title: Novel pullulan bioconjugate for selective breast cancer bone metastases treatment.
abstract: A novel polysaccharide bioconjugate was designed to selectively target breast cancer bone metastases using a bisphosphonate moiety (alendronate, ALN). Paclitaxel (PTX) was first covalently conjugated to pullulan (Pull) through a Cathepsin K-sensitive tetrapeptide spacer followed by a self-immolative aminobenzyl alcohol spacer to obtain Pull-(GGPNle-φ-PTX). ALN was then conjugated to the polymeric backbone of Pull-(GGPNle-φ-PTX) via a PEG spacer. The final bioconjugate Pull-(GGPNle-φ-PTX)-(PEG-ALN) was found to assemble into colloidal spherical structures, which were physically and chemically stable under physiological conditions. In vitro studies showed that Pull-(GGPNle-φ-PTX)-(PEG-ALN) had strong affinity for hydroxyapatite, which simulates the bone tissue. Paclitaxel was rapidly released from the bioconjugate by Cathepsin K cleavage under pathological conditions. All studies performed using human MDA-MB-231-BM (bone metastases-originated clone), murine 4T1 breast cancer cells, murine K7M2, and human SAOS-2 osteosarcoma cells showed that the bioconjugate exerted an enhanced antiproliferative activity compared to the conjugate without the ALN. Furthermore, the nanoconjugate inhibited the migration of cancer cells and further displayed potent anti-angiogenic activity. In conclusion, the results showed that this conjugate has an excellent potential for selective treatment of bone neoplasms such as breast cancer bone metastases and osteosarcoma.
authors.affiliation: †Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via F. Marzolo 5, 35131 Padua, Italy.
authors.forename: Gwénaëlle
authors.initials: G
authors.lastname: Bonzi
authors.affiliation: †Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via F. Marzolo 5, 35131 Padua, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Salmaso
authors.affiliation: ‡Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Scomparin
authors.affiliation: ‡Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Eldar-Boock
authors.affiliation: ‡Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Satchi-Fainaro
authors.affiliation: †Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via F. Marzolo 5, 35131 Padua, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Caliceti
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005936:Glucans / Q000737:chemistry* / Q000627:therapeutic use*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D016896:Treatment Outcome
chemical_list: D005936:Glucans; C009109:pullulan