Multimodal, PSMA-Targeted, PAMAM Dendrimer-Drug Conjugates for Treatment of Prostate Cancer: Preclinical Evaluation.

Introduction: Prostate cancer (PC) is the second most common cancer and the fifth most frequent cause of cancer death among men. Prostate-specific membrane antigen (PSMA) expression is associated with aggressive PC, with expression in over 90% of patients with metastatic disease. Those characteristics have led to its use for PC diagnosis and therapies with radiopharmaceuticals, antibody-drug conjugates, and nanoparticles.

Preclinical Evaluation of a New Series of Albumin-Binding Lu-Labeled PSMA-Based Low-Molecular-Weight Radiotherapeutics.

Prostate-specific membrane antigen (PSMA)-based low-molecular-weight agents using beta(β)-particle-emitting radiopharmaceuticals is a new treatment paradigm for patients with metastatic castration-resistant prostate cancer. Although results have been encouraging, there is a need to improve the tumor residence time of current PSMA-based radiotherapeutics. Albumin-binding moieties have been used strategically to enhance the tumor uptake and retention of existing PSMA-based investigational agents.

Hetero-bivalent agents targeting FAP and PSMA.

Purpose: We developed a theranostic radiopharmaceutical that engages two key cell surface proteases, fibroblast activation protein alpha (FAP) and prostate-specific membrane antigen (PSMA), each frequently overexpressed within the tumor microenvironment (TME). The latter is also expressed in most prostate tumor epithelium. To engage a broader spectrum of cancers for imaging and therapy, we conjugated small-molecule FAP and PSMA-targeting moieties using an optimized linker to provide Cu-labeled compounds.

Dual contrast agents for fluorescence and photoacoustic imaging: evaluation in a murine model of prostate cancer.

Prostate-specific membrane antigen (PSMA) is a promising diagnostic and therapeutic target for prostate cancer (PC). Poly(amidoamine) [PAMAM] dendrimers serve as versatile scaffolds for imaging agents and drug delivery that can be tailored to different sizes and compositions depending upon the application. We have developed PSMA-targeted PAMAM dendrimers for real-time detection of PC using fluorescence (FL) and photoacoustic (PA) imaging.

A prostate-specific membrane antigen (PSMA)-targeted prodrug with a favorable in vivo toxicity profile.

Prostate-specific membrane antigen (PSMA) is a promising target for the treatment of advanced prostate cancer (PC) and various solid tumors. Although PSMA-targeted radiopharmaceutical therapy (RPT) has enabled significant imaging and prostate-specific antigen (PSA) responses, accumulating clinical data are beginning to reveal certain limitations, including a subgroup of non-responders, relapse, radiation-induced toxicity, and the need for specialized facilities for its administration. To date non-radioactive attempts to leverage PSMA to treat PC with antibodies, nanomedicines or cell-based therapies have met with modest success.

Prostate-specific membrane antigen (PSMA)-targeted photodynamic therapy enhances the delivery of PSMA-targeted magnetic nanoparticles to PSMA-expressing prostate tumors.

Enhanced vascular permeability in tumors plays an essential role in nanoparticle delivery. Prostate-specific membrane antigen (PSMA) is overexpressed on the epithelium of aggressive prostate cancers (PCs). Here, we evaluated the feasibility of increasing the delivery of PSMA-targeted magnetic nanoparticles (MNPs) to tumors by enhancing vascular permeability in PSMA(+) PC tumors with PSMA-targeted photodynamic therapy (PDT).

Preclinical Evaluation of Bi- and Ac-Labeled Low-Molecular-Weight Compounds for Radiopharmaceutical Therapy of Prostate Cancer.

Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical therapy is a new option for patients with advanced prostate cancer refractory to other treatments. Previously, we synthesized a β-particle-emitting low-molecular-weight compound, Lu-L1 which demonstrated reduced off-target effects in a xenograft model of prostate cancer. Here, we leveraged that scaffold to synthesize α-particle-emitting analogs of L1, Bi-L1 and Ac-L1, to evaluate their safety and cell kill effect in PSMA-positive (+) xenograft models.

Lu-labeled low-molecular-weight agents for PSMA-targeted radiopharmaceutical therapy.

Purpose: To develop a prostate-specific membrane antigen (PSMA)-targeted radiotherapeutic for metastatic castration-resistant prostate cancer (mCRPC) with optimized efficacy and minimized toxicity employing the β-particle radiation of Lu.

Methods: We synthesized 14 new PSMA-targeted, Lu-labeled radioligands (Lu-L1-Lu-L14) using different chelating agents and linkers. We evaluated them in vitro using human prostate cancer PSMA(+) PC3 PIP and PSMA(-) PC3 flu cells and in corresponding flank tumor models.

Evaluation of PSMA-Targeted PAMAM Dendrimer Nanoparticles in a Murine Model of Prostate Cancer.

The prostate-specific membrane antigen (PSMA) is a validated target for detection and management of prostate cancer (PC). It has also been utilized for targeted drug delivery through antibody-drug conjugates and polymeric micelles. Polyamidoamine (PAMAM) dendrimers are emerging as a versatile platform in a number of biomedical applications due to their unique physicochemical properties, including small size, large number of reactive terminal groups, bulky interior void volume, and biocompatibility.

MRI Assessment of Prostate-Specific Membrane Antigen (PSMA) Targeting by a PSMA-Targeted Magnetic Nanoparticle: Potential for Image-Guided Therapy.

Magnetic nanoparticle (MNP)-induced hyperthermia is currently being evaluated for localized prostate cancer. We evaluated the feasibility of tumor-selective delivery of prostate-specific membrane antigen (PSMA)-targeted MNPs in a murine model with high-resolution magnetic resonance imaging (MRI) after intravenous administration of MNPs at a concentration necessary for hyperthermia. A PSMA-targeted MNP was synthesized and evaluated using T-weighted MRI, after intravenous administration of 50 mg/kg of the MNP.

Elaboration of Sterically Hindered δ-Lactones through Ring-Closing Metathesis: Application to the Synthesis of the C1-C27 Fragment of Hemicalide.

The synthesis of the C1-C27 fragment of hemicalide, a marine metabolite displaying a unique potent antiproliferative activity, has been accomplished. The synthetic approach highlights a remarkably efficient ring-closing metathesis reaction catalyzed by Nolan ruthenium indenylidene complexes to elaborate the highly substituted δ-lactone framework.

Caged glutamates with π-extended 1,2-dihydronaphthalene chromophore: design, synthesis, two-photon absorption property, and photochemical reactivity.

Caging and photochemical uncaging of the excitatory neurotransmitter l-glutamate (glu) offers a potentially valuable tool for understanding the mechanisms of neuronal processes. Designing water-soluble caged glutamates with the appropriate two-photon absorption property is an attractive strategy to achieve this. This paper describes the design, synthesis, and photochemical reactivity of caged glutamates with π-extended 1,2-dihydronaphthalene structures, which possess a two-photon cross-section of ∼120 GM and an excellent buffer solubility (up to 115 mM).

Substituent effect on reactivity of triplet excited state of 2,3-diazabicyclo[2.2.1]hept-2-enes, DBH derivatives: α C-N bond cleavage versus β C-C bond cleavage.

The photoreaction of a series of 2,3-diazabicyclo[2.2.1]hept-2-ene (DBH) derivatives, in which various substituents (X) were introduced at the methano bridge carbon of C(7), was investigated under direct (>290 nm) and triplet-sensitized (Ph2CO, >370 nm) irradiation conditions of the azo chromophore (−Cβ–Cα–N═N–Cα–Cβ−).

Phosphine-mediated cascade reaction of azides with MBH-acetates of acetylenic aldehydes to substituted pyrroles: a facile access to N-fused pyrrolo-heterocycles.

One-pot synthesis of substituted pyrroles by a cascade reaction of azides with Morita-Baylis-Hillman acetates of acetylenic aldehydes is described and the reaction is efficiently mediated by triphenyl phosphine at room temperature. Sodium azide is successfully used to provide N-unsubstituted pyrroles, while alkyl azides afforded the corresponding N-alkylated pyrroles through a sequence of allylic substitution/azide reduction/cycloisomerization reactions. The obtained products have provided a new entry to indolizino indoles, pyrrolo isoquinolines and 8-oxo-5,6,7,8-tetrahydroindolizine.

Morita-Baylis-Hillman acetates of acetylenic aldehydes: versatile synthons for substituted pyrroles via a metal-free tandem reaction.

A mild and metal-free access to 1,2,4-tri or 1,2,4,5-tetrasubstituted pyrroles has been developed by the reaction of Morita-Baylis-Hillman acetates of acetylenic aldehydes with amines and sulfonamides. This new protocol is based on K(2)CO(3)-promoted tandem allylic substitution/cycloisomerization reactions.