title: Antitumor efficacy of a novel polymer-peptide-drug conjugate in human tumor xenograft models.
abstract: We have designed a new dextran-peptide-methotrexate conjugate to achieve tumor-targeted delivery of chemotherapeutics. The dextran carrier was selected to allow passive targeting and enhanced permeation and retention (EPR). The peptide linker has also been optimized to allow drug release in the presence of matrix-metalloproteinase-2 (MMP-2) and matrix-metalloproteinase-9 (MMP-9), 2 important tumor-associated enzymes. The new conjugate was assessed for its in vivo antitumor efficacy and systemic side effects. It was compared with free methotrexate (MTX) and a similar conjugate, differing by an MMP-insensitive linker, at equivalent intraperitoneal dosages. The MMP-sensitive conjugate demonstrated tolerable in vivo side effects and effective inhibition of in vivo tumor growth by 83% in each of the 2 separate tumor models that overexpress MMP (HT-1080 and U-87). The antiproliferative effect of the drug contributed to the inhibition of tumor growth. In contrast, free MTX resulted in no significant tumor reduction in the same models. Neither free MTX nor the conjugate caused any tumor inhibition in the mice bearing RT-112, a slower growing model that does not overexpress MMP. MMP-insensitive conjugates, though able to inhibit tumor growth, caused toxicity in the small intestine and bone marrow.
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. ying_chau@alum.mit.edu
authors.forename: Ying
authors.initials: Y
authors.lastname: Chau
authors.forename: Robert F
authors.initials: RF
authors.lastname: Padera
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Dang
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D002240:Carbohydrate Sequence; D045744:Cell Line, Tumor; D003911:Dextrans / Q000737:chemistry*; D015195:Drug Design; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology; D019394:Ki-67 Antigen / Q000032:analysis; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D008727:Methotrexate / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry*; D016896:Treatment Outcome; D015431:Weight Loss / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003911:Dextrans; D019394:Ki-67 Antigen; D010455:Peptides; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008727:Methotrexate