Boron neutron capture therapy (BNCT) is a radiation therapeutic method for cancer therapy. In the BNCT, internalization of boron-10 (10B) atoms by cancer cells induces the cell death by the generation of alpha particles and recoiling lithium-7 (7Li) nuclei when irradiated with low-energy thermal neutrons. However, insufficient accumulation and cellular uptake efficacy of second-generation boron compounds such as thiododecaborate (BSH) in target tumors have been pointed out. In this presentation, we will introduce our developed BNCT technology using cell-penetrating peptides (CPPs) for enhanced cellular uptake of boron compounds and their controlled locations inside cells. When cell death is induced by organelle damage, the cell death efficacies and pathways are possibly affected by the damaged organelles (e.g. plasma membrane, mitochondria, or nucleus of cancer cells) by BNCT. In this research, we designed and synthesized organelle-targeted peptide-conjugated boron compounds to increase their cellular uptake and to control the intracellular locations for induction of sophisticated anticancer biological activity (including efficacies and mechanisms) under BNCT. For example, boron compounds conjugated with mitochondria target CPP, RLA (amino acid sequence: D[RLARLAR]2), showed significantly enhanced mitochondrial accumulation of the boron compounds, leading to effective cancer cell-killing activity in BNCT. In this presentation, we will also introduce another achievement about modification of hexadeca oligoarginine (R16) CPPs on the BSH-encapsulated extracellular vesicles (exosomes) to effectively induce macropinocytosis, enhanced cellular uptake of BSH, and significantly increased biological activity in BNCT.

Effective usage of functional cell-penetrating peptides for boron neutron capture therapy

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ACS Fall 2022

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