Targeted Delivery of a Sialic Acid-Blocking Glycomimetic to Cancer Cells Inhibits Metastatic Spread

Büll, Christian; Boltje, Thomas J.; Dinther, Eric A. W. van; Peters, Timo; Graaf, Annemarie M.A. de; Leusen, Jeanette H.W.; Kreutz, Martin; Figdor, Carl G.; Brok, Martijn H. den; Adema, Gosse J.

doi:10.1021/nn5061964

Cited by 116 publications

(85 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although these inhibitors have been found to be beneficial in experimental models of cancer [109–111], their lack of selectivity is concerning as off-target effects have been noted, leading to significant morbidity such as irreversible renal injury [112]. Thus, recent efforts have focused on the encapsulation of these inhibitors in nanoparticles, such as poly(lactic-co-glycolic acid) (PLGA), displaying cancer targeting antibodies [113]. However, as this drug delivery based solution requires knowledge of a specific antigen to be targeted, further progress in the development of specific glycosyltransferase inhibitors for clinical use will require increased structural knowledge of native and pathogenic glycosyltransferases.…”

Section: Approaches To Blockade Of Psgl-1/p-selectin Interactionsmentioning

confidence: 99%

Targeting P-selectin glycoprotein ligand-1/P-selectin interactions as a novel therapy for metabolic syndrome

Patel

Miranda-Nieves

Chen

et al. 2017

Translational Research

View full text Add to dashboard Cite

Obesity-induced insulin resistance and metabolic syndrome continue to pose an important public health challenge worldwide as they significantly increase the risk of type 2 diabetes and atherosclerotic cardiovascular disease. Advances in the pathophysiologic understanding of this process has identified that chronic inflammation plays a pivotal role. In this regard, given that both animal models and human studies have demonstrated that the interaction of P-selectin glycoprotein ligand-1 (PSGL-1) with P-selectin are not only critical for normal immune response, but also are upregulated in the setting of metabolic syndrome, PSGL-1/P-selectin interactions provide a novel target for preventing and treating resultant disease. Current approaches of interfering with PSGL-1/P-selectin interactions include targeted antibodies, recombinant immunoglobulins that competitively bind P-selectin, and synthetic molecular therapies. Experimental models as well as clinical trials assessing the role of these modalities in a variety of diseases have continued to contribute to the understanding of PSGL-1/P-selectin interactions and have demonstrated the difficulty in creating clinically relevant therapeutics. Most recently, however, computational simulations have further enhanced our understanding of the structural features of PSGL-1 and related glycomimetics, which are responsible for high affinity selectin interactions. Leveraging these insights for the design of next generation agents has thus led to development of a promising synthetic method for generating PSGL-1 glycosulfopeptide mimetics for the treatment of metabolic syndrome.

show abstract

Section: Approaches To Blockade Of Psgl-1/p-selectin Interactionsmentioning

confidence: 99%

Targeting P-selectin glycoprotein ligand-1/P-selectin interactions as a novel therapy for metabolic syndrome

Patel

Miranda-Nieves

Chen

et al. 2017

Translational Research

View full text Add to dashboard Cite

show abstract

“…In order to avoid disrupting the physiologically important processes, the site specific approaches are much needed related to its therapeutic efficiency. Most recently, this group reported an enhanced pharmacokinetic approach by formulation of P-3F ax -Neu5Ac into poly(lactic-co-glycolic acid) nanoparticles coated with antityrosinase-related protein-1 antibodies for targeted delivery of P-3F ax -Neu5Ac into cancer cells [24]. They showed that an intravenous injection of melanoma-targeting P-3Fax-Neu5Ac nanoparticles prevents metastasis formation in a murine lung metastasis model.…”

Section: Sialic Acid Analogsmentioning

confidence: 99%

Sialyltransferase inhibition and recent advances

Wang

Liu

et al. 2016

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

View full text Add to dashboard Cite

Sialic acids, existing as terminal sugars of glycoconjugates, play important roles in various physiological and pathological processes, such as cell-cell adhesion, immune defense, tumor cell metastasis, and inflammation. Sialyltransferases (STs) catalyze the transfer of sialic acid residues to non-reducing oligosaccharide chains of proteins and lipids, using cytidine monophosphate N-acetylneuraminic acid (CMP-Neu5Ac) as the donor. Elevated sialyltransferase activity leads to overexpression of cell surface sialic acids and contributes to many disease developments, such as cancer and inflammation. Therefore, sialyltransferases are considered as potential drug targets for disease treatment. Inhibitors of sialyltransferases thus are of medicinal interest, especially for the cancer therapy. In addition, sialyltransferase inhibitors are useful tool to study sialyltransferase function and related mechanisms. This review highlights recent development of inhibitors of sialyltransferases reported since 2004. The inhibitors are summarized as eight groups: 1) sialic acid analogs, 2) CMP-sialic acid analogs, 3) cytidine analogs, 4) oligosaccharide derivatives, 5) aromatic compounds, 6) flavonoids, 7) lithocholic acid analogs, and 8) others. This article is part of a Special Issue entitled: Physiological Enzymology and Protein Functions.

show abstract

“…Increased sialylated glycans on tumor cell surfaces is a specific characteristic related to advanced malignancy2. Increasing evidences have revealed that carcinomatosis-associated sialic acids (SA) over-expression on cell surface is confirmed in virtually each cancer type 3-5. SA can help tumor cells escape recognition and elimination by the immune system, thus conducing to cancer metastasis.…”

Section: Introductionmentioning

confidence: 99%

“…SA can help tumor cells escape recognition and elimination by the immune system, thus conducing to cancer metastasis. Aberrantly high SA expression of cell surface is emerging as a hallmark of cancer cell metastasis5. Therefore, targeting sialylated epitopes strategy provides a potent tool for metastatic cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

“…Subsequently, the PEG-shell is detached at tumor extracellular pH due to the unstable conjugation of PBA-catechol. And the exposed PBA moiety binds with over-expressed sialylated epitopes on cancer cells 5, 15, which accelerates the detachment of PEG and results in enhanced cellular internalization by virtue of both prolonged resident time on the cell surface and overexpressed SA receptor-mediated uptake. After internalization into the endosomes/lysosomes, the borate ester bond of PBA-ribose in the cross-linked core would be completely disrupted as the pH value further declines down to 4.5~5.5.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Systemic siRNA Delivery with a Dual pH-Responsive and Tumor-targeted Nanovector for Inhibiting Tumor Growth and Spontaneous Metastasis in Orthotopic Murine Model of Breast Carcinoma

Fan¹,

Kang

Chen

et al. 2017

Theranostics

View full text Add to dashboard Cite

Phenylboronic acid (PBA)-mediated tumor targeting nanovector is an attractive strategy for enhancing siRNA delivery and treatment of metastatic cancers. However, its nonspecific binding with various biological membranes containing cis-diol moieties restricts its potential application by systematic administration. Herein, we constructed a novel pH-activated “sheddable” PEG-coated nanoparticle for effective treatment of primary tumors and metastases, which was based on the conjugation of catechol group modified poly(ethylene glycol) (PEG-Cat) and PBA-terminated polyethylenimine (PEI-PBA) via the borate ester formed between PBA and Cat. By virtue of the pH-dependent stability of borate ester in an aqueous medium, the PEG-shell could “shield” the PBA ligand in systemic circulation to reduce its “off-target effect”, while PEG was detached at tumor extracellular pH (~6.5) to expose intact PBA moiety. Simultaneously, the PBA ligand could bind with overexpressed sialic acid residues on cancer cells, giving rise to enhanced cellular internalization. In addition, the PBA moieties could also couple with each 3'-end ribose of double-stranded siRNA. siRNAs were used as both a payload and a pH-responsive intermolecular cross-linker, and thereby acquired sufficient stability during circulating in blood and a rapidly triggered release in response to acidic endosomal/lysosomal pH-stimuli. As a result, this dual pH-sensitive nanoparticle showed enhanced siRNA uptake, gene silencing efficacy and anti-metastatic effects in vitro. Furthermore, in vivo studies demonstrated that PBA-based nanoparticles effectively accumulated in tumor and inhibited tumor growth and metastasis in 4T1 orthotopic mammary tumor model after intravenous administration.

show abstract

Targeted Delivery of a Sialic Acid-Blocking Glycomimetic to Cancer Cells Inhibits Metastatic Spread

Cited by 116 publications

References 60 publications

Targeting P-selectin glycoprotein ligand-1/P-selectin interactions as a novel therapy for metabolic syndrome

Targeting P-selectin glycoprotein ligand-1/P-selectin interactions as a novel therapy for metabolic syndrome

Sialyltransferase inhibition and recent advances

Systemic siRNA Delivery with a Dual pH-Responsive and Tumor-targeted Nanovector for Inhibiting Tumor Growth and Spontaneous Metastasis in Orthotopic Murine Model of Breast Carcinoma

Contact Info

Product

Resources

About