Sticky Nanoparticles: A Platform for siRNA Delivery by a Bis(zinc(II) dipicolylamine)‐Functionalized, Self‐Assembled Nanoconjugate

Liu, Gang; Choi, Ki Young; Bhirde, Ashwinkumar; Swierczewska, Magdalena; Yin, Juan Juan; Lee, Sang Wook; Park, Jae Hyung; Hong, Jong Ha; Xie, Jin; Niu, Gang; Kiesewetter, Dale O.; Lee, Seulki; Chen, Xiaoyuan

doi:10.1002/anie.201105565

Cited by 91 publications

(75 citation statements)

References 25 publications

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“…16,17 Second, to prepare the HDz nanocarrier, amine-functionalized bis(DPA) molecules were covalently conjugated with the carboxylic groups on the HA backbone of HA-NPs. 24 The 1 H NMR analysis indicated that 15.5 ± 3.4 molecules of CA and 28.5 ± 4.2 molecules of bis(DPA) were bound onto the HA backbone of HDz conjugate (Supporting Information Figure S2). The HDz conjugates were self-assembled in aqueous solution, forming nanosized particles with an average hydrodynamic diameter of 94.3 ± 3.5 nm (Figure 2b).…”

Section: Resultsmentioning

confidence: 99%

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Versatile RNA Interference Nanoplatform for Systemic Delivery of RNAs

et al. 2014

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Development of nontoxic, tumor-targetable, and potent in vivo RNA delivery systems remains an arduous challenge for clinical application of RNAi therapeutics. Herein, we report a versatile RNAi nanoplatform based on tumor-targeted and pH-responsive nanoformulas (NFs). The NF was engineered by combination of an artificial RNA receptor, Zn(II)-DPA, with a tumor-targetable and drug-loadable hyaluronic acid nanoparticle, which was further modified with a calcium phosphate (CaP) coating by in situ mineralization. The NF can encapsulate small-molecule drugs within its hydrophobic inner core and strongly secure various RNA molecules (siRNAs, miRNAs, and oligonucleotides) by utilizing Zn(II)-DPA and a robust CaP coating. We substantiated the versatility of the RNAi nanoplatform by demonstrating effective delivery of siRNA and miRNA for gene silencing or miRNA replacement into different human types of cancer cells in vitro and into tumor-bearing mice in vivo by intravenous administration. The therapeutic potential of NFs coloaded with an anticancer drug doxorubicin (Dox) and multidrug resistance 1 gene target siRNA (siMDR) was also demonstrated in this study. NFs loaded with Dox and siMDR could successfully sensitize drug-resistant OVCAR8/ADR cells to Dox and suppress OVCAR8/ADR tumor cell proliferation in vitro and tumor growth in vivo. This gene/drug delivery system appears to be a highly effective nonviral method to deliver chemo- and RNAi therapeutics into host cells.

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Section: Resultsmentioning

confidence: 99%

“…24 Given considerably high phosphate concentration in the cell culture medium or the bloodstream, the NFs necessitate further protection from phosphate molecules in vitro and in vivo . Therefore, we added complementary calcium phosphate (CaP) layers onto the HDz/RNA-NFs by in situ mineralization of sequentially added calcium and phosphate ions.…”

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confidence: 99%

Versatile RNA Interference Nanoplatform for Systemic Delivery of RNAs

et al. 2014

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“…Here we describe a highly flexible protocol to design a sophisticated RNA carrier that we used for tumor-targeted RNA delivery in our previous studies, which is distinct from the reported gene delivery systems that are based on cationic derivatives or chemically modified RNAs 10,11 . This is an alternative RNA delivery system based on the use of Zn-DPA analog, an artificial receptor for phosphate anion derivatives.…”

Section: Introductionmentioning

confidence: 99%

“…Similar Zn-DPA analogs were also used as probes for necrotic and apoptotic cells by targeting anionic phosphatidylserine on cell surfaces 16,17 . Recently, we applied Zn-DPA analogs as carriers for the delivery of therapeutic molecules, such as siRNA, using the selective and strong binding of Zn-DPA with the phosphodiester groups on the siRNA back-bone 10,11 . In particular, this Zn-DPA platform for RNA delivery is highly flexible and can be used in conjunction with existing delivery systems such as NPs, polymers, proteins and antibodies by simply labeling the small-molecule Zn-DPA by established bioconjugation chemistry.…”

Section: Introductionmentioning

confidence: 99%

A nanoparticle formula for delivering siRNA or miRNAs to tumor cells in cell culture and in vivo

et al. 2014

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To improve RNA delivery, we present a protocol to produce an RNA carrier based on a Zn(II)-dipicolylamine (Zn-DPA) analog, which is an artificial receptor for phosphate anion derivatives. We further functionalized this Zn-DPA analog to hyaluronic acid (HA)-based self-assembled nanoparticles (HA-NPS) with a hydrodynamic diameter of 100 nm by conjugating amine-functionalized Zn-DPA molecules onto the HA-NPS through amide formation, resulting in efficient tumor-targeted delivery of RNAs (siRNAs, miRNA or other short oligoribonucleotides) and small-molecule drugs. The functional group of Zn-DPA can be converted into other groups such as a carboxylic or thiol group, and the DPA analog can be covalently attached to a variety of existing and novel platforms or formulations for the development of multifunctional materials via standard bioconjugation techniques. protocols for RNA formulation and delivery into tumor tissues and tumor cells are also described. our design strategy offers a versatile and practical method for delivering both RNA and chemotherapeutics to tumor cells and expands existing nanomaterial capabilities to further the field of drug and gene delivery.

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“…Hyaluronan (HA), a natural polysaccharide abundant in the extracellular matrix of the body, has received increasing attention as an anticancer drug carrier because it is biocompatible and binds to the CD44 receptor, which is over-expressed in cancer cells [32][33][34][35][36][37]. Previously, it was demonstrated that the CD44 receptor is also over-expressed in the synovial tissue of RA patients [5,38], and anti-CD44 antibody has potential for the treatment of RA [39].…”

Section: Introductionmentioning

confidence: 99%