Evaluation of nanoparticle delivered cisplatin in beagles

Abstract

Intracranial neoplasia is a significant cause of morbidity and mortality in both human and veterinary patients, and is difficult to treat with traditional therapeutic methods. Cisplatin is a platinum (Pt)-containing chemotherapeutic agent approved by the Food and Drug Administration; however, substantial limitations exist for its application in canine brain tumor treatment due to the difficulty in crossing the blood-brain barrier (BBB), development of resistance, and toxicity. A modified Pt(iv)-prodrug of cisplatin, Platin-M, was recently shown to be deliverable to the brain via a biocompatible mitochondria-targeted lipophilic polymeric nanoparticle (NP) that carries the drug across the BBB and to the mitochondria. NP mediated controlled release of Platin-M and subsequent reduction of this prodrug to cisplatin allowed cross-links to be formed with the mitochondrial DNA, which have no nucleotide excision repair system, forcing the overactive cancer cells to undergo apoptosis. Here, we report in vitro effects of targeted Platin-M NPs (T-Platin-M-NPs) in canine glioma and glioblastoma cell lines with results indicating that this targeted NP formulation is more effective than cisplatin. In both the cell lines, T-Platin-M-NP was significantly more efficacious compared to carboplatin, another Pt-based chemotherapy, which is used in the settings of recurrent high-grade glioblastoma. Mitochondrial stress analysis indicated that T-Platin-M-NP is more effective in disrupting the mitochondrial bioenergetics in both the cell types. A 14-day distribution study in healthy adult beagles using a single intravenous injection at 0.5 mg kg(-1) (with respect to Platin-M) of T-Platin-M-NPs showed high levels of Pt accumulation in the brain, with negligible amounts in the other analyzed organs. Safety studies in the beagles monitoring physical, hematological, and serum chemistry evaluations were within the normal limits on days 1, 7, and 14 after injection of either 0.5 mg kg(-1) or 2 mg kg(-1) or 2.2 mg kg(-1) (with respect to Platin-M) of T-Platin-M-NPs. At all doses over the 14-day period, no neurotoxicity was observed based upon periodic neurological examinations and cerebrospinal fluid analysis. These studies demonstrated the translational nature of T-Platin-M-NPs for applications in the treatment of brain tumors.

Nanotechnology inspired tools for mitochondrial dysfunction related diseases

“…Thus, a precise strategy for mitochondria targeting of cisplatin for chemoresistance cancers using a unique dual-targeting approach is an alternative route for cisplatin-based therapy (42). Recently, this technology was studied in a large animal model by demonstrating the safety and toxicity of mitochondria-targeted NPs loaded with Platin-M (91). This study also highlights the ability to manufacture the mitochondria targeted NPs in large scale.…”

A Prodrug of Two Approved Drugs, Cisplatin and Chlorambucil, for Chemo War Against Cancer

“…We previously reported several Pt(IV) prodrugs with ability to release Food and Drug Administration approved drug cisplatin and an additional therapeutic modality such as aspirin or GSH modulator (9,10). Our recent work also demonstrated advantages of delivering Pt(IV) prodrugs to the mitochondria for local release of cisplatin with improved in vitro and in vivo properties compared with cisplatin or non-targeted counterparts (11,12). Although the extent of glutathione (GSH) compartmentalization in the mitochondria is relatively less compared with its cytosolic concentration of 10 to 15 mmol/L; considering mitochondrial volume, mitochondrial GSH (mGSH) concentration attains approximately 10 to 14 mmol/L (13,14).…”

Repurposing platinum-based chemotherapies for multi-modal treatment of glioblastoma

“…65 Furthermore, a mitochondrial-targeted NP loaded with the cisplatin prodrug, Platin-M, successfully delivered the drug to neuroblastoma cells 66 and has shown very little neurotoxicity in animal models despite a high level of drug accumulation in the brain. 67 Another intriguing glioma cell-specific target is the cell surface receptor fibroblast growth factor-inducible 14 (Fn14). NPs targeted to Fn14-positive GBM cells using a monoclonal antibody improved NP tumor localization and internalization.…”