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

• Published in: Biomaterials 2011-07, Vol.32 (19), p.4450-4463
• Main Authors: Segal, Ehud, Pan, Huaizhong, Benayoun, Liat, Kopečková, Pavla, Shaked, Yuval, Kopeček, Jindřich, Satchi-Fainaro, Ronit
• Format: Article
• Language: English
• Subjects: Acrylamides - chemistry; Advanced Basic Science; Alendronate; Alendronate - chemistry; Alendronate - therapeutic use; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - therapeutic use; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Body Weight; Bone Density Conservation Agents - chemistry; Bone Density Conservation Agents - therapeutic use; Bone Neoplasms - drug therapy; Cell Line, Tumor; Cyclohexanes - chemistry; Cyclohexanes - therapeutic use; Dentistry; HPMA copolymer; Humans; Male; Materials Testing; Mice; Mice, Inbred BALB C; Molecular Structure; Osteosarcoma; Osteosarcoma - drug therapy; Polymer therapeutics; Polymers - chemistry; Sesquiterpenes - chemistry; Sesquiterpenes - therapeutic use; Tissue Distribution; TNP-470
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2011.02.059

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.