Inhibition of primary and metastatic tumors in mice by E-selectin-targeted polymer–drug conjugates

Raviv, Lior; Golan, Moran; Voronov, Elena; Apte, Ron N.; David, Ayelet

doi:10.1016/j.jconrel.2015.08.029

Cited by 38 publications

(21 citation statements)

References 44 publications

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“…Realizing the importance of selectins in cancer development and their potential for therapeutic targeting, several selectin-directed delivery systems were recently synthesized. Shamay and colleagues demonstrated an anti-tumor activity of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugated to an E-selectin binding peptide and loaded with different anti-cancer agents ( Shamay et al, 2016b ; Shamay et al, 2015 ). Another P-selectin targeted drug delivery system was designed by encapsulating chemotherapies with fucoidan (Fi), an algae-derived polysaccharide with an affinity to P-selectin.…”

Section: Discussionmentioning

confidence: 99%

Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome

Ferber

Tiram

Sousa-Hervés

et al. 2017

eLife

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Glioblastoma is a highly aggressive brain tumor. Current standard-of-care results in a marginal therapeutic outcome, partly due to acquirement of resistance and insufficient blood-brain barrier (BBB) penetration of chemotherapeutics. To circumvent these limitations, we conjugated the chemotherapy paclitaxel (PTX) to a dendritic polyglycerol sulfate (dPGS) nanocarrier. dPGS is able to cross the BBB, bind to P/L-selectins and accumulate selectively in intracranial tumors. We show that dPGS has dual targeting properties, as we found that P-selectin is not only expressed on tumor endothelium but also on glioblastoma cells. We delivered dPGS-PTX in combination with a peptidomimetic of the anti-angiogenic protein thrombospondin-1 (TSP-1 PM). This combination resulted in a remarkable synergistic anticancer effect on intracranial human and murine glioblastoma via induction of Fas and Fas-L, with no side effects compared to free PTX or temozolomide. This study shows that our unique therapeutic approach offers a viable alternative for the treatment of glioblastoma.

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Section: Discussionmentioning

confidence: 99%

Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome

Ferber

Tiram

Sousa-Hervés

et al. 2017

eLife

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“…Melanoma lung metastases were decreased by an E-selectin-targeted polymer–drug conjugates. In this study, an E-selectin binding peptide was conjugated with N -(2-hydroxylpropyl) methacrylamide and equipped with doxorubicin or a proapoptotic peptide that can be released at mild pH conditions ( 108 ). The copolymer effectively decreased melanoma lungs metastases and significantly improved mice survival.…”

Section: Targeting the Selectins And Their Ligandsmentioning

confidence: 99%

Targeting Selectins and Their Ligands in Cancer

2016

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Aberrant glycosylation is a hallmark of cancer cells with increased evidence pointing to a role in tumor progression. In particular, aberrant sialylation of glycoproteins and glycolipids has been linked to increased immune cell evasion, drug evasion, drug resistance, tumor invasiveness, and vascular dissemination, leading to metastases. Hypersialylation of cancer cells is largely the result of overexpression of sialyltransferases (STs). Differentially, humans express twenty different STs in a tissue-specific manner, each of which catalyzes the attachment of sialic acids via different glycosidic linkages (α2-3, α2-6, or α2-8) to the underlying glycan chain. One important mechanism whereby overexpression of STs contributes to an enhanced metastatic phenotype is via the generation of selectin ligands. Selectin ligand function requires the expression of sialyl-Lewis X and its structural isomer sialyl-Lewis A, which are synthesized by the combined action of alpha α1-3-fucosyltransferases, α2-3-sialyltransferases, β1-4-galactosyltranferases, and N-acetyl-β-glucosaminyltransferases. The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these STs have been linked to increased risk of metastatic disease in solid tumors and poor outcome in multiple myeloma. Thus, targeting selectins and their ligands as well as the enzymes involved in their generation, in particular STs, could be beneficial to many cancer patients. Potential strategies include ST inhibition and the use of selectin antagonists, such as glycomimetic drugs and antibodies. Here, we review ongoing efforts to optimize the potency and selectivity of ST inhibitors, including the potential for targeted delivery approaches, as well as evaluate the potential utility of selectin inhibitors, which are now in early clinical development.

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“…The Esbp peptide (DITWDQLWDLMK) binds E‐selectin with high affinity, which can also be employed as a vascular‐targeted E‐selectin‐binding peptide . Shamay et al synthesized N ‐(2‐hydroxypropyl)methacrylamide copolymers, and conjugated them with an E‐selectin binding peptide (Esbp, DITWDQLWDLMK) and equipped them with the chemotherapeutic drug doxorubicin (P‐(Esbp)‐doxorubicin (DOX)) or with the proapoptotic peptide D(KLAKLAK)2 (P‐(Esbp)‐KLAK). This prodrug polymer formed drug‐loaded nanoparticles with targeting of the tumor vasculature.…”

Section: Targeting Peptidesmentioning

confidence: 99%

Section: Targeting Peptidesmentioning

confidence: 99%

Peptide‐Based Nanocarriers for Cancer Therapy

et al. 2018

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Chemotherapy is one of the main means for cancer treatment. Because of the capability of alleviating the side effects of drugs and improving the therapeutic effect, nanoparticle-based drugdelivery systems have played a significant role in this area. Due to the EPR effect, self-assembled peptide-based NPs can penetrate leaky tumor vasculature, [27] enhance the intracellular Peptides, which are made up of amino acids, are an excellent candidate as a composition component of a nanocarrier for drug delivery due to their biocompatibility, bioavailability, and stability in vivo. Here, the progress in peptides as nanocarriers for applications in cancer therapy are summarized, including as a nanocarrier matrix for self-assembled nanoparticles, as surface modification moieties of nanocarriers for targeting and/or penetrating function, and as enzyme-responsive linkers of nanoparticles for triggering drug release. Peptide-based nanocarriers should receive more attention, and they have great potential in biomedical applications.

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Inhibition of primary and metastatic tumors in mice by E-selectin-targeted polymer–drug conjugates

Cited by 38 publications

References 44 publications

Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome

Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome

Targeting Selectins and Their Ligands in Cancer

Peptide‐Based Nanocarriers for Cancer Therapy

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