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

Heidel, Jeremy D.; Yu, Zhongping; Liu, Joanna Yi-Ching; Rele, Shyam; Liang, Yongchao; Zeidan, Ryan K.; Kornbrust, Douglas J.; Davis, Mark E.

doi:10.1073/pnas.0701458104

Cited by 357 publications

(226 citation statements)

References 39 publications

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“…Additionally, other cationic polymer-based siRNA/nanoparticle systems have been shown to not elicit a pronounced immune response in vivo (18). Preclinical data characterizing the immune response to CALAA-01 dosing in monkeys has previously been reported (19). Elevated levels of IL-6 were observed at the highest dosing group (27 mg/kg).…”

Section: Mild Dose-dependent Elevations In Serum Cytokines Followingmentioning

confidence: 93%

Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA

Zuckerman

Gritli

Tolcher

et al. 2014

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

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320

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Nanoparticle-based experimental therapeutics are currently being investigated in numerous human clinical trials. CALAA-01 is a targeted, polymer-based nanoparticle containing small interfering RNA (siRNA) and, to our knowledge, was the first RNA interference (RNAi)-based, experimental therapeutic to be administered to cancer patients. Here, we report the results from the initial phase I clinical trial where 24 patients with different cancers were treated with CALAA-01 and compare those results to data obtained from multispecies animal studies to provide a detailed example of translating this class of nanoparticles from animals to humans. The pharmacokinetics of CALAA-01 in mice, rats, monkeys, and humans show fast elimination and reveal that the maximum concentration obtained in the blood after i.v. administration correlates with body weight across all species. The safety profile of CALAA-01 in animals is similarly obtained in humans except that animal kidney toxicities are not observed in humans; this could be due to the use of a predosing hydration protocol used in the clinic. Taken in total, the animal models do appear to predict the behavior of CALAA-01 in humans.translational medicine | DNA proliferation | DNA replication | maximum tolerance dose | dose limiting toxicity

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Section: Mild Dose-dependent Elevations In Serum Cytokines Followingmentioning

confidence: 93%

Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA

Zuckerman

Gritli

Tolcher

et al. 2014

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

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320

233

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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.

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304

260

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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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“…Chemically modified CDs have been already incorporated into polycationic polymers that can effectively complex and deliver plasmid DNA (pDNA) (20)(21). More recently, monodisperse polycationic CD conjugates with promising pDNA delivery capabilities were prepared by homogeneous functionalization of the CD primary rim (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Insights in cellular uptake mechanisms of pDNA–polycationic amphiphilic cyclodextrin nanoparticles (CDplexes)

Díaz‐Moscoso

Vercauteren

Rejman

et al. 2010

Journal of Controlled Release

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have equally contributed to the reported work. Abstr actIt is generally recognized that the major obstacle to efficient gene delivery is cellular internalization and endosomal escape of the DNA. Recently, we have developed a modular strategy for the preparation of well-defined polycationic amphiphilic cyclodextrins (paCDs) capable of complexing and compacting DNA into homogeneous nanoparticles (<70 nm).Since paCDs resemble both cationic polymers and cationic lipids, it is conceivable that the corresponding pDNA-paCD nanoparticles (CDplexes) might use the cell uptake and endosomal escape mechanisms described for both lipoplexes and polyplexes. To verify this hypothesis, we have now investigated the uptake and transfection efficiencies of CDplexes in the presence of several inhibitors of endocytosis, namely chlorpromazine, genistein, dynasore and methylated β-cyclodextrin (MbCD). Our data show that CDplexes obtained from paCD 1, which ranks among the most efficient paCD gene vectors reported up to date, are internalized by both clathrin-dependent (CDE) and clathrin-independent endocytosis (CIE), both processes being cholesterol-and dynamin-dependent. We observed that the largest fraction of gene complexes is taken up via CDE, but this fraction is less relevant for transfection. The smaller fraction that is internalized via the CIE pathway is predominantly responsible for successful transfection. Intr oductionThe successful delivery of therapeutic genes into cells and their availability at the intracellular site of action are crucial requirements for successful gene therapy. During the last decade, under the advent of nanotechnology, a broad diversity of creative materials featuring promising properties for nonviral gene delivery applications has emerged, (1). Cationic polymers and lipids, or their combinations, have shown the ability to bind nucleic acids through electrostatic interactions and condense them into complexes that can be readily internalized by cells (2-3). The gene delivering capabilities of many of these systems have been thoroughly investigated. Yet, drawing firm conclusions that might serve to provide feedback for the design of improved delivery entities is a delicate issue as a consequence of the essentially polydisperse nature of such structures (4).The control of the architecture of multifunctional macromolecules is a major determinant in the rational design of successful nonviral gene delivery systems. Novel 3 strategies have been implemented to build up well defined constructs featuring selfassembling capabilities in the presence of nucleic acids. In this context, the unique characteristics of dendrimers and other highly ordered clusters, such as uniformity, monodispersity and multivalency, have attracted increasing attention (5-8). Homogeneous external functionalization of these platforms becomes, however, exponentially more complicated as the dendrimer generation increases (9-10). The use of preorganized macrocyclic scaffolds, such as calixarenes, to achieve a precise alignment of functiona...

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

Cited by 357 publications

References 39 publications

Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA

Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA

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

Insights in cellular uptake mechanisms of pDNA–polycationic amphiphilic cyclodextrin nanoparticles (CDplexes)

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