title: cRGD-installed polymeric micelles loading platinum anticancer drugs enable cooperative treatment against lymph node metastasis.
abstract: Lymph node metastasis (LNM) is correlated with decreased survival, indicating high tumor malignancy and being a potential source for subsequent fatal metastases. Targeted therapies inhibiting the formation of LNM, while eliminating established metastatic foci, could provide synergistic effects by reducing the incidence and growth of metastasis. Based on the inhibitory activity of cRGD peptide against the development of metastasis, and the LNM targeting ability of systemically injected drug-loaded polymeric micelles, herein, we studied the capability of cRGD-installed polymeric micelles incorporating the platinum anticancer drug (1,2-diaminocylohexane)platinum(II) (DACHPt) for cooperatively inhibiting the formation and progression of LNM. As cRGD-installed DACHPt-loaded micelles (cRGD-DACHPt/m) presented similar size, drug loading and surface charge to non-conjugated micelles (MeO-DACHPt/m), the differences in the biological performance of the micelles were endorsed to the effect of the ligand. In a syngeneic melanoma model, both MeO-DACHPt/m and cRGD-DACHPt/m showed comparable antitumor activity against the primary tumors and the established metastatic foci in lymph nodes. However, cRGD-DACHPt/m significantly enhanced the efficacy against LNM draining from primary tumors through the effective inhibition of the spreading of cancer cells. This improved inhibition was associated with the ability of cRGD-DACHPt/m to reduce the migration of melanoma cells, which was higher than that of MeO-DACHPt/m, free cRGD and their combination. These results support our strategy of using cRGD-installed micelles for attaining cooperative therapies against LNM exploiting the inhibitory function of the peptide and the cytotoxic effect of the micelles.
authors.affiliation: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Makino
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. Electronic address: horacio@bmw.t.u-tokyo.ac.jp.
authors.forename: Horacio
authors.initials: H
authors.lastname: Cabral
authors.affiliation: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Miura
authors.affiliation: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.affiliation: The Innovation Center of Nanomedicine, 66-20 Horikawa-cho, Saiwai-ku, Kawasaki 212-0013, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kinoh
authors.affiliation: The Innovation Center of Nanomedicine, 66-20 Horikawa-cho, Saiwai-ku, Kawasaki 212-0013, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Mochida
authors.affiliation: Polymer Chemistry Division, Chemical Resources Laboratory, Tokyo Institute of Technology, R1-11, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.affiliation: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan; Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan; The Innovation Center of Nanomedicine, 66-20 Horikawa-cho, Saiwai-ku, Kawasaki 212-0013, Japan. Electronic address: kataoka@bmw.t.u-tokyo.ac.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008810:Mice, Inbred C57BL; D008823:Micelles; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D010316:Particle Size; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D011108:Polymers / Q000737:chemistry*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013499:Surface Properties; D013997:Time Factors
chemical_list: C554217:((1R,2R)-1,2-diaminocyclohexane)platinum(II); D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D009944:Organoplatinum Compounds; D010456:Peptides, Cyclic; D011108:Polymers; C507169:cyclic arginine-glycine-aspartic acid peptide
keywords: Cell migration; Lymph node metastasis; Melanoma; Polymeric micelles; cRGD peptide