Lu-labeling of nuclear localization sequence (NLS)-grafted HER2-receptor affine peptide.

Tagging of cell permeable nuclear localization sequence (NLS) with receptor targeting peptide vectors is an attractive strategy for selectively targeted translocation of therapeutic cargoes. The present study aimed at grafting nuclear localization sequence (NLS) onto breast cancer targeting rL-A9 peptide. Molecular docking analysis revealed higher binding affinity of the peptide, DOTA-NLS-rL-A9 (-26.

Peptide-drug conjugate designated for targeted delivery to HER2-expressing cancer cells.

Targeted therapy of the highest globally incident breast cancer shall resolve the issue of off-target toxicity concurring with augmented killing of specific diseased cells. Thus, the goal of this study was to prepare a peptide-drug conjugate targeting elevated expression of HER2 receptors in breast cancer. Towards this, the rL-A9 peptide was conjugated with the chemotherapeutic drug doxorubicin (DOX) through a N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linker.

Nuclear Localization Signal Enhances the Targeting and Therapeutic Efficacy of a Porphyrin-Based Molecular Cargo: A Systemic In Vitro and Ex Vivo Evaluation.

The objective of the present work was to evaluate the potential of a nuclear localization signal (NLS) toward facilitating intracellular delivery and enhancement in the therapeutic efficacy of the molecular cargo. Toward this, an in-house synthesized porphyrin derivative, namely, 5-carboxymethyelene-oxyphenyl-10,15,20-(4-methoxyphenyl) porphyrin (UTriMA), was utilized for conjugation with the NLS sequence [PKKKRKV]. The three compounds synthesized during the course of the present work, namely DOTA-Lys-NLS, DOTA-UTriMA-Lys-NLS, and DOTA-Lys-UTriMA, were evaluated for cellular toxicity in cancer cell lines (HT1080), wherein all exhibited minimal dark toxicity.

Design, synthesis and evaluation of Lu-labeled inverso and retro-inverso A9 peptide variants targeting HER2-overexpression.

Several HER2-specific peptides are being continuously explored to find a candidate with suitable pharmacokinetic properties for development of effective radiopharmaceutical that can find applications for clinical screening of breast cancer patients. In the present work with an aim of preparing a radiopeptide with improved metabolic stability and in vivo pharmacokinetic performance we modified our previously reported [Lu]DOTA-L-A9 peptide. Here we designed an 'inverso' peptide with all d-amino acids and a 'retro-inverso' peptide where sequence of d-amino acids was reversed.

Synthesis and Lu Labeling of the First Retro Analog of the HER2-Targeting A9 Peptide: A Superior Variant.

The retro analog of the HER2-targeting A9 peptide was synthesized by coupling amino acids in a reverse fashion and switching the N-terminal in the original sequence of the L-A9 peptide (QDVNTAVAW) to the C-terminal in rL-A9 (WAVATNVDQ). Modification in the backbone resulted in higher conformational stability of the retro peptide as evident from CD spectra. Molecular docking analysis revealed a higher HER2 binding affinity of [Lu]Lu-DOTA-rL-A9 than the original radiopeptide [Lu]Lu-DOTA-L-A9.

Targeting HER2-receptors with Lu-labeled triazole stapled cyclic peptidomimetic.

In this study on-resin Cu(I)-catalyzed click reaction was performed to synthesize triazole-stapled cyclic peptidomimetic, DOTA-c[TZ]A9 targeting HER2 receptor expression in breast cancers. Spectroscopic (circular dichroism) and docking analysis provided evidence of enhanced helicity and secondary structure stabilization along with improved HER2 affinity in comparison to the corresponding linear peptide, DOTA-[Pra, Aza]A9. Lu-labeled cyclic peptide, Lu-DOTA-c[TZ]A9 displayed higher in vitro serum stability and in vivo metabolic stability and better HER2 binding affinity {K of 16.

[Tc]Tc-HYNIC-RM2: A potential SPECT probe targeting GRPR expression in prostate cancers.

Introduction: Elevated density of gastrin releasing peptide receptors (GRPR) in prostate cancer has led to exploration of several radiolabeled peptides for imaging and staging of the disease. The GRPR antagonist peptide RM2 has been successfully conjugated with several chelators and radiolabeled with gallium-68. The goal of this study was to synthesize a Tc-labeled probe and investigate its potential for SPECT imaging of prostate cancer.

Evaluation of the effect of a cell penetrating peptide (TAT) towards tailoring the targeting efficacy and tumor uptake of porphyrin.

Cell penetrating peptides (CPPs) are known to possess a unique capacity to penetrate biological membranes and translocate various molecules into the cells. Therefore, porphyrin-CPP conjugates could be envisaged to boost the intracellular delivery of porphyrins thereby providing an improved tool for the development of agents for multi-modal applications for cancer management. Working in this direction, an unsymmetrically substituted porphyrin derivative was conjugated with a transactivating transcriptional activator peptide (TAT) and various and  studies were carried out in order to study the effect of adding a CPP to the porphyrin derivative.

Preparation of radiolabeled erlotinib analogues and analysis of the effect of linkers.

Erlotinib is a first generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) which was granted Food and Drug administration (FDA) approval for treatment of patients with locally advanced or metastatic NSCLC. The present study aimed at development of radiolabeled erlotinib variants as tyrosine kinase inhibitors. Three DOTA-erlotinib conjugates were prepared for radiolabeling with Lu.

Synthesis and comparative evaluation of Lu-labeled PEG and non-PEG variant peptides as HER2-targeting probes.

Highest global cancer incidence of female breast cancer is a matter of great concern. HER2-positive breast cancers have high mortality rate hence detection at an early stage is vital for successful treatment, improved cancer care and survival rate. Radiolabeled peptides have emerged as new alternatives to radiolabeled antibodies to overcome the limitations of slow clearance and uptake in non-target tissues.

Assessment of Lu-labeled carboxyl-terminated polyamidoamine (PAMAM) dendrimer-RGD peptide conjugate.

Structurally unique polyamidoamine (PAMAM) dendrimers implanted with targeting biological moiety along with complexed radiometal constitute a favorable nano-system for diagnosis and therapy of targeted tumor sites. In the present study, carboxyl functionalities of PAMAM- generation 4 dendrimer (PAMAM-G4-COOH) were conjugated with ε-amino group of lysine of cRGDfK peptide to impart integrin α β targeting capability. Reaction of p-NH -Bn-DOTA with PAMAM was accomplished via acid-amine coupling using EDC/NHS for Lu-complexation.

Recent Breakthrough in Ga-Radiopharmaceuticals Cold Kits for Convenient PET Radiopharmacy.

Ga-PET has emerged as an important diagnostic tool for precise detection and monitoring of oncological situations. Availability, cost, and radiosynthesis procedure are determining steps for success of a radioisotope/radiopharmaceutical in nuclear medicine. Availability of Ga from a Ge/Ga generator containing a long-lived parent radioisotope (Ge: = 271 days) and an inexpensive, simplified production of Ga-radiopharmaceuticals through kit methodology has allowed smooth accommodation of Ga-PET in clinics.

Preparation and clinical translation of Tc-PSMA-11 for SPECT imaging of prostate cancer.

This study explores the feasibility of radiolabeling the HBED-CC-PSMA (PSMA-11) ligand with Tc-99m for SPECT imaging of prostate cancer patients. Ga-HBED-CC-PSMA (PSMA-11) is used clinically for PET/CT imaging of prostate cancer (PCa) patients. However, a PET/CT facility may not be affordable and/or accessible to remotely located health centers.

Ga-labeling of internalizing RGD (iRGD) peptide functionalized with DOTAGA and NODAGA chelators.

The dual interaction with integrins and neuropilin-1 receptor is the peculiar feature of iRGD peptide. Hence, in the present study, two iRGD peptide analogs were synthesized with DOTAGA and NODAGA as bifunctional chelator and aminohexanoic acid as a spacer for radiometalation with GaCl . Negatively charged Ga-DOTAGA-iRGD and neutral Ga-NODAGA-iRGD radiotracers were investigated through in vitro cell uptake studies and in vivo biodistribution studies.

Synthesis, radiolabeling, and evaluation of gastrin releasing peptide receptor antagonist Ga-HBED-CC-RM26.

The acyclic chelator HBED-CC has attained huge clinical significance owing to high thermodynamic and kinetic stability of Ga-HBED-CC chelate. It provides an excellent platform for quick preparation of Ga-based radiotracers in high yield. Thus, the present study aimed at conjugation of gastrin releasing peptide receptor (GRPr) antagonist, RM26, with HBED-CC chelator for Ga-labeling.

Design, synthesis, and comparative evaluation of Tc(CO) -labeled N-terminal and C-terminal modified asparagine-glycine-arginine peptide constructs.

The present study describes modification of asparagine-glycine-arginine (NGR) peptide at N-terminally and C-terminally by introduction of a tridentate chelating scaffold via click chemistry reaction. The N-terminal and C-terminal modified peptides were radiometalated with [ Tc(CO) ] precursor. The influence of these moieties at the two termini on the targeting properties of NGR peptide was determined by in vitro cell uptake studies and in vivo biodistribution studies.

Single vial cold kits optimized for preparation of gastrin releasing peptide receptor (GRPR)-radioantagonist Ga-RM2 using three different Ge/Ga generators.

Ga-RM2 is a gastrin releasing peptide receptor (GRPR) antagonist PET (positron emission tomography) radiotracer which is being investigated in clinical trials as a potential prostate cancer imaging agent. Simple, one-step kit formulation of Ga-RM2 would facilitate multicentre trials and allow easier integration in hospital radiopharmacy. Herein we report development of three sets of single-vial RM2 cold kits validated for formulation with three respective Ge/Ga generators eluted in 0.

Ga-labeled HBED-CC Variant of uPAR Targeting Peptide AE105 Compared with Ga-NODAGA-AE105.

Aims: The urokinase Plasminogen Activator Receptors (uPAR) over-expressed on tumor cells and their invasive microenvironment are clinically significant molecular targets for cancer research. uPARexpressing cancerous lesions can be suitably identified and their progression can be monitored with radiolabeled uPAR targeted imaging probes. Hence this study aimed at preparing and evaluating two 68Ga-labeled AE105 peptide conjugates, 68Ga-NODAGA-AE105 and 68Ga-HBED-CC-AE105 as uPAR PET-probes.

Lu-labeled cyclic Asn-Gly-Arg peptide tagged carbon nanospheres as tumor targeting radio-nanoprobes.

This study explores the potential of Lu-labeled carbon nanospheres as radio-nanoprobes for molecular imaging and therapy. The carboxyl functionalized surface of carbon nanospheres (CNS) was conjugated with [Gly-Gly-Gly-c(Asn-Gly-Arg)], G3-cNGR peptide through amide bond for targeting tumor vasculature and with [2-(4-Aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid], p-NH-Bz-DOTA for chelation with Lu. The nanosphere-peptide conjugate, DOTA-CNS-cNGR, was characterized by dynamic light scattering and zeta potential measurements, IR and UV experiments and did not show any in vitro cytotoxicity.

Preparation and comparative evaluation of Tc-HYNIC-cNGR and Tc-HYNIC-PEG -cNGR as tumor-targeting molecular imaging probes.

The tripeptide sequence asparagine-glycine-arginine (NGR) specifically recognizes aminopeptidase N (APN or CD13) receptors highly expressed on tumor cells and vasculature. Thus, NGR peptides can precisely deliver therapeutic and diagnostic compounds to CD13 expressing cancer sites. In this regard, 2 NGR peptide ligands, HYNIC-c(NGR) and HYNIC-PEG -c(NGR), were synthesized, radiolabeled with Tc, and evaluated in CD13-positive human fibrosarcoma HT-1080 tumor xenografts.

Comparative evaluation of Ga-labeled NODAGA, DOTAGA, and HBED-CC-conjugated cNGR peptide chelates as tumor-targeted molecular imaging probes.

The biological behavior of Ga-based radiopharmaceuticals can be significantly affected by the chelators' attributes (size, charge, lipophilicity). Thus, this study aimed at examining the influence of three different chelators, DOTAGA, NODAGA, and HBED-CC on the distribution pattern of Ga-labeled NGR peptides targeting CD13 receptors. Ga-DOTAGA-c(NGR), Ga-NODAGA-c(NGR), and Ga-HBED-CC-c(NGR) were observed to be hydrophilic with respective log p values being -3.

Tc-labeled NGR-chlorambucil conjugate, Tc-HYNIC-CLB-c(NGR) for targeted chemotherapy and molecular imaging.

Targeted delivery of chemotherapeutic drug at the tumor site enhances the efficacy with minimum systemic exposure. Towards this, drugs conjugated with peptides having affinity towards a particular molecular target are recognized as affective agents for targeted chemotherapy. Thus, in the present study, tumor-homing asparagine-glycine-arginine (NGR) peptide ligand was conjugated to DNA alkylating nitrogen mustard, chlorambucil (CLB).

Preliminary PET/CT Imaging with Somatostatin Analogs [Ga]DOTAGA-TATE and [Ga]DOTAGA-TOC.

Purpose: Somatostatin receptor positron emission tomography/X-ray computed tomography (SSTR-PET/CT) is a well-established technique for staging and detection of neuroendocrine tumors (NETs). Ga-68-labeled DOTA-conjugated octreotide analogs are the privileged radiotracers for diagnosis and therapeutic monitoring of NETs. Hence, we were interested in assessing the influence of promising, newer variant DOTAGA on the hydrophilicity, pharmacokinetics, and lesion pick-up of somatostatin analogs.