Triazine Dendrimers as Nonviral Vectors for in Vitro and in Vivo RNAi: The Effects of Peripheral Groups and Core Structure on Biological Activity

Merkel, Olivia M.; Mintzer, Meredith A.; Librizzi, Damiano; Samsonova, Olga; Dicke, Tanja; Sproat, Brian S.; Garn, Holger; Barth, Peter; Simanek, Eric E.; Kissel, Thomas

doi:10.1021/mp100101s

Cited by 93 publications

(119 citation statements)

References 49 publications

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“…Like most cationic polymer-based siRNA delivery systems (5)(6)(7)(8)(9), the siRNA/CDP nanoparticle is rapidly eliminated from circulation (shown in mice, monkeys, and humans) (10)(11)(12). In fact, polymer complexation often does not extend the circulation time of siRNA.…”

Section: Pharmacokinetics | Glomerulusmentioning

confidence: 99%

Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane

Zuckerman

Choi²,

Han³

et al. 2012

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

324

269

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Despite being engineered to avoid renal clearance, many cationic polymer (polycation)-based siRNA nanoparticles that are used for systemic delivery are rapidly eliminated from the circulation. Here, we show that a component of the renal filtration barrier-the glomerular basement membrane (GBM)-can disassemble cationic cyclodextrin-containing polymer (CDP)-based siRNA nanoparticles and, thereby, facilitate their rapid elimination from circulation. Using confocal and electron microscopies, positron emission tomography, and compartment modeling, we demonstrate that siRNA nanoparticles, but not free siRNA, accumulate and disassemble in the GBM. We also confirm that the siRNA nanoparticles do not disassemble in blood plasma in vitro and in vivo. This clearance mechanism may affect any nanoparticles that assemble primarily by electrostatic interactions between cationic delivery components and anionic nucleic acids (or other therapeutic entities). pharmacokinetics | glomerulusA major challenge with the use of small interfering RNA (siRNA) in mammals is their delivery to intracellular locations in specific tissues (1). The two most investigated approaches to siRNA delivery involve the combination of siRNA with cationic lipids (lipoplexes, liposomes, micelles) or cationic polymers (polyplexes) (2). Polymer-based siRNA delivery vehicles can be tuned to be nonimmunogenic, nononcogenic, nontoxic, and targeted (3). A targeted nanoparticle formulation of siRNA (not chemically modified) with a cationic, cyclodextrin-containing polymer (CDP)-based delivery vehicle (clinical version denoted CALAA-01) was shown to accumulate in human tumors and deliver functional siRNA from a systemic, i.v. infusion (4). This first-in-human study demonstrated the clinical potential for cationic polymerbased siRNA delivery systems.Like most cationic polymer-based siRNA delivery systems (5-9), the siRNA/CDP nanoparticle is rapidly eliminated from circulation (shown in mice, monkeys, and humans) (10-12). In fact, polymer complexation often does not extend the circulation time of siRNA. The rapid clearance of these siRNA nanoparticles is puzzling because they are engineered to be above the size cutoff for single-pass clearance via renal filtration (13). In understanding the mechanism behind the rapid clearance of this type of cancer therapeutic, we can efficiently seek ways to increase their circulation time and, thus, enhance their anticancer efficacy (3).We hypothesize that the paradoxical renal clearance of polycation-nucleic acid nanoparticles results from their binding and disassembly by components of the renal filtration barrier. Three key properties of such nanoparticles (diameters between 10 and 100 nm, positive zeta potentials, and electrostatically driven selfassembly) make them susceptible to this mechanism of clearance.The renal filtration barrier, located within the glomerulus of the nephron, consists of three layers that must be traversed to enter the urinary space. These three layers are the glomerular endothelial fenestrations (≈100 n...

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Section: Pharmacokinetics | Glomerulusmentioning

confidence: 99%

Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane

Zuckerman

Choi²,

Han³

et al. 2012

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

324

269

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“…Each sample was measured in 5 runs. For both measurements, N/P ratios of 5, 10, 15, and 20 were tested and analyzed with the Zetasizer Nano ZS Software 6.20 (Malvern, Herrenberg, Germany) as reported previously [37].…”

Section: Hydrodynamic Diameter and Zeta-potential Of Pdna-polymer Commentioning

confidence: 99%

Low Molecular Weight pDMAEMA-block-pHEMA Block-Copolymers Synthesized via RAFT-Polymerization: Potential Non-Viral Gene Delivery Agents?

et al. 2011

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Abstract:The aim of this study was to investigate non-viral pDNA carriers based on diblock-copolymers consisting of poly(2-(dimethyl amino)ethyl methacrylate) (pDMAEMA) and poly(2-hydroxyethyl methacrylate) (pHEMA). Specifically the block-lengths and molecular weights were varied to determine the minimal requirements for transfection. Such vectors should allow better transfection at acceptable toxicity levels and the entire diblock-copolymer should be suitable for renal clearance. For this purpose, a library of linear poly(2-(dimethyl amino)ethyl methacrylate-block-poly(2-hydroxyl methacrylate) (pDMAEMA-block-pHEMA) copolymers was synthesized via RAFT (reversible additionfragmentation chain transfer) polymerization in a molecular weight (Mw) range of 17-35.7 kDa and analyzed using 1 H and 13 C NMR (nuclear magnetic resonance), ATR (attenuated total reflectance), GPC (gel permeation chromatography) and DSC (differential scanning calorimetry). Copolymers possessing short pDMAEMA-polycation chains were 1.4-9.7 times less toxic in vitro than polyethylenimine (PEI) 25 kDa, and complexed DNA into polyplexes of 100-170 nm, favorable for cellular uptake. The DNA-binding affinity and polyplex stability against competing polyanions was comparable with OPEN ACCESSPolymers 2011, 3 694 PEI 25 kDa. The zeta-potential of polyplexes of pDMAEMA-grafted copolymers remained positive (+15-30 mV). In comparison with earlier reported low molecular weight homo pDMAEMA vectors, these diblock-copolymers showed enhanced transfection efficacy under in vitro conditions due to their lower cytotoxicity, efficient cellular uptake and DNA packaging. The homo pDMAEMA 115 (18.3 kDa) self-assembled with DNA into small positively charged polyplexes, but was not able to transfect cells. The grafting of 6 and 57 repeating units of pHEMA (0.8 and 7.4 kDa) to pDMAEMA 115 increased the transfection efficacy significantly, implying a crucial impact of pHEMA on vector-cell interactions. The intracellular trafficking, in vivo transfection efficacy and kinetics of low molecular weight pDMAEMA-block-pHEMA are subject of ongoing studies.

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“…However, because the drug is delivered to the site of action extremely rapidly with IV injection, there is a risk of overdose if the dose has been calculated incorrectly, and there is an increased risk of side effects if the drug is administered too rapidly. Numerous reports of IV administered dendrimer-drug complexes have appeared [85][86][87][88][89]. For example, 2'-(benzo[1,2-c] 1,2,5-oxadiazol-5(6)-yl(N 1 -oxide) methylidene)-1-methoxy methane hydrazide presents antichagasic activity but has low water solubility.…”

Section: Drug Delivery By Injectionmentioning

confidence: 99%

Polyester Dendrimers: Smart Carriers for Drug Delivery

Twibanire

Grindley

2014

Polymers

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Polyester dendrimers have been shown to be outstanding candidates for biomedical applications. Compared to traditional polymeric drug vehicles, these biodegradable dendrimers show excellent advantages especially as drug delivery systems because they are non-toxic. Here, advances on polyester dendrimers as smart carriers for drug delivery applications have been surveyed. Both covalent and non-covalent incorporation of drugs are discussed.

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Triazine Dendrimers as Nonviral Vectors for in Vitro and in Vivo RNAi: The Effects of Peripheral Groups and Core Structure on Biological Activity

Cited by 93 publications

References 49 publications

Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane

Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane

Low Molecular Weight pDMAEMA-block-pHEMA Block-Copolymers Synthesized via RAFT-Polymerization: Potential Non-Viral Gene Delivery Agents?

Polyester Dendrimers: Smart Carriers for Drug Delivery

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