Synthesis and Preliminary Biological Assessment of Carborane-Loaded Theranostic Nanoparticles to Target Prostate-Specific Membrane Antigen

• Published in: ACS applied materials & interfaces Vol. 13; no. 46; pp. 54739 - 54752
• Main Authors: Meher, Niranjan, Seo, Kyounghee, Wang, Sinan, Bidkar, Anil P, Fogarty, Miko, Dhrona, Suchi, Huang, Xiao, Tang, Ryan, Blaha, Charles, Evans, Michael J, Raleigh, David R, Jun, Young-Wook, VanBrocklin, Henry F, Desai, Tejal A, Wilson, David M, Ozawa, Tomoko, Flavell, Robert R
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24.11.2021
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and Medical Applications of Materials and Interfaces; Boron Compounds - chemical synthesis; Boron Compounds - chemistry; Boron Compounds - pharmacology; Boron Neutron Capture Therapy; Deferoxamine - chemistry; Deferoxamine - pharmacology; Humans; Male; Mice; Mice, Nude; Molecular Structure; Nanoparticles - chemistry; PC-3 Cells; Polyethylene Glycols - chemistry; Polyglactin 910 - chemistry; Positron-Emission Tomography; Prostate-Specific Antigen - antagonists & inhibitors; Prostate-Specific Antigen - metabolism; Prostatic Neoplasms - diagnostic imaging; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Theranostic Nanomedicine; Tumor Cells, Cultured; nanoparticles; amphiphilic block copolymer; positron emission tomography (PET) imaging; prostate-specific membrane antigen (PSMA); boron neutron capture therapy (BNCT)
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.1c16383

Boron neutron capture therapy (BNCT) is an encouraging therapeutic modality for cancer treatment. Prostate-specific membrane antigen (PSMA) is a cell membrane protein that is abundantly overexpressed in prostate cancer and can be targeted with radioligand therapies to stimulate clinical responses in patients. In principle, a spatially targeted neutron beam together with specifically targeted PSMA ligands could enable prostate cancer-targeted BNCT. Thus, we developed and tested PSMA-targeted poly­(lactide-co-glycolide)-block-poly­(ethylene glycol) (PLGA-b-PEG) nanoparticles (NPs) loaded with carborane and tethered to the radiometal chelator deferoxamine B (DFB) for simultaneous positron emission tomography (PET) imaging and selective delivery of boron to prostate cancer. Monomeric PLGA-b-PEGs were covalently functionalized with either DFB or the PSMA ligand ACUPA. Different nanoparticle formulations were generated by nanoemulsification of the corresponding unmodified and DFB- or ACUPA-modified monomers in varying percent fractions. The nanoparticles were efficiently labeled with 89Zr and were subjected to in vitro and in vivo evaluation. The optimized DFB(25)­ACUPA(75) NPs exhibited strong in vitro binding to PSMA in direct binding and competition radioligand binding assays in PSMA­(+) PC3-Pip cells. [89Zr]­DFB­(25) NPs and [89Zr]­DFB­(25)­ACUPA­(75) NPs were injected to mice with bilateral PSMA(−) PC3-Flu and PSMA­(+) PC3-Pip dual xenografts. The NPs demonstrated twofold superior accumulation in PC3-Pip tumors to that of PC3-Flu tumors with a tumor/blood ratio of 25; however, no substantial effect of the ACUPA ligands was detected. Moreover, fast release of carborane from the NPs was observed, resulting in a low boron delivery to tumors in vivo. In summary, these data demonstrate the synthesis, characterization, and initial biological assessment of PSMA-targeted, carborane-loaded PLGA-b-PEG nanoparticles and establish the foundation for future efforts to enable their best use in vivo.