An orally delivered small-molecule formulation with antiangiogenic and anticancer activity

Benny, Ofra; Fainaru, Ofer; Adini, Avner; Cassiola, Flávia; Bazinet, Lauren; Adini, Irit; Pravda, Elke; Nahmias, Yaakov; Koirala, Samir; Corfas, Gabriel; D’Amato, Robert J.; Folkman, Judah

doi:10.1038/nbt1415

Cited by 165 publications

(135 citation statements)

References 30 publications

(18 reference statements)

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“…At present, efficient drugs for treatment of gliomas are very limited (1). A hallmark of current cancer treatment is inhibition of tumor angiogenesis (2,3). Antiangiogenic inhibitors of VEGF receptors and VEGF-independent inhibitors combined with chemotherapy have shown some promise, but the patients' survival in clinical trials was not significantly changed (4).…”

Section: Inhibition Of Brain Tumor Growth By Intravenous Poly (β-L-mamentioning

confidence: 99%

“…Polymer conjugates introduce other possibilities to treat cancers by targeting specific tumor markers and providing precise inhibitor delivery to the tumor with minimum side effects (3,14,15). The endocytosed carriers, including polymers, are routed to the endosomal pathway, and their design must ensure the drug escape from the endosomes into the cytoplasm to avoid lysosomal degradation.…”

Section: Inhibition Of Brain Tumor Growth By Intravenous Poly (β-L-mamentioning

confidence: 99%

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Inhibition of brain tumor growth by intravenous poly(β- l -malic acid) nanobioconjugate with pH-dependent drug release

Inoue

Ljubimov

Patil

et al. 2010

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

160

180

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Effective treatment of brain neurological disorders such as Alzheimer's disease, multiple sclerosis, or tumors should be possible with drug delivery through blood–brain barrier (BBB) or blood–brain tumor barrier (BTB) and targeting specific types of brain cells with drug release into the cell cytoplasm. A polymeric nanobioconjugate drug based on biodegradable, nontoxic, and nonimmunogenic polymalic acid as a universal delivery nanoplatform was used for design and synthesis of nanomedicine drug for i.v. treatment of brain tumors. The polymeric drug passes through the BTB and tumor cell membrane using tandem monoclonal antibodies targeting the BTB and tumor cells. The next step for polymeric drug action was inhibition of tumor angiogenesis by specifically blocking the synthesis of a tumor neovascular trimer protein, laminin-411, by attached antisense oligonucleotides (AONs). The AONs were released into the target cell cytoplasm via pH-activated trileucine, an endosomal escape moiety. Drug delivery to the brain tumor and the release mechanism were both studied for this nanobiopolymer. Introduction of a trileucine endosome escape unit resulted in significantly increased AON delivery to tumor cells, inhibition of laminin-411 synthesis in vitro and in vivo, specific accumulation in brain tumors, and suppression of intracranial glioma growth compared with pH-independent leucine ester. The availability of a systemically active polymeric drug delivery system that passes through the BTB, targets tumor cells, and inhibits glioma growth gives hope for a successful strategy of glioma treatment. This delivery system with drug release into the brain-specific cell type could be useful for treatment of various brain pathologies.

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Section: Inhibition Of Brain Tumor Growth By Intravenous Poly (β-L-mamentioning

confidence: 99%

Section: Inhibition Of Brain Tumor Growth By Intravenous Poly (β-L-mamentioning

confidence: 99%

Inhibition of brain tumor growth by intravenous poly(β- l -malic acid) nanobioconjugate with pH-dependent drug release

Inoue

Ljubimov

Patil

et al. 2010

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

160

180

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“…increase the membrane permeability to the drug and/or to the carrier has been also reported (Benny et al, 2008;Gaucher et al, 2010;Mathot et al, 2007).…”

Section: In Vivo Experimentsmentioning

confidence: 77%

“…This fact could be explained considering both the increased effect on bioavailability due to entrapment into polymeric colloidal carriers and also their potential absorption towards the gastro-intestinal mucosa (Benny et al, 2008;Gaucher et al, 2010;Mathot et al, 2007;Roger et al, 2010).…”

Section: In Vivo Experimentsmentioning

confidence: 99%

Galactosylated polymeric carriers for liver targeting of sorafenib

Craparo

Sardo

Serio

et al. 2014

International Journal of Pharmaceutics

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“…For example, NPs have been used for in vivo tumor detection and targeting (16) and for the delivery of antiangiogenic compounds (17). NPs have also been used to induce pathogen-specific immunity in vaccination regimens (18,19).…”

Section: Ultiple Sclerosis (Ms) Is An Autoimmune Disease Driven Bymentioning

confidence: 99%

Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis

Yeste

Nadeau²,

Burns³

et al. 2012

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

267

277

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The immune response is normally controlled by regulatory T cells (Tregs). However, Treg deficits are found in autoimmune diseases, and therefore the induction of functional Tregs is considered a potential therapeutic approach for autoimmune disorders. The activation of the ligand-activated transcription factor aryl hydrocarbon receptor by 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) or other ligands induces dendritic cells (DCs) that promote FoxP3 + Treg differentiation. Here we report the use of nanoparticles (NPs) to coadminister ITE and a T-cell epitope from myelin oligodendrocyte glycoprotein (MOG) M ultiple sclerosis (MS) is an autoimmune disease driven by an immune response directed against antigens in the CNS (1). The autoreactive components of the immune system are normally under the control of specialized regulatory T cells (Tregs); of particular importance are FoxP3 + (2) and IL-10 + Tregs (3). Treg deficits have been found in MS and other autoimmune diseases (4, 5). Conversely, Tregs have been shown to arrest the development of several experimental models of autoimmune disease (5). Thus, the induction of antigen-specific tolerance is considered a promising approach for the treatment of MS and other autoimmune disorders (6).As a result of our studies on immunoregulation in the zebrafish (7), we found that the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) controls the differentiation of FoxP3 + and IL-10 + Tregs and Th17 cells in mice and humans (8)(9)(10)(11)(12). AhR activation with the nontoxic mucosal ligand 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) expands Tregs and suppresses EAE (11). We (11) and others (13)(14)(15) showed that the generation of Tregs by AhR ligands involves the induction of tolerogenic dendritic cells (DCs). Indeed, the activation of AhR signaling in DCs by ITE or other ligands induces DCs that promote FoxP3 + Treg differentiation (11,(13)(14)(15). Nanoparticles (NPs) have unique features that prompted their use in medicine. For example, NPs have been used for in vivo tumor detection and targeting (16) and for the delivery of antiangiogenic compounds (17). NPs have also been used to induce pathogen-specific immunity in vaccination regimens (18,19). In the context of the therapeutic management of inflammation, NPs have been recently used to deliver siRNAs to silence ccr2 expression and prevent the accumulation of inflammatory monocytes at sites of inflammation (20). However, the use of NPs to induce antigen-specific tolerance and treat autoimmune disorders remains largely unexplored.In this work, we report the use of NPs to coadminister ITE and the T-cell epitope from myelin oligodendrocyte protein located between residues 35 and 55 to promote the generation of CNSspecific Tregs by DCs. NP-treated DCs displayed a tolerogenic phenotype and promoted the differentiation of Tregs. Moreover, NPs carrying ITE and a peptide corresponding to residues 35-55 of the myelin oligodendrocyte glycoprotein ) ex...

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An orally delivered small-molecule formulation with antiangiogenic and anticancer activity

Cited by 165 publications

References 30 publications

Inhibition of brain tumor growth by intravenous poly(β- l -malic acid) nanobioconjugate with pH-dependent drug release

Inhibition of brain tumor growth by intravenous poly(β- l -malic acid) nanobioconjugate with pH-dependent drug release

Galactosylated polymeric carriers for liver targeting of sorafenib

Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis

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