title: Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug.
abstract: Taxanes are highly effective chemotherapeutic drugs against proliferating cancer and an established option in the standard treatment of ovarian and breast cancer. However, treatment with paclitaxel is associated with severe side effects, including sensory axonal neuropathy, and its poor solubility in water complicates its formulation. In this paper we report the in vitro and in vivo activity of a new form of paclitaxel, modified for conjugation with a tumor-selective tetrabranched peptide carrier (NT4). NT4 selectively targets tumor cells by binding to membrane sulfated glycosaminoglycans (GAG) and to endocytic receptors, like LRP1 and LRP6, which are established tumor markers. Biological activity of NT4-paclitaxel was tested in vitro on MDA-MB 231 and SKOV-3 cell lines, representing breast and ovarian cancer, respectively, and in vivo in an orthotopic mouse model of human breast cancer. Using in vivo bioluminescence imaging, we found that conjugation of paclitaxel with the NT4 peptide led to increased therapeutic activity of the drug in vivo. NT4-paclitaxel induced tumor regression, whereas treatment with unconjugated paclitaxel only produced a reduction in tumor growth. Moreover, unlike paclitaxel, NT4-paclitaxel is very hydrophilic, which may improve its pharmacokinetic profile and allow the use of less toxic dilution buffers, further decreasing its general chemotherapic toxicity.
authors.affiliation: University of Siena, Department of Medical Biotechnologies, Siena, 53100, Italy.
authors.forename: Jlenia
authors.initials: J
authors.lastname: Brunetti
authors.affiliation: University of Florence, Department of Experimental and Clinical Medicine, Florence, 50139, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Pillozzi
authors.affiliation: SetLance srl, Toscana Life Sciences, Siena, 53100, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Falciani
authors.affiliation: University of Siena, Department of Medical Biotechnologies, Siena, 53100, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Depau
authors.affiliation: University of Florence, Department of Chemistry, Florence, 50019, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Tenori
authors.affiliation: University of Siena, Department of Medical Biotechnologies, Siena, 53100, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Scali
authors.affiliation: University of Siena, Department of Medical Biotechnologies, Siena, 53100, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Lozzi
authors.affiliation: University of Siena, Department of Medical Biotechnologies, Siena, 53100, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pini
authors.affiliation: University of Florence, Department of Experimental and Clinical Medicine, Florence, 50139, Italy.
authors.forename: Annarosa
authors.initials: A
authors.lastname: Arcangeli
authors.affiliation: University of Florence, Department of Chemistry, Florence, 50019, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Menichetti
authors.affiliation: University of Siena, Department of Medical Biotechnologies, Siena, 53100, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Bracci
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004337:Drug Carriers; D010455:Peptides; D017239:Paclitaxel