ABSTRACT
Boron neutron capture therapy (BNCT) is a therapeutic modality which has been used for the treatment of cancers, including brain and head and neck tumors. For effective treatment via BNCT, efficient and selective delivery of a high boron dose to cancer cells is needed. Prostate-specific membrane antigen (PSMA) is a target for prostate cancer imaging and drug delivery. In this study, we conjugated boronic acid or carborane functional groups to a well-established PSMA inhibitor scaffold to deliver boron to prostate cancer cells and prostate tumor xenograft models. Eight boron-containing PSMA inhibitors were synthesized. All of these compounds showed a strong binding affinity to PSMA in a competition radioligand binding assay (IC50 from 555.7 to 20.3 nM). Three selected compounds 1a, 1d, and 1f were administered to mice, and their in vivo blocking of 68Ga-PSMA-11 uptake was demonstrated through a positron emission tomography (PET) imaging and biodistribution experiment. Biodistribution analysis demonstrated boron uptake of 4-7 µg/g in 22Rv1 prostate xenograft tumors and similar tumor/muscle ratios compared to the ratio for the most commonly used BNCT compound, 4-borono-l-phenylalanine (BPA). Taken together, these data suggest a potential role for PSMA targeted BNCT agents in prostate cancer therapy following suitable optimization.
Subject(s)
Antigens, Surface/metabolism , Boron Neutron Capture Therapy/methods , Boronic Acids/chemistry , Boronic Acids/pharmacokinetics , Drug Delivery Systems/methods , Glutamate Carboxypeptidase II/antagonists & inhibitors , Glutamate Carboxypeptidase II/metabolism , Prostatic Neoplasms/radiotherapy , Animals , Boron Compounds/chemistry , Boron Compounds/pharmacokinetics , Cell Line, Tumor , Cell Survival/drug effects , Edetic Acid/analogs & derivatives , Edetic Acid/pharmacokinetics , Gallium Isotopes , Gallium Radioisotopes , Humans , Inhibitory Concentration 50 , Ligands , Male , Mice , Mice, Nude , Oligopeptides/pharmacokinetics , Phenylalanine/analogs & derivatives , Phenylalanine/chemistry , Phenylalanine/pharmacokinetics , Positron Emission Tomography Computed Tomography , Prostatic Neoplasms/pathology , Radiation-Sensitizing Agents/chemistry , Radiation-Sensitizing Agents/pharmacokinetics , Tissue Distribution , Xenograft Model Antitumor AssaysABSTRACT
Lipid and micelle-based nanocarriers have been explored for anticancer drug delivery to improve accumulation and uptake in tumor tissue. As an experimental opportunity in this area, our lab has developed a protein-based micelle nanocarrier consisting of a hydrophilic intrinsically disordered protein (IDP) domain bound to a hydrophobic tail, termed IDP-2Yx2A. This construct can be used to encapsulate hydrophobic chemotherapeutics that would otherwise be too insoluble in water to be administered. In this study, we evaluate the in vivo efficacy of IDP-2Yx2A by delivering a highly potent but water-insoluble cancer drug, SN38, into glioblastoma multiforme (GBM) tumors via convection-enhanced delivery (CED). The protein carriers alone are shown to elicit minimal toxicity effects in mice; furthermore, they can encapsulate and deliver concentrations of SN38 that would otherwise be lethal without the carriers. CED administration of these drug-loaded micelles into mice bearing U251-MG GBM xenografts resulted in slowed tumor growth and significant increases in median survival times compared to nonencapsulated SN38 and PBS controls.
Subject(s)
Brain Neoplasms , Glioblastoma , Intrinsically Disordered Proteins , Animals , Humans , Mice , Brain Neoplasms/drug therapy , Convection , Excipients , Glioblastoma/drug therapy , Micelles , WaterABSTRACT
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.