Cyclic RGDyk-conjugated LMWH-taurocholate derivative as a targeting angiogenesis inhibitor

Adulnirath, Asarasin; Chung, Soo Kyo; Park, Jooho; Hwang, Seong Youn; Kim, Ji Young; Yang, Victor C.; Kim, Sang Yoon; Moon, Hyun Tae; Byun, Youngro

doi:10.1016/j.jconrel.2012.10.001

Cited by 13 publications

(12 citation statements)

References 28 publications

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“…These results might be explained by the higher binding affinity of cRHG nanoparticles to VEGF (and probably other angiogenic factors) and disruption of VEGF–VEGFR2 interaction . Previous reports suggested that hydrophobized LMWH derivatives showed higher binding affinity to VEGF and thus improved antiangiogenic effect . Meanwhile, GA might also antagonize the VEGF‐triggered angiogenesis by blocking VEGFR2 receptors .…”

Section: Resultsmentioning

confidence: 99%

“…However, the clinical application of heparin in tumor therapy has been hindered by the potential hemorrhagic risk and poor in vivo delivery to the tumor . In this respect, chemical modification of LMWH with hydrophobic segments, such as deoxycholate and lithocholate, was reported to significantly reduce the anticoagulant activity of the resulting conjugates, i.e., decreased risk of bleeding, and thus can be used as safer drug carriers with inherent anticancer activity …”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, the pharmaceutical design of such delivery systems seems relatively difficult and complex. α v β 3 integrins represent an appealing target to realize this dual‐targeted delivery owing to their simultaneous expression in tumor endothelium and many tumor cell lines such as late stage glioblastoma, melanoma, ovarian, and prostate cancer . These molecules are crucially involved in various cancer processes, i.e., cell survival, adhesion, migration, invasion, and angiogenesis .…”

Section: Introductionmentioning

confidence: 99%

“…α v β 3 integrins represent an appealing target to realize this dual‐targeted delivery owing to their simultaneous expression in tumor endothelium and many tumor cell lines such as late stage glioblastoma, melanoma, ovarian, and prostate cancer . These molecules are crucially involved in various cancer processes, i.e., cell survival, adhesion, migration, invasion, and angiogenesis . Recently, cyclic RGD pentapeptides, such as cyclic arginine–glycine–asparagine–tyrosine–lysine (c(RGDyK)) peptide, have been used for “double‐targeting” oncotherapy and tumor imaging due to their high specificity and affinity toward α v β 3 integrin receptors along with their good stability .…”

Section: Introductionmentioning

confidence: 99%

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Retracted: Multifunctional Polymeric Nanosystems for Dual‐Targeted Combinatorial Chemo/Antiangiogenesis Therapy of Tumors

Dahmani

Xiao

Zhang

et al. 2016

Adv Healthcare Materials

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Combination of antiangiogenesis and chemotherapy holds vast promise for effective inhibition of tumor proliferation and invasion. Herein, a multifunctional self-assembled nanosystem consisting of amphiphilic c(RGDyK)-functionalized low-molecular-weight heparin-gambogic acid conjugate (cRHG) is developed, using c(RGDyK) peptide as αv β3 integrin targeting moiety to realize a double-targeted delivery to both tumor cells and angiogenic vasculature. cRHG with a markedly decreased anticoagulant activity can self-assemble into nanosized particles (around 150 nm). cRHG nanoparticles effectively inhibit vascular endothelial growth factor (VEGF)-triggered tube-like formation of HUVEC and neovascularization of subcutaneous Matrigel plugs. More importantly, the targeting ability of cRHG nanoparticles is revealed by their efficient internalization by αv β3 integrin-positive cells (U87MG and HUVEC) in vitro and obvious accumulation of Cy7/cRHG in the tumor site with strong fluorescence signals in both cancer cells and neovasculature. Besides, cRHG maintains the in vitro cytotoxic activity of gambogic acid, while achieving the highest in vivo antitumor activity in U87MG mouse xenograft model and displaying better safety profile than free drugs solutions. Mechanistic investigations reveal the substantial inhibition of hypoxia-inducible factor-1 alpha, VEGF, and CD31 expression by cRHG nanoparticles with remarkable down-regulation of VEGFR2 phosphorylation. These results suggest that cRHG nanoparticles provide a versatile nanoplatform for efficacious combinatorial tumor therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Retracted: Multifunctional Polymeric Nanosystems for Dual‐Targeted Combinatorial Chemo/Antiangiogenesis Therapy of Tumors

Dahmani

Xiao

Zhang

et al. 2016

Adv Healthcare Materials

View full text Add to dashboard Cite

show abstract

“…This same multitarget approach is at the bases of the development of an compounds generated by the fusion of a modified heparin (LHT7) with cyclic RGDyk. The resulting cRGD-LHT7 binds to both α v β 3 integrin expressed on the surface of tumor and endothelial cells and to VEGF, resulting in a strong antiangiogenic, anti-tumor activity [ 321 ].…”

Section: Discussionmentioning

confidence: 99%

Heparin/Heparan Sulfate Proteoglycans Glycomic Interactome in Angiogenesis: Biological Implications and Therapeutical Use

et al. 2015

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Angiogenesis, the process of formation of new blood vessel from pre-existing ones, is involved in various intertwined pathological processes including virus infection, inflammation and oncogenesis, making it a promising target for the development of novel strategies for various interventions. To induce angiogenesis, angiogenic growth factors (AGFs) must interact with pro-angiogenic receptors to induce proliferation, protease production and migration of endothelial cells (ECs). The action of AGFs is counteracted by antiangiogenic modulators whose main mechanism of action is to bind (thus sequestering or masking) AGFs or their receptors. Many sugars, either free or associated to proteins, are involved in these interactions, thus exerting a tight regulation of the neovascularization process. Heparin and heparan sulfate proteoglycans undoubtedly play a pivotal role in this context since they bind to almost all the known AGFs, to several pro-angiogenic receptors and even to angiogenic inhibitors, originating an intricate network of interaction, the so called “angiogenesis glycomic interactome”. The decoding of the angiogenesis glycomic interactome, achievable by a systematic study of the interactions occurring among angiogenic modulators and sugars, may help to design novel antiangiogenic therapies with implications in the cure of angiogenesis-dependent diseases.

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Angiogenic growth factors interactome and drug discovery: The contribution of surface plasmon resonance

Rusnati

Presta

2015

Cytokine & Growth Factor Reviews

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Angiogenesis is implicated in several pathological conditions, including cancer, and in regenerative processes, including the formation of collateral blood vessels after stroke. Physiological angiogenesis is the outcome of a fine balance between the action of angiogenic growth factors (AGFs) and anti-angiogenic molecules, while pathological angiogenesis occurs when this balance is pushed toward AGFs. AGFs interact with multiple endothelial cell (EC) surface receptors inducing cell proliferation, migration and proteases upregulation. On the contrary, free or extracellular matrix-associated molecules inhibit angiogenesis by sequestering AGFs (thus hampering EC stimulation) or by interacting with specific EC receptors inducing apoptosis or decreasing responsiveness to AGFs. Thus, angiogenesis results from an intricate network of interactions among pro- and anti-angiogenic molecules, EC receptors and various modulators. All these interactions represent targets for the development of pro- or anti-angiogenic therapies. These aims call for suitable technologies to study the countless interactions occurring during neovascularization. Surface plasmon resonance (SPR) is a label-free optical technique to study biomolecular interactions in real time. It has become the golden standard technology for interaction analysis in biomedical research, including angiogenesis. From a survey of the literature it emerges that SPR has already contributed substantially to the better understanding of the neovascularization process, laying the basis for the decoding of the angiogenesis "interactome" and the identification of "hub molecules" that may represent preferential targets for an efficacious modulation of angiogenesis. Here, the still unexploited full potential of SPR is enlightened, pointing to improvements in its use for a deeper understanding of the mechanisms of neovascularization and the identification of novel anti-angiogenic drugs.

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Cyclic RGDyk-conjugated LMWH-taurocholate derivative as a targeting angiogenesis inhibitor

Cited by 13 publications

References 28 publications

Retracted: Multifunctional Polymeric Nanosystems for Dual‐Targeted Combinatorial Chemo/Antiangiogenesis Therapy of Tumors

Retracted: Multifunctional Polymeric Nanosystems for Dual‐Targeted Combinatorial Chemo/Antiangiogenesis Therapy of Tumors

Heparin/Heparan Sulfate Proteoglycans Glycomic Interactome in Angiogenesis: Biological Implications and Therapeutical Use

Angiogenic growth factors interactome and drug discovery: The contribution of surface plasmon resonance

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