body weight maintenance and normal serum enzyme and protein levels. In summary, we have demonstrated that chemo- and immunotherapies can be co-loaded into sHDLs, delivered locally to the tumor, and can be used to improve survival outcomes significantly compared to chemotherapy alone.
Highlights
The standard-of-care for patients with colon adenocarcinoma is surgery, radiation, chemotherapy, and possibly immunotherapy via immune checkpoint blockade
Buhtoiarov et al demonstrated that co-delivery of CpG with vincristine, cyclophosphamide, and doxorubicin in murine melanoma and neuroblastoma models significantly improved the antitumor effects of multidrug chemotherapy regimens alone
In 2015, Lollo et al used lipid nanocapsules with a cationic chitosan shell to deliver paclitaxel and CpG simultaneously to glioblastoma tumors in mice through convection-enhanced delivery and showed that this co-delivery significantly improved survival outcomes compared to Taxol® and separate injections of paclitaxel and CpG [4,5,6]
Summary
The standard-of-care for patients with colon adenocarcinoma is surgery, radiation, chemotherapy, and possibly immunotherapy via immune checkpoint blockade Though effective, both chemotherapy and immune checkpoint blockade agents are administered systemically and reach the tumor itself in very limited amounts [1]. Though effective, both chemotherapy and immune checkpoint blockade agents are administered systemically and reach the tumor itself in a very limited amount. We hypothesize that sHDL encapsulating docetaxel chemotherapy and decorated with Toll-like receptor 9 (TLR9) agonist CpG oligonucleotide will ensure effective delivery to colon adenocarcinoma tumors, leading to suppressed tumor growth and long-term survival as compared to monotherapy delivery. Tinogceetlhluelra,r thuepsteakreesoufltssHshDoLwwtihthatiMncCre3a8sicnegllsperexthriebaittmhiegnht dSRos-Bes oefxBprLeTs-s1io(np
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