Systemic delivery of siRNA by aminated poly(α)glutamate for the treatment of solid tumors

Polyak, Dina; Krivitsky, Adva; Scomparin, Anna; Eliyahu, Shay; Kalinski, Hagar; Avkin-Nachum, Sharon; Satchi‐Fainaro, Ronit

doi:10.1016/j.jconrel.2016.06.034

Cited by 24 publications

(30 citation statements)

References 52 publications

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“…In order to overcome these limitations of RNAi as anticancer treatment, several non-viral delivery systems have been developed, the majority of them based on a lipidic or polymeric scaffold 21 . Potential novel nanocarriers for the delivery of miRNA/siRNA are poly-(α)glutamic acid (PGA)-based 22 , 23 . PGA is a promising synthetic polymer with attractive properties: it is water-soluble, non-immunogenic and biodegradable by cathepsin B 24 , an enzyme that is highly expressed in most tumor tissues 25 .…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, PGA conjugated to the chemotherapeutic drug paclitaxel (OPAXIO) was shown to be safe at the required doses in clinical trials for the treatment of several cancer types 26 – 28 . We have recently synthesized a library of aminated polyglutamates for small oligonucleotides complexation 23 , out of which a fully aminated polyglutamate backbone was used in vivo for the treatment of ovarian cancer showing promising results 22 .…”

Section: Introductionmentioning

confidence: 99%

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Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer

et al. 2018

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The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies. Here we show a potent combination of microRNA and siRNA delivered by an efficient nanocarrier to PDAC tumors. Using proteomic-microRNA profiles and survival data of PDAC patients from TCGA, we found a novel signature for prolonged survival. Accordingly, we used a microRNA-mimic to increase miR-34a together with siRNA to silence PLK1 oncogene. For in vivo dual-targeting of this combination, we developed a biodegradable amphiphilic polyglutamate amine polymeric nanocarrier (APA). APA-miRNA–siRNA polyplexes systemically administered to orthotopically inoculated PDAC-bearing mice showed no toxicity and accumulated at the tumor, resulting in an enhanced antitumor effect due to inhibition of MYC oncogene, a common target of both miR-34a and PLK1. Taken together, our findings warrant this unique combined polyplex’s potential as a novel nanotherapeutic for PDAC.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer

et al. 2018

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“…For example, chemically synthesized siRNAs are most effectively introduced into cells using electroporation or commercially available lipid reagents, but these methods are poorly suited for in vivo delivery. Nevertheless, recent developments by independent teams have demonstrated the feasibility of systemic administration of either chemically modified or complexed AOs [9,55,56], holding promise for the translation of RNA-based gene knockdown therapies to the clinic. Different teams have been assessing different complexation methods with functional [57] and/or different vectors: exosomes [58] including lipid nanocarriers such as pegylated immunoliposomes (PILs; [59]), stable-nucleic-acid-lipid-particles (SNALPs; [60]), or polyhydroxyalkanoate-based nanovehicles [61].…”

Section: Discussionmentioning

confidence: 99%

Genetic Substrate Reduction Therapy: A Promising Approach for Lysosomal Storage Disorders

et al. 2016

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Abstract:Lysosomal storage diseases are a group of rare genetic disorders characterized by the accumulation of storage molecules in late endosomes/lysosomes. Most of them result from mutations in genes encoding for the catabolic enzymes that ensure intralysosomal digestion. Conventional therapeutic options include enzyme replacement therapy, an approach targeting the functional loss of the enzyme by injection of a recombinant one. Even though this is successful for some diseases, it is mostly effective for peripheral manifestations and has no impact on neuropathology. The development of alternative therapeutic approaches is, therefore, mandatory, and striking innovations including the clinical development of pharmacological chaperones and gene therapy are currently under evaluation. Most of them, however, have the same underlying rationale: an attempt to provide or enhance the activity of the missing enzyme to re-establish substrate metabolism to a level that is consistent with a lack of progression and/or return to health. Here, we will focus on the one approach which has a different underlying principle: substrate reduction therapy (SRT), whose uniqueness relies on the fact that it acts upstream of the enzymatic defect, decreasing storage by downregulating its biosynthetic pathway. Special attention will be given to the most recent advances in the field, introducing the concept of genetic SRT (gSRT), which is based on the use of RNA-degrading technologies (RNA interference and single stranded antisense oligonucleotides) to promote efficient substrate reduction by decreasing its synthesis rate.

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“…Solid tumors [107] Paclitaxel [108] Oligonucleotides [111,112] Camptothecin [110] Paclitaxel, Doxorubicin [109] Gly-Phe-Leu-Gly HPMA copolymer Paclitaxel Solid tumors [116] Gemcitabine [117] , Doxorubicin [118] Gemcitabine Paclitaxel His-Pro-Gly-Gly-Pro-Gln PEG Doxorubicin [126] Gly-Gly-Pro-Nle Pullulan Paclitaxel, Alendronate [125] Legumain Ala-Ala-Asn-Leu PEG Doxorubicin Solid tumor [131] Ala-Ala-Asn-Leu HA Doxorubicin [132] Matrix…”

Section: Matrix Metalloproteinases (Mmp)-cleavable Conjugatesmentioning

confidence: 99%

Two-step polymer- and liposome-enzyme prodrug therapies for cancer: PDEPT and PELT concepts and future perspectives

Scomparin

Florindo

Tiram

et al. 2017

Advanced Drug Delivery Reviews

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Polymer-directed enzyme prodrug therapy (PDEPT) and polymer enzyme liposome therapy (PELT) are two-step therapies developed to provide anticancer drugs site-selective intratumoral accumulation and release. Nanomedicines, such as polymer-drug conjugates and liposomal drugs, accumulate in the tumor site due to extravasation-dependent mechanism (enhanced permeability and retention - EPR - effect), and further need to cross the cellular membrane and release their payload in the intracellular compartment. The subsequent administration of a polymer-enzyme conjugate able to accumulate in the tumor tissue and to trigger the extracellular release of the active drug showed promising preclinical results. The development of polymer-enzyme, polymer-drug conjugates and liposomal drugs had undergone a vast advancement over the past decades. Several examples of enzyme mimics for in vivo therapy can be found in the literature. Moreover, polymer therapeutics often present an enzyme-sensitive mechanism of drug release. These nanomedicines can thus be optimal substrates for PDEPT and this review aims to provide new insights and stimuli toward the future perspectives of this promising combination.

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Systemic delivery of siRNA by aminated poly(α)glutamate for the treatment of solid tumors

Cited by 24 publications

References 52 publications

Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer

Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer

Genetic Substrate Reduction Therapy: A Promising Approach for Lysosomal Storage Disorders

Two-step polymer- and liposome-enzyme prodrug therapies for cancer: PDEPT and PELT concepts and future perspectives

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