Polymeric nanoparticles for dual-targeted theranostic gene delivery to hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) develops predominantly in the inflammatory environment of a cirrhotic liver caused by hepatitis, toxin exposure, or chronic liver disease. A targeted therapeutic approach is required to enable cancer killing without causing toxicity and liver failure. Poly(beta-amino-ester) (PBAE) nanoparticles (NPs) were used to deliver a completely CpG-free plasmid harboring mutant herpes simplex virus type 1 sr39 thymidine kinase (sr39) DNA to human HCC cells.

A Series of PSMA-Targeted Near-Infrared Fluorescent Imaging Agents.

We have synthesized a series of 10 new, PSMA-targeted, near-infrared imaging agents intended for use in vivo for fluorescence-guided surgery (FGS). Compounds were synthesized from the commercially available amine-reactive active NHS ester of DyLight800. We altered the linker between the PSMA-targeting urea moiety and the fluorophore with a view to improve the pharmacokinetics.

Dual-Modality PET-SPECT Image-Guided Pretargeting Delivery in HER2(+) Breast Cancer Models.

Pretargeted drug delivery has been explored for decades as a promising approach in cancer therapy. An image-guided pretargeting strategy significantly enhances the intrinsic advantages of this approach since imaging the pretargeting step can be used for diagnostic purposes, while imaging of the drug delivery step can be utilized to evaluate drug distribution and assess therapeutic response. A trastuzumab (Tz)-based HER2 pretargeting component (Tz-TCO-[Zr-DFO]) was developed by conjugating with -cyclooctene (TCO) bioorthogonal click chemistry functional groups and deferoxamine (DFO) to enable radiolabeling with a Zr PET tracer.

Pharmacodynamic measures within tumors expose differential activity of PD(L)-1 antibody therapeutics.

Macromolecules such as monoclonal antibodies (mAbs) are likely to experience poor tumor penetration because of their large size, and thus low drug exposure of target cells within a tumor could contribute to suboptimal responses. Given the challenge of inadequate quantitative tools to assess mAb activity within tumors, we hypothesized that measurement of accessible target levels in tumors could elucidate the pharmacologic activity of a mAb and could be used to compare the activity of different mAbs. Using positron emission tomography (PET), we measured the pharmacodynamics of immune checkpoint protein programmed-death ligand 1 (PD-L1) to evaluate pharmacologic effects of mAbs targeting PD-L1 and its receptor programmed cell death protein 1 (PD-1).

An Improved At-Labeled Agent for PSMA-Targeted α-Therapy.

α-Particle emitters targeting the prostate-specific membrane antigen (PSMA) proved effective in treating patients with prostate cancer who were unresponsive to the corresponding β-particle therapy. At is an α-emitter that may engender less toxicity than other α-emitting agents. We synthesized a new At-labeled radiotracer targeting PSMA that resulted from the search for a pharmacokinetically optimized agent.

Imaging of Fibroblast Activation Protein in Cancer Xenografts Using Novel (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine-Based Small Molecules.

Fibroblast activation protein (FAP) has become a favored target for imaging and therapy of malignancy. We have synthesized and characterized two new (4-quinolinoyl)-glycyl-2-cyanopyrrolidine-based small molecules for imaging of FAP, and [In], using optical and single-photon computed tomography/CT, respectively. Binding of imaging agents to FAP was assessed in six human cancer cell lines of different cancer types: glioblastoma (U87), melanoma (SKMEL24), prostate (PC3), NSCLC (NCIH2228), colorectal carcinoma (HCT116), and lung squamous cell carcinoma (NCIH226).

Synthesis and preliminary evaluation of At-labeled inhibitors of prostate-specific membrane antigen for targeted alpha particle therapy of prostate cancer.

Introduction: The high potency and short tissue range of α-particles are attractive features for targeted radionuclide therapy, particularly for cancers with micro-metastases. In the current study, we describe the synthesis of a series of At-labeled prostate-specific membrane antigen (PSMA) inhibitors and their preliminary evaluation as potential agents for metastatic prostate cancer treatment.

Methods: Four novel Glu-urea based PSMA ligands containing a trialkyl stannyl group were synthesized and labeled with At, and for comparative purposes, I, via halodestannylation reactions with N-chlorosuccinimide as the oxidant.

Process validation, current good manufacturing practice production, dosimetry, and toxicity studies of the carbonic anhydrase IX imaging agent [ In]In-XYIMSR-01 for phase I regulatory approval.

[ In]In-XYIMSR-01 is a promising single-photon emission computed tomography (SPECT) imaging agent for identification of tumors that overexpress carbonic anhydrase IX. To translate [ In]In-XYIMSR-01 to phase I trials, we performed animal toxicity and dosimetry studies, determined the maximum dose for human use, and completed the chemistry, manufacturing, and controls component of a standard regulatory application. The production process, quality control testing, stability studies, and specifications for sterile drug product release were based on United States Pharmacopeia chapters <823> and <825>, FDA 21 CFR Part 212.

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.

Prospective Evaluation of F-DCFPyL PET/CT in Detection of High-Risk Localized Prostate Cancer: Comparison With mpMRI.

The purpose of this study was to assess the utility of PET with (2)-2-[[(1)-1-carboxy-5-[(6-(F)fluoranylpyridine-3-carbonyl)amino]pentyl]carbamoylamino]pentanedioic acid (F-DCFPyL), a prostate-specific membrane antigen (PSMA)-targeted radiotracer, in the detection of high-risk localized prostate cancer as compared with multiparametric MRI (mpMRI). This HIPAA-compliant prospective study included 26 consecutive patients with localized high-risk prostate cancer (median age, 69.5 years [range, 53-81 years]; median prostate-specific antigen [PSA] level, 18.

In Vitro and In Vivo Characterization of Dibenzothiophene Derivatives [I]Iodo-ASEM and [F]ASEM as Radiotracers of Homo- and Heteromeric α7 Nicotinic Acetylcholine Receptors.

The α7 nicotinic acetylcholine receptor (α7 nAChR) is involved in several cognitive and physiologic processes; its expression levels and patterns change in neurologic and psychiatric diseases, such as schizophrenia and Alzheimer's disease, which makes it a relevant drug target. Development of selective radioligands is important for defining binding properties and occupancy of novel molecules targeting the receptor. We tested the in vitro binding properties of [I]Iodo-ASEM [(3-(1,4-diazabycyclo[3.

Auger radiopharmaceutical therapy targeting prostate-specific membrane antigen in a micrometastatic model of prostate cancer.

Auger radiopharmaceutical therapy is a promising strategy for micrometastatic disease given high linear energy transfer and short range in tissues, potentially limiting normal tissue toxicities. We previously demonstrated anti-tumor efficacy of a small-molecule Auger electron emitter targeting the prostate-specific membrane antigen (PSMA), 2-[3-[1-carboxy-5-(4-[I]iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid), or I-DCIBzL, in a mouse xenograft model. Here, we investigated the therapeutic efficacy, long-term toxicity, and biodistribution of I-DCIBzL in a micrometastatic model of prostate cancer (PC).

Radiosynthesis and PET Bioimaging of Br-Bedaquiline in a Murine Model of Tuberculosis.

Bedaquiline is a promising drug against tuberculosis (TB), but limited data are available on its intralesional pharmacokinetics. Moreover, current techniques rely on invasive tissue resection, which is difficult in humans and generally limited even in animals. In this study, we developed a novel radiosynthesis for Br-bedaquiline and performed noninvasive, longitudinal whole-body positron emission tomography (PET) in live, -infected mice over 48 h.

Preclinical Evaluation of Pb-Labeled Low-Molecular-Weight Compounds for Targeted Radiopharmaceutical Therapy of Prostate Cancer.

Targeted radiopharmaceutical therapy (TRT) using α-particle radiation is a promising approach for treating both large and micrometastatic lesions. We developed prostate-specific membrane antigen (PSMA)-targeted low-molecular-weight agents for Pb-based TRT of patients with prostate cancer (PC) by evaluating the matching γ-emitting surrogate, Pb. Five rationally designed low-molecular-weight ligands (L1-L5) were synthesized using the lysine-urea-glutamate scaffold, and PSMA inhibition constants were determined.

Iodination of terminal alkynes using KI/CuSO - A facile method with potential for radio-iodination.

Herein, we report an efficient new method for the iodination of terminal alkynes using stoichiometric KI and CuSO in a mix of acetonitrile and acetate buffer that holds promise for further development into a method for radio-iodination.

Development of [F]FPy-WL12 as a PD-L1 Specific PET Imaging Peptide.

Expression of programmed cell death ligand 1 (PD-L1) within tumors is an important biomarker for guiding immune checkpoint therapies; however, immunohistochemistry-based methods of detection fail to provide a comprehensive picture of PD-L1 levels in an entire patient. To facilitate quantification of PD-L1 in the whole body, we developed a peptide-based, high-affinity PD-L1 imaging agent labeled with [F]fluoride for positron emission tomography (PET) imaging. The parent peptide, WL12, and the nonradioactive analog of the radiotracer, FPy-WL12, inhibit PD-1/PD-L1 interaction at low nanomolar concentrations (half maximal inhibitory concentration [IC], 26-32 nM).

A comparison of prostate cancer bone metastases on F-Sodium Fluoride and Prostate Specific Membrane Antigen (F-PSMA) PET/CT: Discordant uptake in the same lesion.

Purpose: Prostate-Specific Membrane Antigen (PSMA) PET/CT has been introduced as a sensitive method for characterizing metastatic prostate cancer. The purpose of this study is to compare the spatial concordance of F-NaF PET/CT and F-PSMA-targeted PET/CT within prostate cancer bone metastases.

Methods: Prostate cancer patients with known bone metastases underwent PSMA-targeted PET/CT (F-DCFBC or F-DCFPyL) and F-NaF PET/CT.

Positron Emission Tomography Imaging with 2-[F]F- p-Aminobenzoic Acid Detects Staphylococcus aureus Infections and Monitors Drug Response.

Staphylococcus aureus is the leading cause of life-threatening infections, frequently originating from unknown or deep-seated foci. Source control and institution of appropriate antibiotics remain challenges, especially with infections due to methicillin-resistant S. aureus (MRSA).

Peptide-Based Ga-PET Radiotracer for Imaging PD-L1 Expression in Cancer.

Tumors create and maintain an immunosuppressive microenvironment that promotes cancer cell escape from immune surveillance. The immune checkpoint protein programmed death-ligand 1 (PD-L1) is expressed in many cancers and is an important contributor to the maintenance of the immunosuppressive tumor microenvironment. PD-L1 is a prominent target for cancer immunotherapy.

Radioligand Therapy of Prostate Cancer with a Long-Lasting Prostate-Specific Membrane Antigen Targeting Agent Y-DOTA-EB-MCG.

Several radioligands targeting prostate-specific membrane antigen (PSMA) have been clinically introduced as a new class of radiotheranostics for the treatment of prostate cancer. Among them, ((( R)-1-carboxy-2-mcercaptoethyl)carbamoyl)-l-glutamic acid (MCG) has been successfully labeled with radioisotopes for prostate cancer imaging. The aim of this study is to conjugate MCG with an albumin binding moiety to further improve the in vivo pharmacokinetics.

A Prospective Comparison of F-Sodium Fluoride PET/CT and PSMA-Targeted F-DCFBC PET/CT in Metastatic Prostate Cancer.

The purpose of this study was to compare the diagnostic performance of F-DCFBC PET/CT, a first-generation F-labeled prostate-specific membrane antigen (PSMA)-targeted agent, and F-NaF PET/CT, a sensitive marker of osteoblastic activity, in a prospective cohort of patients with metastatic prostate cancer. Twenty-eight prostate cancer patients with metastatic disease on conventional imaging prospectively received up to 4 PET/CT scans. All patients completed baseline F-DCFBC PET/CT and F-NaF PET/CT scans, and 23 patients completed follow-up imaging, with a median follow-up interval of 5.

Low-Level Endogenous PSMA Expression in Nonprostatic Tumor Xenografts Is Sufficient for In Vivo Tumor Targeting and Imaging.

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and within the neovasculature of other solid tumors. The nonprostatic expression of PSMA has been reported exclusively within the neovasculature endothelial cells of nonprostatic cancers; however, there are few reports on PSMA expression in epithelial cells. Herein, we describe PSMA expression in nonprostatic epithelial cells and characterize the potential of PSMA-binding agents to noninvasively detect that expression.

Clinical impact of PSMA-based F-DCFBC PET/CT imaging in patients with biochemically recurrent prostate cancer after primary local therapy.

Purpose: The purpose of our study was to assess F-DCFBC PET/CT, a PSMA targeted PET agent, for lesion detection and clinical management of biochemical relapse in prostate cancer patients after primary treatment.

Methods: This is a prospective IRB-approved study of 68 patients with documented biochemical recurrence after primary local therapy consisting of radical prostatectomy (n = 50), post radiation therapy (n = 9) or both (n = 9), with negative conventional imaging. All 68 patients underwent whole-body F-DCFBC PET/CT, and 62 also underwent mpMRI within one month.

18F-DCFBC Prostate-Specific Membrane Antigen-Targeted PET/CT Imaging in Localized Prostate Cancer: Correlation With Multiparametric MRI and Histopathology.

Purpose: To assess the ability of (N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-F-fluorobenzyl-L-cysteine) (F-DCFBC), a prostate-specific membrane antigen-targeted PET agent, to detect localized prostate cancer lesions in correlation with multiparametric MRI (mpMRI) and histopathology.

Methods: This Health Insurance Portability and Accountability Act of 1996-compliant, prospective, institutional review board-approved study included 13 evaluable patients with localized prostate cancer (median age, 62.8 years [range, 51-74 years]; median prostate-specific antigen, 37.

Imaging Macrophage Accumulation in a Murine Model of Chronic Pancreatitis with I-Iodo-DPA-713 SPECT/CT.

Pancreatitis remains a diagnostic challenge in patients with mild to moderate disease, with current imaging modalities being inadequate. Given the prominent macrophage infiltration in chronic pancreatitis, we hypothesized that I-iodo-DPA-713, a small-molecule radiotracer that specifically targets macrophages, could be used with SPECT/CT to image pancreatic inflammation in a relevant experimental model. Chronic pancreatitis was induced with cerulein in C57BL/6 mice, which were contrasted with saline-injected control mice.