In vitro efficacy and in vivo toxicity and retention of targeted nanoformulated carboplatin in a sustained release carrier for treatment of osteosarcoma
Objectiveevaluate 1) if targeting of platinum magnetic nanoclusters will promote uptake in osteosarcoma cells in vitro, 2) targeting will improve uptake and delivery in murine OSA in vivo compared to free carboplatin, 3) incorporation into a sustained release carrier (SRC) will prolong local retention in vivo. MethodsComplex stability and peptide loading was assessed. Drug release was tested at pH 7.4 and 5.5 and cellular uptake and cytotoxity determined for canine, human and mouse osteosarcoma. Subcutaneous murine osteosarcoma was induced and optimal dose and time until tumor growth were established. Tumor bearing mice were equally distributed between 8 treatment (0.5mg carboplatin/mouse) and 1 control group and sacrificed at 8 predetermined time points between 1 hour and 8 days. Blood, tumor site and organs were harvested for tissue ferron and platinum content analysis (ICP-MS). ResultsCarboplatin was preferentially released at pH5.5. Targeting increased cellular uptake for carboplatin 15.2-fold, and decreased IC50 at 24h and 48h. At 2 weeks, a SC injection of 1-1.56 live cells/mouse reliably resulted in a palpable tumor. Plasma platinum peaked prior to 6 hours while plasma ferron peaked at 24-48 hours. Intratumoral delivery did not lead to a sustained local presence while local delivery in a SRC after surgery did. ConclusionsTargeting of MNC-carboplatin is possible with an increased osteosarcoma cell uptake in vitro. In vivo metastatic uptake could not be assessed due to lack of metastases, but local delivery in a SRC yielded high local, and low systemic platinum concentrations in mice.