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A Focused Library Approach to Discover Discrete Dipeptide Bolaamphiphiles for siRNA Delivery.
In this study, we report a new dipeptide functionalization strategy for developing new dendritic bolaamphiphile vectors for efficient siRNA transfection. A focused library of dipeptides was constructed using four amino acids: L-arginine, L-histidine, L-lysine and L-tryptophan. The dipeptides were coupled to two dendritic bolaamphiphile scaffolds that we developed previously, allowing us to quickly access a focused library of discrete vectors with multivalent dendritic dipeptide functionalities. The resulting discrete bolaamphiphiles were screened for siRNA delivery in vitro in HEK-293 and HeLa cells. Bolaamphiphiles functi...
Source: Biomacromolecules - August 25, 2016 Category: Biochemistry Authors: Eldredge AC, Johnson ME, Oldenhuis NJ, Guan Z Tags: Biomacromolecules Source Type: research

Structure-function correlation of aminated poly(α)glutamate as siRNA nanocarriers.
Abstract It has been two decades since cationic polymers were introduced to the world of oligonucleotides delivery. However, the optimal physico-chemical properties to make them a successful delivery vehicle are yet unknown. An ideal system became particularly interesting and necessary with the introduction of RNA interference as a promising therapeutic approach. Such nanocarrier should overcome challenges such as low plasma stability, poor cellular internalization and endosomal escape to induce gene silencing. To that end, we synthesized a library of biodegradable aminated poly(α)glutamate varied by amine moieti...
Source: Biomacromolecules - July 4, 2016 Category: Biochemistry Authors: Krivitsky A, Polyak D, Scomparin A, Eliyahu S, Ori A, Avkin Nachum S, Krivitsky V, Satchi-Fainaro R Tags: Biomacromolecules Source Type: research

A rationally optimized nanoparticle system for the delivery of RNA interference therapeutics into pancreatic tumors in vivo.
Abstract Pancreatic cancer is a devastating disease with a dismal prognosis. Short-interfering RNA (siRNA) based therapeutics hold promise for the treatment of cancer. However, development of efficient and safe delivery vehicles for siRNA remains a challenge. Here, we describe the synthesis and physicochemical characterization of star polymers (star 1, star 2, star 3) using reversible addition-fragmentation chain transfer polymerization (RAFT) for the delivery of siRNA to pancreatic cancer cells. These star polymers were designed to contain different lengths of cationic poly(dimethylaminoethyl methacrylate) (PDMAE...
Source: Biomacromolecules - June 14, 2016 Category: Biochemistry Authors: Teo J, McCarroll JA, Boyer C, Youkhana J, Sagnella SM, Duong HT, Liu J, Sharbeen G, Goldstein D, Davis TP, Kavallaris M, Phillips PA Tags: Biomacromolecules Source Type: research

Improvements in rational design strategies of inulin derivative polycation for sirna delivery.
IMPROVEMENTS IN RATIONAL DESIGN STRATEGIES OF INULIN DERIVATIVE POLYCATION FOR SIRNA DELIVERY. Biomacromolecules. 2016 May 29; Authors: Sardo C, Craparo EF, Porsio B, Giammona G, Cavallaro G Abstract The advances of short interfering RNA (siRNA) mediated therapy provide a powerful option for the treatment of many diseases, including cancer, by silencing the expression of targeted genes involved in the progression of the pathology. On this regard, a new pH-responsive polycation derived from inulin, Inulin-g-imidazole-g-diethylenetriamine (INU-IMI-DETA), was designed and employed to produce INU-IMI-DETA...
Source: Biomacromolecules - May 28, 2016 Category: Biochemistry Authors: Sardo C, Craparo EF, Porsio B, Giammona G, Cavallaro G Tags: Biomacromolecules Source Type: research

Optimal Hydrophobicity in ROMP-based Protein Mimics Required for siRNA Internalization.
Abstract Exploring the role of polymer structure for the internalization of biologically relevant cargo, specifically siRNA, is of critical importance to the development of improved delivery reagents. Herein, we report guanidinium-rich protein transduction domain mimics (PTDMs) based on a ring-opening metathesis polymerization scaffold containing tunable hydrophobic moieties that promote siRNA internalization. Structure-activity relationships using Jurkat T cells and HeLa cells were explored to determine how the length of the hydrophobic block and the hydrophobic side chain compositions of these PTDMs impacted siR...
Source: Biomacromolecules - April 20, 2016 Category: Biochemistry Authors: deRonde BM, Posey ND, Otter R, Caffrey LM, Minter LM, Tew GN Tags: Biomacromolecules Source Type: research

Enzyme- and pH-responsive microencapsulated nanogels for oral delivery of siRNA to induce TNF-α knockdown in the intestine.
Abstract Inflammatory bowel diseases (IBD) manifest from excessive intestinal inflammation. Local delivery of siRNA that targets these inflammatory cytokines would provide a novel treatment approach. Microencapsulated nanogels are designed and validated as platforms for oral delivery of siRNA targeting TNF-α, a common clinical target of IBD treatments. The preferred platform was designed to (i) protect siRNA-loaded nanogels from the harsh acidic environment of the upper GI tract; and (ii) enzymatically degrade and release the nanogels once the carrier has reached the intestinal region. This platform consists of m...
Source: Biomacromolecules - January 26, 2016 Category: Biochemistry Authors: Knipe JM, Strong LE, Peppas NA Tags: Biomacromolecules Source Type: research

Folate Receptor Targeted Delivery of siRNA and Paclitaxel to Ovarian Cancer Cells via Folate Conjugated Triblock Co-polymer to Overcome TLR4 Driven Chemotherapy Resistance.
This study demonstrates that PEI-g-PCL-b-PEG-Fol conjugates are a reliable delivery system for siRNA and are able to mediate therapeutic protein knockdown within ovarian cancer cells. Additionally, this study provides further evidence to link TLR4 levels to chemotherapy resistance. PMID: 26636884 [PubMed - as supplied by publisher]
Source: Biomacromolecules - December 4, 2015 Category: Biochemistry Authors: Jones SK, Lizzio V, Merkel O Tags: Biomacromolecules Source Type: research

siRNA-Loaded Polyion Complex Micelle Decorated with Charge-Conversional Polymer Tuned to Undergo Stepwise Response to Intra-Tumoral and Intra-Endosomal pHs for Exerting Enhanced RNAi Efficacy.
This study aimed to develop an siRNA-loaded polyion complex (PIC) micelle equipped with a smart polymeric shell featuring tumor-targetability and endosome-escapability for enhanced RNAi activity in cancer cells. To this end, an acidic pH-responsive polypeptide was designed to exert a stepwise change in its charged state from negative to modestly positive and highly positive in response to slightly acidic environment of tumor (pH ~6.7) and further lowered-pH condition of late endosomal compartments (pH ~5.0), respectively, for selective binding to cancer cell surface and subsequent endosome disruption. This polypeptide, ter...
Source: Biomacromolecules - November 30, 2015 Category: Biochemistry Authors: Tangsangasaksri M, Takemoto H, Naito M, Maeda Y, Sueyoshi D, Kim HJ, Miura Y, Ahn J, Azuma R, Nishiyama N, Miyata K, Kataoka K Tags: Biomacromolecules Source Type: research

Amino Acid Functionalized Dendritic Polyglycerol for Safe and Effective siRNA Delivery.
In this study, we aimed to develop new synthetic transfection agents based on dendritic polyglycercol (dPG), which has shown great biocompatibility in several biomaterial applications. Histidine and aromatic amino acids were conjugated to the amine-terminated dPGs through amide bond. We systematically tuned the amino acids combination, functionalization ratio, ligand density and dPG core size to find optimal vectors. It was found that histidine-tryptophan functionalized dPGs exhibited improved delivery efficiency and greatly reduced toxicity over simple amine-terminated dPGs. Furthermore, the optimized vectors exhibited st...
Source: Biomacromolecules - November 16, 2015 Category: Biochemistry Authors: Zeng H, Schlesener C, Cromwell OR, Hellmund M, Haag R, Guan Z Tags: Biomacromolecules Source Type: research

Phosphonium polymethacrylates for siRNA delivery: effect of polymer and RNA structural parameters on polyplex assembly and gene knockdown.
Abstract Synthetic polymers containing quaternary phosphonium salts are an emerging class of materials for the delivery of oligo/polynucleotides. In this work, cationic phosphonium salt-containing polymethacrylates -and their corresponding ammonium analogues- were synthesized by RAFT polymerization. Both the nature of the charged heteroatom (N vs. P) and the length of the spacer separating the cationic units along the polymer backbone (oxyethylene vs. trioxyethylene) were systematically varied. Polymers efficiently bound siRNA at N+/P- or P+/P- ratios of 2 and above. At a 20:1 ratio, small polyplexes (Rh: 4-15 nm)...
Source: Biomacromolecules - September 23, 2015 Category: Biochemistry Authors: Loczenski Rose V, Shubber S, Sajeesh S, Spain SG, Puri S, Allen S, Lee DK, Winkler GS, Mantovani G Tags: Biomacromolecules Source Type: research

Development of Guanidinium-rich Protein Mimics for Efficient siRNA Delivery into Human T Cells.
Abstract RNA interference is gaining attention as a means to explore new molecular pathways and for its potential as a therapeutic; however, its application in immortal and primary T cells is limited due to challenges with efficient delivery in these cells types. Herein, we report the development of guanidinium-rich protein transduction domain mimics (PTDMs) based on a ring-opening metathesis polymerization scaffold that delivers siRNA into Jurkat T cells and human peripheral blood mononuclear cells (hPBMCs). Homopolymer and block copolymer PTDMs with varying numbers of guanidinium moieties were designed and teste...
Source: Biomacromolecules - August 31, 2015 Category: Biochemistry Authors: deRonde BM, Torres JA, Minter LM, Tew GN Tags: Biomacromolecules Source Type: research

Redox-Sensitive PEG-Polypeptide Nanoporous Particles for Survivin Silencing in Prostate Cancer Cells.
We report the engineering of intracellular redox-responsive nanoporous poly(ethylene glycol)-poly(l-lysine) particles (NPEG-PLLs). The obtained particles exhibit no toxicity while maintaining the capability to deliver a small interfering RNA sequence (siRNA) targeting the anti-apoptotic factor, survivin, in prostate cancer cells. The redox-mediated cleavage of the disulfide bonds stabilizing the NPEG-PLL-siRNA complex results in the release of bioactive siRNA into the cytosol of prostate cancer PC-3 cells, which, in turn, leads to the effective silencing (∼59 ± 8%) of the target gene. These findings, obtained under opti...
Source: Biomacromolecules - June 29, 2015 Category: Biochemistry Authors: Cavalieri F, Beretta GL, Cui J, Braunger JA, Yan Y, Richardson JJ, Tinelli S, Folini M, Zaffaroni N, Caruso F Tags: Biomacromolecules Source Type: research

Triblock copolymer nanovesicles for pH-responsive targeted delivery and controlled release of siRNA to cancer cells.
Abstract New pH-responsive polymersomes for active anticancer oligonucleotide delivery were prepared from triblock copolymers. The delivery systems were formed by two terminal hydrophilic blocks, PEG and poly-glycerolmethacrylate (poly-GMA), and a central weakly-basic block, poly-imidazole-hexyl methacrylate (poly-ImHeMA), which can complex with oligonucleotides and control vesicle formation/disassembly via pH variations. Targeted polymersomes were prepared by mixing folate-derivatised and underivatised copolymers. At pH 5, ds-DNA was found to complex with the pH-responsive copolymers at a N/P molar ratio above ~2...
Source: Biomacromolecules - May 19, 2015 Category: Biochemistry Authors: Gallon E, Matini T, Sasso L, Mantovani G, Armiñan de Benito A, Sanchis J, Caliceti P, Alexander C, Vicent MJ, Salmaso S Tags: Biomacromolecules Source Type: research

EpCAM-Antibody-Labeled Noncytotoxic Polymer Vesicles for Cancer Stem Cells-Targeted Delivery of Anticancer Drug and siRNA.
Abstract Cancer stem cells (CSCs) have the capability to initiate tumor, to sustain tumor growth, to maintain the heterogeneity of tumor, and are closely linked to the failure of chemotherapy due to their self-renewal and multilineage differentiation capability with an innate resistance to cytotoxic agents. Herein, we designed and synthesized a novel anti-EpCAM (epithelial cell adhesion molecule)-monoclonal-antibody-labeled CSCs-targeting, noncytotoxic and pH-sensitive block copolymer vesicle as a nano-carrier of anticancer drug and siRNA (to overcome CSCs drug resistance by silencing the expression of oncogenes)....
Source: Biomacromolecules - May 19, 2015 Category: Biochemistry Authors: Chen J, Liu Q, Xiao J, Du J Tags: Biomacromolecules Source Type: research

A biodegradable stearylated peptide with internal disulfide bonds for efficient delivery of siRNA in vitro and in vivo.
In this study, a stearyl-peptide (SHR) was synthesized using arginine, histidine, cysteine and stearyl moiety. Further, the stearyl-peptides were cross linked by disulfide bonds to obtain cross-linked polypeptides (SHRss) with different molecular weight (SHRss1, SHRss2, SHRss3, SHRss4). The SHRss could effectively condense small interfering RNA (siRNA) into polyplexes with a hydrodynamic size of 100-300 nm and zeta potential of 20-40 mV. Flow cytometry and confocal laser scanning microscope studies revealed high cellular uptake and rapid dissociation behavior of SHRss2/siRNA complexes. Long-lasting high concentration of si...
Source: Biomacromolecules - February 16, 2015 Category: Biochemistry Authors: Tai Z, Wang X, Tian J, Gao Y, Zhang L, Yao C, Wu X, Zhang W, Zhu Q, Gao S Tags: Biomacromolecules Source Type: research

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