Albumin nanocomplex of BCL-2/xL inhibitor reduced platelet toxicity and improved anticancer efficacy in myeloproliferative neoplasm and lymphoma.

in Biomaterials by Hongxiang Hu, Chengyi Li, Yudong Song, Jizhao Xie, Qiuxia Li, Fang Ke, Bo Wen, Shaomeng Wang, Wei Gao, Duxin Sun

TLDR

  • The study develops a novel formulation, Nano-1252, to overcome the platelet toxicity of APG-1252 and improve its efficacy in cancer treatment.
  • Nano-1252 forms stable nanoparticles, reduces platelet toxicity, and shows enhanced anticancer efficacy in mouse models.
  • The study's findings have significant implications for the clinical application of BCL-2/xL inhibitors and the development of novel formulations to overcome their limitations.

Abstract

The clinical application of BCL-2/xL inhibitors for cancer treatment is limited by the on-target thrombocytopenia. Although APG-1252 was designed to mitigate this issue, platelet toxicity at higher doses in clinical trials restricts dose escalation for greater efficacy. We have developed albumin nanocomplexes of APG-1252 (Nano-1252) to reduce platelet toxicity while improving drug efficacy through enhancing drug delivery to lymphoid organs. Nano-1252 forms stable nanoparticles due to the strong binding affinity between APG-1252 and albumin, reducing the platelet toxicity threshold by fourfold by limiting premature drug release and conversion to its active forms in circulation. Furthermore, Nano-1252 exhibited preferential accumulation in lymphoid organs, leading to enhanced anticancer efficacy in Mantle Cell Lymphoma (MCL) and Myeloproliferative Neoplasms (MPNs) mouse models. Our study not only develops a potential formulation to overcome the current translational barrier of APG-1252 but also reveals novel properties of the well-established albumin nanoformulation, thereby expanding its clinical applications.

Overview

  • The study aims to develop a novel formulation of APG-1252, a BCL-2/xL inhibitor, to mitigate platelet toxicity and improve its efficacy in cancer treatment.
  • The authors design albumin nanocomplexes of APG-1252 (Nano-1252) to reduce platelet toxicity and enhance drug delivery to lymphoid organs.
  • The study investigates the properties and anticancer efficacy of Nano-1252 in mouse models of Mantle Cell Lymphoma (MCL) and Myeloproliferative Neoplasms (MPNs).

Comparative Analysis & Findings

  • Nano-1252 forms stable nanoparticles due to the strong binding affinity between APG-1252 and albumin, reducing the platelet toxicity threshold by fourfold.
  • Nano-1252 exhibited preferential accumulation in lymphoid organs, leading to enhanced anticancer efficacy in MCL and MPNs mouse models.
  • The study reveals that Nano-1252 shows improved efficacy in cancer treatment while mitigating platelet toxicity, overcoming the current translational barrier of APG-1252.

Implications and Future Directions

  • The study's findings have significant implications for the clinical application of BCL-2/xL inhibitors and the development of novel formulations to overcome their limitations.
  • Future studies should investigate the safety and efficacy of Nano-1252 in clinical trials and explore its potential use in other cancer indications.
  • The study's novel properties of albumin nanoformulation may expand its clinical applications beyond cancer treatment, warranting further investigation.
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