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- Title
Drug Combination Nanoparticles Containing Gemcitabine and Paclitaxel Enable Orthotopic 4T1 Breast Tumor Regression.
- Authors
Yu, Jesse; Xu, Xiaolin; Griffin, James Ian; Mu, Qingxin; Ho, Rodney J. Y.
- Abstract
Simple Summary: Breast cancer typically originates and metastasizes from the mammary fat pad. The tumor within the fat pad is supported by enriched lymphatic vessels, to a greater degree than that of blood vessels. Recently, we have successfully co-formulated two physically disparate cancer drugs, water-soluble gemcitabine (G) and water-insoluble paclitaxel (T), into a drug combination nanoparticle (DcNP) referred to as GT-in-DcNP. This GT-in-DcNP dosage form is stable and scalable. When it is given to mice, it enables synchronized delivery of GT into tumors via enriched lymph vessels. A single dose of GT-in-DcNP in mice has been found to suppress breast tumor growth in the mammary fat pad more effectively than an equivalent dose of the free GT combination. We observed tumor regression and restoration of mammary fat tissue at higher doses of GT-in-DcNP. This concept has been extended to demonstrate the ability to suppress human breast cancer in a xenograft model. With these observations, GT-in-DcNP may be considered for clinical development to treat breast cancer. Early diagnosis, intervention, and therapeutic advancements have extended the lives of breast cancer patients; however, even with molecularly targeted therapies, many patients eventually progress to metastatic cancer. Recent data suggest that residual breast cancer cells often reside in the lymphatic system before rapidly spreading through the bloodstream. To address this challenge, an effective drug combination composed of gemcitabine (G) and paclitaxel (T) is administered intravenously in sequence at the metastatic stage, but intravenous GT infusion may limit lymphatic GT drug accessibility and asynchronous drug exposure in cancer cells within the lymph. To determine whether co-localization of intracellular gemcitabine and paclitaxel (referred to as GT) could overcome these limitations and enhance the efficacy of GT, we have evaluated a previously reported GT drug-combination formulated in nanoparticle (referred to as GT-in-DcNP) evaluated in an orthotopic breast tumor model. Previously, with indocyanine green-labeled nanoparticles, we reported that GT-in-DcNP particles after subcutaneous dosing were taken up rapidly and preferentially into the lymph instead of blood vessels. The pharmacokinetic study showed enhanced co-localization of GT within the tumors and likely through lymphatic access, before drug apparency in the plasma leading to apparent long-acting plasma time-course. The mechanisms may be related to significantly greater inhibitions of tumor growth—by 100 to 140 times—in both sub-iliac and axillary regions compared to the equivalent dosing with free-and-soluble GT formulation. Furthermore, GT-in-DcNP exhibited dose-dependent effects with significant tumor regression. In contrast, even at the highest dose of free GT combination, only a modest tumor growth reduction was notable. Preliminary studies with MDA-231-HM human breast cancer in an orthotopic xenograft model indicated that GT-in-DcNP may be effective in suppressing human breast tumor growth. Taken together, the synchronized delivery of GT-in-DcNP to mammary tumors through the lymphatic system offers enhanced cellular retention and greater efficacy.
- Subjects
THERAPEUTIC use of antineoplastic agents; BIOLOGICAL models; LYMPHATICS; RESEARCH funding; BREAST tumors; BLOOD vessels; EARLY detection of cancer; XENOGRAFTS; MICE; INTRAVENOUS therapy; GEMCITABINE; ANIMAL experimentation; MOLECULAR structure; PACLITAXEL; COMPARATIVE studies; NANOPARTICLES; SUBCUTANEOUS injections
- Publication
Cancers, 2024, Vol 16, Issue 16, p2792
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers16162792