An improved synthesis of a selective αvβ3-integrin antagonist cyclo(-RGDfK-)

Dai, Xuezhi; Su, Zhuang; Liu, Jun O.

doi:10.1016/s0040-4039(00)01060-1

Cited by 46 publications

(29 citation statements)

References 17 publications

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“…The cyclic peptides, cRGDfK and cRADfK (f denotes D-phenylalanine), were synthesized by using standard Fmoc solid-phase chemistry as described (26). Peptides were purified by reverse-phase HPLC, and exact mass was confirmed by mass spectroscopy.…”

Section: Methodsmentioning

confidence: 99%

Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis

Murphy

Majeti

Barnes

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

439

299

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Integrin ␣ ␤3 is found on a subset of tumor blood vessels where it is associated with angiogenesis and malignant tumor growth. We designed an ␣ ␤3-targeted nanoparticle (NP) encapsulating the cytotoxic drug doxorubicin (Dox) for targeted drug delivery to the ␣ ␤3-expressing tumor vasculature. We observed real-time targeting of this NP to tumor vessels and noted selective apoptosis in regions of the ␣ ␤3-expressing tumor vasculature. In clinically relevant pancreatic and renal cell orthotopic models of spontaneous metastasis, targeted delivery of Dox produced an antimetastatic effect. In fact, ␣ ␤3-mediated delivery of this drug to the tumor vasculature resulted in a 15-fold increase in antimetastatic activity without producing drug-associated weight loss as observed with systemic administration of the free drug. These findings reveal that NP-based delivery of cytotoxic drugs to the ␣ ␤3-positive tumor vasculature represents an approach for treating metastatic disease.antiangiogenic ͉ intravital microscopy ͉ pancreatic cancer ͉ renal cell carcinoma ͉ liposome A ngiogenesis contributes to tumor malignancy and is linked to a wide variety of inflammatory and ischemic diseases. Integrin ␣v␤3, an internalization receptor for a number of viruses (1, 2), was shown to be preferentially expressed on the angiogenic endothelium in malignant or diseased tissues (3, 4). These characteristics of integrin ␣v␤3 make it an attractive targeting molecule for molecular imaging and delivery of therapeutics for cancer. Previous studies have shown that ␣v␤3-targeted nanoparticles (NPs) coupled to contrast agents can readily image the tumor vasculature revealing ''hot spots'' of angiogenesis within the tumor (5, 6). Therapeutic studies using the ␣v integrin-targeting peptide, RGD-4C, demonstrated that this peptide effectively targeted doxorubicin (Dox) to the tumor neovasculature and enhanced efficacy in human breast cancer xenografts in mice (7). In another study, an ␣v␤3-targeted NP delivering a suicide gene to angiogenic blood vessels was capable of producing an anticancer response (8). Although integrin ␣v␤3 is a marker of angiogenic endothelium, histological analysis of breast cancer biopsy tissue revealed that ␣v␤3 was a primary marker of blood vessels within the most malignant tumors (4). In fact, a strong correlation was established between the percent of ␣v␤3-positive vessels within the tumor and disease progression (9).Here, we report the design and characterization of an ␣v␤3-targeted NP capable of delivering various pharmacological agents to the ␣v␤3-expressing tumor vasculature. Evidence is provided that an ␣v␤3-targeted NP carrying the cytotoxic drug Dox is capable of controlling the metastatic behavior of pancreatic and renal cell cancer in mice. Importantly, targeted delivery of Dox to the tumor vasculature provided a 15-fold increase in the efficacy of the drug while producing few, if any, side effects. Results Design of NPs Targeted to Angiogenic Endothelium.A schematic representation of the targeted NP (RGD-NP) (Fig. ...

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Section: Methodsmentioning

confidence: 99%

Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis

Murphy

Majeti

Barnes

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

439

299

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“…The peptide was cleaved from the resin with a mixture of acetic acid/2,2,2-trifluoroethane/dichloromethane 1:1:3. Head-to-tail cyclization took place in solution at room temperature (RT) overnight, after the addition of 50% 1-propanephosphonic acid cyclic anhydride in ethylacetate, triethylamine, and 4-di(methylamino) pyridine, as previously described (11). The protected cyclic peptide was purified on a Silica gel 60 column (ethyl acetate/methanol 9:1).…”

Section: Peptide-conjugate Synthesismentioning

confidence: 99%

Novel ⁶⁴Cu- and ⁶⁸Ga-Labeled RGD Conjugates Show Improved PET Imaging of α_νβ₃ Integrin Expression and Facile Radiosynthesis

et al. 2011

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PET with 18 F-labeled arginine-glycine-aspartic acid (RGD) peptides can visualize and quantify a n b 3 integrin expression in patients, but radiolabeling is complex and image contrast is limited in some tumor types. The development of 68 Ga-RGD peptides would be of great utility given the convenience of 68 Ga production and radiolabeling, and 64 Cu-RGD peptides allow for delayed imaging with potentially improved tumor-tobackground ratios. Methods: We used the chelators DOTA,1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), and 4,11-bis(carboxymethyl)-1, 4,8,11-tetraazabicyclo[6.6.2] hexadecane (CB-TE2A) to radiolabel the cyclic pentapeptide c(RGDfK) with 68 Ga or 64 Cu. NODAGA-c(RGDfK) was labeled at room temperature with both radionuclides within 10 min. Incubation at 95°C for up to 30 min was used for the other conjugates. The affinity profile of the metallopeptides was evaluated by a cell-based receptor-binding assay. Small-animal PET studies and biodistribution studies were performed in nude mice bearing subcutaneous U87MG glioblastoma xenografts. Results: The conjugates were labeled with a radiochemical purity greater than 97% and specific activities of 15-20 GBq/mmol. The affinity profile was similar for all metallopeptides and comparable to the reference standard c(RGDfV). In the biodistribution studies, all compounds demonstrated a relatively similar tumor and normal organ uptake at 1 h after injection that was comparable to published data on 18 F-labeled RGD peptides. At 18 h after injection, however, 64 Cu-NODAGA-c(RGDfK) and 64 Cu-CB-TE2A-c(RGDfK) showed up to a 20-fold increase in tumor-to-organ ratios. PET studies demonstrated high-contrast images of the U87MG tumors at 18 h, confirming the biodistribution data. Conclusion: The ease of radiolabeling makes 68 Ga-NODAGA-c(RGDfK) an attractive alternative to 18 F-labeled RGD peptides. The high tumor-to-background ratios of 64 Cu-NODAGA-c(RGDfK) and 64 Cu-CB-TE2A-c(RGDfK) at 18 h warrant testing of 64 Cu-labeled RGD peptides in patients.

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“…For the click chemistry, 1 mg of DONoxime (2.84 µmol) was reacted with 1.78 mg of cyclic peptide (2.84 µmol) under the previously mentioned conditions. Under CDI reaction conditions, the obtained DON-cyclic peptide (2.84 µmol) was coupled to 3.9 mg of BSA in water-DMSO (1/5, v/v) for 3 h at RT (Dai et al 2000;Dijkgraaf et al 2007). …”

Section: Preparation Of Don Immunogensmentioning

confidence: 99%

An immunogen synthesis strategy for the development of specific anti-deoxynivalenol monoclonal antibodies

Sanders

Guo

Iyer

et al. 2014

Food Additives & Contaminants: Part A

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An immunogen synthesis strategy was designed to develop anti-deoxynivalenol (DON) monoclonal antibodies with low cross-reactivity against structurally similar trichothecenes. A total of eight different DON immunogens were synthesised, differing in the type and position of the linker on the DON molecule. After immunisation, antisera from mice immunised with different DON immunogens were checked for the presence of relevant antibodies. Then, both homologous and heterologous enzyme-linked immunosorbent assays (ELISAs) were performed for hybridoma screening. Finally, three monoclonal antibodies against DON and its analogues were generated. In addition, monoclonal antibody 13H1 could recognise DON and its analogues in the order of HT-2 toxin > 15-acetyldeoxynivalenol (15-ADON) > DON, with IC₅₀ ranging from 1.14 to 2.13 µg ml⁻¹. Another monoclonal antibody 10H10 manifested relatively close sensitivities to DON, 3-acetyldeoxynivalenol (3-ADON) and 15-ADON, with IC₅₀ values of 22, 15 and 34 ng ml⁻¹, respectively. Using an indirect ELISA format decreases the 10H10 sensitivity to 15-ADON with 92%. A third monoclonal antibody 2A9 showed to be very specific and sensitive to 3-ADON, with IC₅₀ of 0.38 ng ml⁻¹. Using both 2A9 and 10H10 monoclonal antibodies allows determining sole DON contamination.

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An improved synthesis of a selective αvβ3-integrin antagonist cyclo(-RGDfK-)

Cited by 46 publications

References 17 publications

Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis

Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis

Novel ⁶⁴Cu- and ⁶⁸Ga-Labeled RGD Conjugates Show Improved PET Imaging of α_νβ₃ Integrin Expression and Facile Radiosynthesis

An immunogen synthesis strategy for the development of specific anti-deoxynivalenol monoclonal antibodies

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An improved synthesis of a selective αvβ3-integrin antagonist cyclo(-RGDfK-)

Cited by 46 publications

References 17 publications

Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis

Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis

Novel 64Cu- and 68Ga-Labeled RGD Conjugates Show Improved PET Imaging of ανβ3 Integrin Expression and Facile Radiosynthesis

An immunogen synthesis strategy for the development of specific anti-deoxynivalenol monoclonal antibodies

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Novel ⁶⁴Cu- and ⁶⁸Ga-Labeled RGD Conjugates Show Improved PET Imaging of α_νβ₃ Integrin Expression and Facile Radiosynthesis