Abstract
Colorectal cancer (CRC) is the most frequently diagnosed cancer and leading cause of cancer-related deaths worldwide. Because of the use of first-line CRC treatments, such as irinotecan (IRI), is hindered by dose-limiting side effects, improved drug delivery systems may have major clinical benefits for CRC treatment. In this study, we generate and characterize liposomal irinotecan (Lipo-IRI), a lipid-based nanoparticle, which shows excellent bioavailability and pharmacokinetics. Additionally, this formulation allows IRI to be maintained in active form and prolongs its half-life in circulation compared to IRI in solution. Compared with IRI statistically, the level of prostaglandin E2 (PGE2) in colonic tissue decreases, and Bifidobacterium spp. (beneficial intestinal microbiota) content increases in the Lipo-IRI-treated group. Moreover, no damage is observed by the hematoxylin and eosin staining of the normal tissue samples from the Lipo-IRI-treated group. In a xenograft mouse model, CRC tumors shrink markedly following Lipo-IRI treatment, and mice receiving a targeted combination of Lipo-IRI and liposomal doxorubicin (Lipo-Dox) extend their survival rate significantly. Overall, our results demonstrate that this formulation of Lipo-IRI shows a great potential for the treatment of colorectal cancer.
Highlights
Colorectal cancer (CRC), known as bowel cancer, is the third most common malignant disease worldwide [1]
Our results revealed that this new formulation of Lipo-IRI has markedly increased the pharmacokinetics and drug delivery into the tumor tissue, thereby significantly increasing the therapeutic index compared with free IRI
Dulbecco’s Modified Eagle’s Medium (DMEM), RPMI-1640 media, fetal bovine serum (FBS), and penicillin-streptomycin were purchased from Invitrogen (Carlsbad, CA, USA)
Summary
Colorectal cancer (CRC), known as bowel cancer, is the third most common malignant disease worldwide [1]. The disease usually develops slowly, and most cases are adenocarcinomas [2]. Screening of at-risk individuals can help to detect CRC at early stages, which greatly improves the prognosis and decreases the CRC mortality. If cancerous polyps are detected early, the five-year survival rate after treatment is over 90% [3]. The majority of colon cancer patients are diagnosed with a late-stage disease, when the survival rates are much lower. Physicians will sometimes suggest a combination treatment regimen, which includes either chemotherapy or radiotherapy. In such cases, the first-line chemotherapeutic drug for CRC patients is irinotecan (IRI or CPT-11), an analog of camptothecin (CPT)
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