1. A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma.
- Author
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Doddapaneni BS, Kyryachenko S, Chagani SE, Alany RG, Rao DA, Indra AK, and Alani AWG
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols chemistry, Antineoplastic Combined Chemotherapy Protocols metabolism, Cell Line, Tumor, Cell Survival drug effects, Chromones chemistry, Chromones metabolism, Docetaxel, Drug Compounding, Drug Resistance, Neoplasm, Everolimus chemistry, Everolimus metabolism, Humans, Lymph Nodes metabolism, Lymph Nodes pathology, Melanocytes drug effects, Melanocytes pathology, Melanoma genetics, Melanoma metabolism, Melanoma secondary, Mice, Transgenic, Morpholines chemistry, Morpholines metabolism, Nanotechnology, Skin Neoplasms genetics, Skin Neoplasms metabolism, Skin Neoplasms pathology, Solubility, Surface Properties, Taxoids chemistry, Taxoids metabolism, Time Factors, Tumor Burden drug effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Chromones administration & dosage, Drug Carriers, Everolimus administration & dosage, Lactones chemistry, Lymph Nodes drug effects, Melanoma drug therapy, Morpholines administration & dosage, Nanoparticles, Polyethylene Glycols chemistry, Skin Neoplasms drug therapy, Taxoids administration & dosage
- Abstract
Metastatic melanoma has a high mortality rate due to lymphatic progression of the disease. Current treatment is surgery followed by radiation and intravenous chemotherapy. However, drawbacks for current chemotherapeutics lie in the fact that they develop resistance and do not achieve therapeutic concentrations in the lymphatic system. We hypothesize that a three-drug nanoscale drug delivery system, tailored for lymphatic uptake, administered subcutaneously, will have decreased drug resistance and therefore offer better therapeutic outcomes. We prepared and characterized nanoparticles (NPs) with docetaxel, everolimus, and LY294002 in polyethyleneglycol-block-poly(ε-caprolactone) (PEG-PCL) polymer with different charge distributions by modifying the ratio of anionic and neutral end groups on the PEG block. These NPs are similarly sized (~48 nm), with neutral, partially charged, or fully charged surface. The NPs are able to load ~2mg/mL of each drug and are stable for 24h. The NPs are assessed for safety and efficacy in two transgenic metastatic melanoma mouse models. All the NPs were safe in both models based on general appearance, weight changes, death, and blood biochemical analyses. The partially charged NPs are most effective in decreasing the number of melanocytes at both the proximal (sentinel) lymph node (LN) and the distal LN from the injection site. The neutral NPs are efficacious at the proximal LN, while the fully charged NPs have no effect on either LNs. Thus, our data indicates that the NP surface charge and lymphatic efficacy are closely tied to each other and the partially charged NPs have the highest potential in treating metastatic melanoma., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
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