Enhanced anti-tumor activity and safety profile of targeted nano-scaled HPMA copolymer-alendronate-TNP-470 conjugate in the treatment of bone malignances

Ehud Segal, Huaizhong Pan, Liat Benayoun, Pavla Kopečková, Yuval Shaked, Jindřich Kopeček, Ronit Satchi-Fainaro*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

Bone neoplasms, such as osteosarcoma, exhibit a propensity for systemic metastases resulting in adverse clinical outcome. Traditional treatment consisting of aggressive chemotherapy combined with surgical resection, has been the mainstay of these malignances. Therefore, bone-targeted non-toxic therapies are required. We previously conjugated the aminobisphosphonate alendronate (ALN), and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. HPMA copolymer-ALN-TNP-470 conjugate exhibited improved anti-angiogenic and anti-tumor activity compared with the combination of free ALN and TNP-470 when evaluated in a xenogeneic model of human osteosarcoma. The immune system has major effect on toxicology studies and on tumor progression. Therefore, in this manuscript we examined the safety and efficacy profiles of the conjugate using murine osteosarcoma syngeneic model. Toxicity and efficacy evaluation revealed superior anti-tumor activity and decreased organ-related toxicities of the conjugate compared with the combination of free ALN plus TNP-470. Finally, comparative anti-angiogenic activity and specificity studies, using surrogate biomarkers of circulating endothelial cells (CEC), highlighted the advantage of the conjugate over the free agents. The therapeutic platform described here may have clinical translational relevance for the treatment of bone-related angiogenesis-dependent malignances.

Original languageEnglish
Pages (from-to)4450-4463
Number of pages14
JournalBiomaterials
Volume32
Issue number19
DOIs
StatePublished - Jul 2011

Funding

FundersFunder number
Alon Foundation
Fine, Jacobs and Israel Student Education Foundation
Ministry of Health, Israel, THE ISRAEL SCIENCE FOUNDATION1309/10
TAU Center for Nanoscience and Nanotechnology
National Institutes of Health
National Institute of General Medical SciencesR01GM069847
Russell Sage Foundation
Israel Cancer Research Fund
European Association for Cancer Research
Iowa Science Foundation
Marie Curie
Seventh Framework Programme

    Keywords

    • Alendronate
    • HPMA copolymer
    • Osteosarcoma
    • Polymer therapeutics
    • TNP-470

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