Imidazole groups on a linear, cyclodextrin-containing polycation produce enhanced gene delivery via multiple processes

Mishra, Swaroop; Heidel, Jeremy D.; Webster, Paul; Davis, Mark E.

doi:10.1016/j.jconrel.2006.06.018

Cited by 102 publications

(67 citation statements)

References 39 publications

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“…S3 A and B), consistent in morphology with unpackaging nanoparticles within endosomes (20). These data are consistent with the results from our confocal microscopy study, where we observed some nonglomerular renal vessels with appreciable fluorescence signal in their walls in tissue from mice receiving siRNA nanoparticle treatment.…”

Section: Nanoparticle Components Remain Assembled In Vivo and Willsupporting

confidence: 91%

“…HS is a major constituent of the GBM and is responsible for its negative charge (15). HS is known to disassemble nucleic acid-containing, cationic polymer polyplexes (20). We confirmed that HS (extracted from bovine kidney) released siRNA from the nanoparticle at charge ratios (HS/CDP) above ±0.8 in 50% mouse plasma, whereas plasma alone could not (Fig.…”

Section: Nanoparticle Components Remain Assembled In Vivo and Willsupporting

confidence: 66%

“…We examined kidney tissue from mice 10 min after receiving free siRNA or siRNA nanoparticles because at this time point we observed maximal glomerular siRNA signals in both PET and confocal microscopy studies. We used uranyl acetate to detect the presence of nucleic acid nanoparticles in tissue sections because it preferentially binds to nucleic acids, including the siRNA within the nanoparticles (4,20).…”

Section: Nanoparticle Components Remain Assembled In Vivo and Willmentioning

confidence: 99%

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

Zuckerman

Choi²,

Han³

et al. 2012

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

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305

266

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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: Nanoparticle Components Remain Assembled In Vivo and Willsupporting

confidence: 91%

Section: Nanoparticle Components Remain Assembled In Vivo and Willsupporting

confidence: 66%

Section: Nanoparticle Components Remain Assembled In Vivo and Willmentioning

confidence: 99%

See 1 more Smart Citation

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

Zuckerman

Choi²,

Han³

et al. 2012

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

Self Cite

305

266

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“…Davis et al synthesized an α-cationic cyclodextrin polymer by copolymerization of 6A, 6D-dideoxy-6A, 6D-di(2-aminoethanethio)-β-cyclodextrin [69]. This type of compound was used for DNA and siRNA transfection, as well as for the targeting and imaging of tumors after IV [70]. The capacity to include hydrophobic molecules, such as adamantine, in the hydrophobic cavity of cyclodrextrin can be exploited to decorate CDplexes with adamantyl derivatives in order to: (i) generate stealth when used in conjunction with adamantyl-PEG; or (ii) cell specificity when used with adamantyl-ligands.…”

Section: Development Of Cyclodextrins For Use In Gene Delivery Systemsmentioning

confidence: 99%

Synthetic vectors for gene delivery: An overview of their evolution depending on routes of administration.

Belmadi

Midoux

Loyer

et al. 2015

Biotechnology Journal

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Nucleic acid delivery constitutes an emerging therapeutic strategy to cure various human pathologies. This therapy consists of introducing genetic material into the whole body or isolated cells to correct a cellular abnormality or disfunction. As with any drug, the main objective of nucleic acid delivery is to establish optimal balance between efficacy and tolerance. The methods of administration and the vectors used are selected depending on whether the goal of treatment is the production of an active protein; the replacement of a missing or inactive gene; or the combat of acquired diseases, such as cancer or AIDS. In that sense, synthetic vectors represent a valuable solution because they are well characterized, their structure can be fine tuned, and their potential toxicity can be reduced, since toxicity depends on the composition of the formulations. Here we review various synthetic vectors for gene delivery and address the question of their biodistribution as a function of the route of administration. We highlight the modifications to vectors structure and formulations necessary to overcome the major hurdles limiting the effectiveness of nucleic acid therapies.

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“…Interestingly, the delivery of siRNA via the cyclodextrin polycation system developed in our laboratory at the California Institute of Technology did not produce immune stimulation in mice, even when the siRNA contained a highly stimulatory base sequence motif (19). Possible reasons for the lack of immune stimulation include endosomal buffering by this delivery system (20,21) [inhibitors of endosomal acidification have been shown to block immune activation (16)] and lack of uptake by specific immunocompetent cell populations (this system does not enter CD34 ϩ progenitor cells; J.D.H. and J. J. Rossi, unpublished data).…”

mentioning

confidence: 97%

Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA

Heidel

Liu

et al. 2007

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

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227

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The results of administering escalating, i.v. doses of targeted nanoparticles containing a siRNA targeting the M2 subunit of ribonucleotide reductase to non-human primates are reported. The nanoparticles consist of a synthetic delivery system that uses a linear, cyclodextrin-containing polycation, transferrin (Tf) protein targeting ligand, and siRNA. When administered to cynomolgus monkeys at doses of 3 and 9 mg siRNA/kg, the nanoparticles are well tolerated. At 27 mg siRNA/kg, elevated levels of blood urea nitrogen and creatinine are observed that are indicative of kidney toxicity. Mild elevations in alanine amino transferase and aspartate transaminase at this dose level indicate that the liver is also affected to some extent. Analysis of complement factors does not reveal any changes that are clearly attributable to dosing with the nanoparticle formulation. Detection of increased IL-6 levels in all animals at 27 mg siRNA/kg and increased IFN-␥ in one animal indicate that this high dose level produces a mild immune response. Overall, no clinical signs of toxicity clearly attributable to treatment are observed. The multiple administrations spanning a period of 17-18 days enable assessment of antibody formation against the human Tf component of the formulation. Low titers of anti-Tf antibodies are detected, but this response is not associated with any manifestations of a hypersensitivity reaction upon readministration of the targeted nanoparticle. Taken together, the data presented show that multiple, systemic doses of targeted nanoparticles containing nonchemically modified siRNA can safely be administered to non-human primates.systemic administration ͉ RNA interference

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Imidazole groups on a linear, cyclodextrin-containing polycation produce enhanced gene delivery via multiple processes

Cited by 102 publications

References 39 publications

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

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

Synthetic vectors for gene delivery: An overview of their evolution depending on routes of administration.

Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA

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