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