Pharmacokinetic and safety assessment of carboplatin‐impregnated calcium sulfate hemihydrate beads in eight rats

Abstract

Objective: Evaluate local tissue toxicity and plasma platinum (Pt) in vivo after subcutaneous implantation of carboplatin-impregnated calcium sulfate hemihydrate (CI-CSH) beads. Study design:In vivo experimental study. Animals: Eight male Sprague-Dawley rats.Methods: CI-CSH beads were implanted subcutaneously (5 mg carboplatin/ rat; 13.5 mg/kg carboplatin; 7.08 mg/kg Pt; 1.18 mg/m 2 Pt) in eight rats (d0). Wound healing (daily), radiographic bead dissolution (weekly), systemic Pt uptake (plasma-Pt), local tissue Pt (d28), and histologic changes compared to nonincised and incised catheterization sites (d28) were assessed. Blood and tissue samples were analyzed by inductively coupled plasma mass spectrometry for Pt, and pharmacokinetic analysis was performed using noncompartmental methods.Results: One rat died at d10, the remainder survived until d28. No wound complications were seen. The CI-CSH implantation site had higher histopathology scores than the other sites for necrosis (p = .013) and fibrosis (p = .013). Beads decreased in density radiographically (d0 to d28) (p = .062).Peak plasma-Pt concentration was 225.78 ng/ml at 12 h, and decreased over time, but Pt was still detectable on d28. The elimination half-life was 5.03 ± 1.13 days. Only 1.69% of implanted Pt remained in the beads at d28.Conclusions: CI-CSH beads incited microscopic mild inflammation but wound healing was not impaired. Pt was absorbed systemically and the release from the beads was near complete at d28.The results of this study were presented at the 2020 ECVS Small Animal Residents' forum (2 July 2020; virtual) and 2020 ACVS Small Animal Residents' forum (22 October 2020; virtual).

In vitroefficacy andin vivotoxicity and retention of targeted nanoformulated carboplatin in a sustained release carrier for treatment of osteosarcoma

“…The overall lack of local tissue and wound complications was in line with prior studies where carboplatin was administered subcutaneously with a different SRC, either in poloxamer Risselada 2017a or in CaSO 4 beads. Belda 2021 However, due to differences in species (rats Risselada 2017a, Belda 2021 vs mice) and methodology (local Pt only measured at d7 Risselada 2017a, d28 Belda 2021 vs multiple time points up to d7), no direct comparison of the SRC’s ability to local retain carboplatin could be made.…”

“…Localized cancer therapy has attracted considerable attention due to the ability to deliver higher local drug load, regardless of vascular status, and reduce systemic toxicity, with various delivery systems used (such as hydrogels, Risselada-2017a, Risselada2016,Risselada 2020 polymers Vishwarao2016 and calcium sulfate hemihydrate Tulipan2016, Tulipan2017,Maxwell2020,Phillips2018,Risselada2015,Worth2020, Belda2021 ). In addition, local drug delivery systems have been used to visualize and/or treat metastasis in a theranostic approach.…”