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-phi-PTX). ALN was then conjugated to the polymeric backbone of Pull-(GGPNle-phi-PTX) via a PEG spacer. The final bioconjugate Pull-(GGPNle-phi-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-phi-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.

Novel Pullulan Bioconjugate for Selective Breast Cancer Bone Metastases Treatment

Salmaso Stefano;Scomparin Anna;Caliceti Paolo
2015-01-01

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-phi-PTX). ALN was then conjugated to the polymeric backbone of Pull-(GGPNle-phi-PTX) via a PEG spacer. The final bioconjugate Pull-(GGPNle-phi-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-phi-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.
2015
26
3
489
501
http://pubs.acs.org/journal/bcches
Animals; Cell Line; Tumor; Cell Proliferation; Female; Glucans; Human Umbilical Vein Endothelial Cells; Humans; Mice; Treatment Outcome; Bone Neoplasms; Breast Neoplasms; Biotechnology; Bioengineering; Organic Chemistry; 3003; Biomedical Engineering; Pharmacology; Medicine (all)
Bonzi Gwénaëlle; Salmaso Stefano; Scomparin Anna; Eldar-Boock Anat; Satchi-Fainaro Ronit; Caliceti Paolo
File in questo prodotto:
File Dimensione Formato  
Bonzi 2015 BC.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 2.15 MB
Formato Adobe PDF
2.15 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Bonzi et al, post-print.pdf

Accesso aperto

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 681.21 kB
Formato Adobe PDF
681.21 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1688978
Citazioni
  • ???jsp.display-item.citation.pmc??? 7
  • Scopus 38
  • ???jsp.display-item.citation.isi??? 34
social impact