Folic acid-decorated polyamidoamine dendrimer exhibits high tumor uptake and sustained highly localized retention in solid tumors: Its utility for local siRNA delivery

Melanoma is a cancer with increasing incidence and there is a need for alternatives to immunotherapy within effective approaches to treatment of metastatic melanoma. We performed comparative radioimmunotherapy (RIT) of experimental B16-F10 melanoma with novel humanized IgG to melanin h8C3 labeled with a beta emitter, 177Lu, and an alpha-emitter, 213Bi, as well as biodistribution, microSPECT/CT imaging, and mouse and human dosimetry calculations. microSPECT/CT imaging showed that a humanized antibody that targets “free” melanin in the tumor microenvironment had high tumor uptake in B16F10 murine melanoma in C57Bl/6 mice, with little to no uptake in naturally melanized tissues. Extrapolation of the mouse dosimetry data to an adult human demonstrated that doses delivered to major organs and the whole body by 177Lu-h8C3 would be approximately two times higher than those delivered by 213Bi-h8C3, while the doses to the tumor would be almost similar. RIT results indicated that 213Bi-h8C3 was more effective in slowing down the tumor growth than 177Lu-h8C3, while both radiolabeled antibodies did not produce significant hematologic or systemic side effects. We concluded that h8C3 antibody labeled with 213Bi is a promising reagent for translation into a clinical trial in patients with metastatic melanoma.

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Synthesis and evaluation of radiolabeled, folic acid-PEG conjugated, amino silane coated magnetic nanoparticles in tumor bearing Balb/C mice

Nukleonika ◽

10.1515/nuka-2015-0066 ◽

2015 ◽

Vol 60 (3) ◽

pp. 497-502 ◽

Cited By ~ 6

Author(s):

Javad Razjouyan ◽

Hamidreza Zolata ◽

Omid Khayat ◽

Fereidoun Nowshiravan ◽

Nami Shadanpour ◽

...

Keyword(s):

Folic Acid ◽

Folate Receptor ◽

Superparamagnetic Iron Oxide ◽

Fibroblast Cell ◽

Mouse Fibroblast ◽

Tumor Uptake ◽

Mri Imaging ◽

Tumor Bearing ◽

Biodistribution Studies

Abstract To design a potent agent for positron emission tomography/magnetic resonance imaging (PET/MRI) imaging and targeted magnetic hyperthermia-radioisotope cancer therapy radiolabeled surface modified superparamagnetic iron oxide nanoparticles (SPIONs) were used as nanocarriers. Folic acid was conjugated for increasing selective cellular binding and internalization through receptor-mediated endocytosis. SPIONs were synthesized by the thermal decomposition of tris (acetylacetonato) iron (III) to achieve narrow and uniform nanoparticles. To increase the biocompatibility of SPIONs, they were coated with (3-aminopropyl) triethoxysilane (APTES), and then conjugated with synthesized folic acid-polyethylene glycol (FA-PEG) through amine group of (3-aminopropyl) triethoxysilane. Finally, the particles were labeled with 64Cu (t1/2 = 12.7 h) using 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono (N-hydroxy succinimide ester) DOTA-NHS chelator. After the characterization of SPIONs, their cellular internalization was evaluated in folate receptor (FR) overexpressing KB (established from a HeLa cell contamination) and mouse fibroblast cell (MFB) lines. Eventually, active and passive targeting effects of complex were assessed in KB tumor-bearing Balb/C mice through biodistribution studies. Synthesized bare SPIONs had low toxicity effect on healthy cells, but surface modification increased their biocompatibility. Moreover, KB cells viability was reduced when using folate conjugated SPIONs due to FR-mediated endocytosis, while having little effect on healthy cells (MFB). Moreover, this radiotracer had tolerable in vivo characteristics and tumor uptake. In the receptor blocked case, tumor uptake was decreased, indicating FR-specific uptake in tumor tissue while enhanced permeability and retention effect was major mechanism for tumor uptake.

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Phase I Trial and Pharmacokinetic Study of Pemetrexed in Children With Refractory Solid Tumors: The Children's Oncology Group

Journal of Clinical Oncology ◽

10.1200/jco.2006.09.1694 ◽

2007 ◽

Vol 25 (12) ◽

pp. 1505-1511 ◽

Cited By ~ 20

Author(s):

Suman Malempati ◽

H. Stacy Nicholson ◽

Joel M. Reid ◽

Susan M. Blaney ◽

Ashish M. Ingle ◽

...

Keyword(s):

Folic Acid ◽

Phase I ◽

Solid Tumors ◽

Pharmacokinetic Study ◽

Phase I Trial ◽

Maximum Tolerated Dose ◽

Vitamin B ◽

Pharmacokinetic Studies ◽

Purine Nucleotides ◽

Phase Ii Studies

Purpose We report results of a phase I trial and pharmacokinetic study of pemetrexed (LY231514) in children and adolescents with refractory solid tumors. Pemetrexed is a novel antifolate that inhibits multiple enzymes necessary for the biosynthesis of thymidine and purine nucleotides. The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic properties of pemetrexed in children. Patients and Methods Pemetrexed was administered as a 10-minute intravenous infusion every 21 days. Patients received vitamin B12 and folic acid supplementation as well as dexamethasone prophylaxis. Cohorts of three to six children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. Pharmacokinetic studies were performed during the first course of treatment. Results Thirty-three patients (31 assessable) with a median age of 12 years were enrolled. DLT occurred in one of six patients at 1,470 mg/m2 and two of four patients at 2,480 mg/m2. The MTD was 1,910 mg/m2. The primary DLTs were neutropenia and rash. No objective antitumor responses were seen. Mean plasma clearance, half-life, and steady-state volume of distribution values were 2.3 L/h/m2, 2.5 hours, and 5.4 L/m2, respectively. Conclusion Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase II studies is 1,910 mg/m2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.

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Noninvasive brain cancer imaging with a bispecific antibody fragment, generated via click chemistry

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1509667112 ◽

2015 ◽

Vol 112 (41) ◽

pp. 12806-12811 ◽

Cited By ~ 26

Author(s):

Haiming Luo ◽

Reinier Hernandez ◽

Hao Hong ◽

Stephen A. Graves ◽

Yunan Yang ◽

...

Keyword(s):

Early Detection ◽

Near Infrared ◽

Bispecific Antibody ◽

Growth Factor Receptor ◽

Antibody Fragment ◽

Tumor Uptake ◽

High Tumor Uptake ◽

Epidermal Growth ◽

Detection And Diagnosis ◽

Near Infrared Fluorescence Imaging

Early diagnosis remains a task of upmost importance for reducing cancer morbidity and mortality. Successful development of highly specific companion diagnostics targeting aberrant molecular pathways of cancer is needed for sensitive detection, accurate diagnosis, and opportune therapeutic intervention. Herein, we generated a bispecific immunoconjugate [denoted as Bs-F(ab)2] by linking two antibody Fab fragments, an anti-epidermal growth factor receptor (EGFR) Fab and an anti-CD105 Fab, via bioorthogonal “click” ligation of trans-cyclooctene and tetrazine. PET imaging of mice bearing U87MG (EGFR/CD105+/+) tumors with 64Cu-labeled Bs-F(ab)2 revealed a significantly enhanced tumor uptake [42.9 ± 9.5 percentage injected dose per gram (%ID/g); n = 4] and tumor-to-background ratio (tumor/muscle ratio of 120.2 ± 44.4 at 36 h postinjection; n = 4) compared with each monospecific Fab tracer. Thus, we demonstrated that dual targeting of EGFR and CD105 provides a synergistic improvement on both affinity and specificity of 64Cu-NOTA-Bs-F(ab)2. 64Cu-NOTA-Bs-F(ab)2 was able to visualize small U87MG tumor nodules (<5 mm in diameter), owing to high tumor uptake (31.4 ± 10.8%ID/g at 36 h postinjection) and a tumor/muscle ratio of 76.4 ± 52.3, which provided excellent sensitivity for early detection. Finally, we successfully confirmed the feasibility of a ZW800-1–labeled Bs-F(ab)2 for near-infrared fluorescence imaging and image-guided surgical resection of U87MG tumors. More importantly, our rationale can be used in the construction of other disease-targeting bispecific antibody fragments for early detection and diagnosis of small malignant lesions.

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Folic acid-decorated polyamidoamine dendrimer mediates selective uptake and high expression of genes in head and neck cancer cells

Nanomedicine ◽

10.2217/nnm-2016-0244 ◽

2016 ◽

Vol 11 (22) ◽

pp. 2959-2973 ◽

Cited By ~ 15

Author(s):

Leyuan Xu ◽

Shannon Kittrell ◽

W Andrew Yeudall ◽

Hu Yang

Keyword(s):

Head And Neck Cancer ◽

Folic Acid ◽

Head And Neck ◽

Cancer Cells ◽

Neck Cancer ◽

High Expression ◽

Selective Uptake ◽

Polyamidoamine Dendrimer ◽

Expression Of Genes

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[18F]Fluoroethyltriazolyl Monocyclam Derivatives as Imaging Probes for the Chemokine Receptor CXCR4

Molecules ◽

10.3390/molecules24081612 ◽

2019 ◽

Vol 24 (8) ◽

pp. 1612 ◽

Cited By ~ 4

Author(s):

Alejandro Amor-Coarasa ◽

James M. Kelly ◽

Pradeep K. Singh ◽

Shashikanth Ponnala ◽

Anastasia Nikolopoulou ◽

...

Keyword(s):

Chemokine Receptor ◽

Cxcr4 Expression ◽

Tumor Uptake ◽

Multiple Tumor ◽

Chemokine Receptor Cxcr4 ◽

Positron Emission ◽

Imaging Probes ◽

High Tumor Uptake ◽

Tumor Types

Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [68Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical properties of 68Ga. We screened a library of >200 fluorine-containing structural derivatives of AMD-3465 to identify promising candidates for in vivo imaging of CXCR4 expression by positron emission tomography (PET). Compounds containing fluoroethyltriazoles consistently achieved higher docking scores. Six of these higher scoring compounds were radiolabeled by click chemistry and evaluated in PC3-CXCR4 cells and BALB/c mice bearing bilateral PC3-WT and PC3-CXCR4 xenograft tumors. The apparent CXCR4 affinity of the ligands was relatively low, but tumor uptake was CXCR4-specific. The tumor uptake of [18F]RPS-534 (7.2 ± 0.3 %ID/g) and [18F]RPS-547 (3.1 ± 0.5 %ID/g) at 1 h p.i. was highest, leading to high tumor-to-blood, tumor-to-muscle, and tumor-to-lung ratios. Total cell-associated activity better predicted in vivo tumor uptake than did the docking score or apparent CXCR4 affinity. By this metric, and on the basis of their high yielding radiosynthesis, high tumor uptake, and good contrast to background, [18F]RPS-547, and especially [18F]RPS-534, are promising 18F-labeled candidates for imaging CXCR4 expression.

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