期刊
ACS APPLIED MATERIALS & INTERFACES
卷 13, 期 46, 页码 54739-54752出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.1c16383
关键词
prostate-specific membrane antigen (PSMA); boron neutron capture therapy (BNCT); nanoparticles; amphiphilic block copolymer; positron emission tomography (PET) imaging
资金
- New Directions in Prostate Cancer Research Award from the University of California
- San Francisco Prostate Cancer Research Program
- American Cancer Society Individual Research Grant [IRG-97-150-13]
- Helen Diller Family Comprehensive Cancer Center Support Grant of the National Institutes of Health [P30 CA 82103]
- Prostate Cancer Foundation
- Fukushima SiC Applied Engineering
- Department of Radiology & Biomedical Imaging, University of California San Francisco
PSMA-targeted poly(lactide-co-glycolide)-block-poly(ethylene glycol) nanoparticles loaded with carborane show strong PSMA binding capability and potential for prostate cancer treatment in vivo.
Boron neutron capture therapy (BNCT) is an encouraging therapeutic modality for cancer treatment. Prostatespecific 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 PSMAtargeted 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 Zr-89 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. [Zr-89]DFB(25) NPs and [Zr-89]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.
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