title: A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma.
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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, USA.
authors.forename: Bhuvana S
authors.initials: BS
authors.lastname: Doddapaneni
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, USA.
authors.forename: Sergiy
authors.initials: S
authors.lastname: Kyryachenko
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, USA.
authors.forename: Sharmeen E
authors.initials: SE
authors.lastname: Chagani
authors.affiliation: School of Pharmacy and Chemistry, Drug Discovery, Delivery and Patient Care (DDDPC) Theme, Kingston University, London, UK.
authors.forename: Raid G
authors.initials: RG
authors.lastname: Alany
authors.affiliation: School of Pharmacy, Pacific University, Hillsboro, OR, USA.
authors.forename: Deepa A
authors.initials: DA
authors.lastname: Rao
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, USA.
authors.forename: Arup K
authors.initials: AK
authors.lastname: Indra
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, USA. Electronic address: Adam.Alani@oregonstate.edu.
authors.forename: Adam W G
authors.initials: AWG
authors.lastname: Alani
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D000077143:Docetaxel; D004337:Drug Carriers; D004339:Drug Compounding; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000737:chemistry*; D008198:Lymph Nodes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008544:Melanocytes / Q000187:drug effects / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008822:Mice, Transgenic; D009025:Morpholines / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D053758:Nanoparticles; D036103:Nanotechnology; D011092:Polyethylene Glycols / Q000737:chemistry*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012995:Solubility; D013499:Surface Properties; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D002867:Chromones; D004337:Drug Carriers; D007783:Lactones; D009025:Morpholines; D043823:Taxoids; C521904:poly(ethylene glycol)-block-poly(epsilon-caprolactone); D000077143:Docetaxel; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011092:Polyethylene Glycols; D000068338:Everolimus
keywords: Combination therapy; Lymphatic drug delivery; Melanoma transgenic mouse model; Melanoma treatment; Nanoparticles