Versatile RNA Interference Nanoplatform for Systemic Delivery of RNAs

Choi, Ki Young; Silvestre, Óscar F.; Huang, Xinglu; Min, Kyung Hyun; Howard, Gregory P.; Hida, Naoki; Jin, Albert J.; Carvajal, Nicole; Lee, Sang Wook; Hong, Jong‐In; Chen, Xiaoyuan

doi:10.1021/nn500085k

Cited by 97 publications

(86 citation statements)

References 36 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The lower tumor:liver ratio observed with in vivo jetPEI and nanoparticle systems in the literature is consistent with reported challenges in achieving efficient nanoparticle delivery to tumor sites; in a comprehensive analysis of nanoparticle delivery to solid tumors, the median injected dose delivered to the tumor site was 0.7% (47). It is notable that even in recent, advanced, and promising nanoparticle systems, including those that use modifications for "stealth" or targeting mechanisms, the ratio of tumor:liver accumulation is consistently close to or below 1:1 (3,5,(57)(58)(59)(60)(61)(62). The marked improvement of siRNA-L 2 in relative tumor accumulation supports its translational promise.…”

Section: Discussionsupporting

confidence: 77%

Lipophilic siRNA targets albumin in situ and promotes bioavailability, tumor penetration, and carrier-free gene silencing

Sarett

Werfel

Lee

et al. 2017

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

103

View full text Add to dashboard Cite

Clinical translation of therapies based on small interfering RNA (siRNA) is hampered by siRNA's comprehensively poor pharmacokinetic properties, which necessitate molecule modifications and complex delivery strategies. We sought an alternative approach to commonly used nanoparticle carriers by leveraging the long-lived endogenous serum protein albumin as an siRNA carrier. We synthesized siRNA conjugated to a diacyl lipid moiety (siRNA-L2), which rapidly binds albumin in situ. siRNA-L2, in comparison with unmodified siRNA, exhibited a 5.7-fold increase in circulation half-life, an 8.6-fold increase in bioavailability, and reduced renal accumulation. Benchmarked against leading commercial siRNA nanocarrier in vivo jetPEI, siRNA-L2 achieved 19-fold greater tumor accumulation and 46-fold increase in per-tumor-cell uptake in a mouse orthotopic model of human triple-negative breast cancer. siRNA-L2 penetrated tumor tissue rapidly and homogeneously; 30 min after i.v. injection, siRNA-L2 achieved uptake in 99% of tumor cells, compared with 60% for jetPEI. Remarkably, siRNA-L2 achieved a tumor:liver accumulation ratio >40:1 vs. <3:1 for jetPEI. The improved pharmacokinetic properties of siRNA-L2 facilitated significant tumor gene silencing for 7 d after two i.v. doses. Proof-of-concept was extended to a patient-derived xenograft model, in which jetPEI tumor accumulation was reduced fourfold relative to the same formulation in the orthotopic model. The siRNA-L2 tumor accumulation diminished only twofold, suggesting that the superior tumor distribution of the conjugate over nanoparticles will be accentuated in clinical situations. These data reveal the immense promise of in situ albumin targeting for development of translational, carrier-free RNAi-based cancer therapies.

show abstract

Section: Discussionsupporting

confidence: 77%

Lipophilic siRNA targets albumin in situ and promotes bioavailability, tumor penetration, and carrier-free gene silencing

Sarett

Werfel

Lee

et al. 2017

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

103

View full text Add to dashboard Cite

show abstract

“…There is a critical need to develop drug delivery platforms in order to expedite the clinical translation of miRNA based therapeutics. 19 26 Delivery approaches employed thus far for gene delivery range from viral platforms 27 to nonviral carriers based on polymer, 28 lipid, 29 and dendrimeric 30 backbones. Although viral platforms have been shown to provide potent gene knockdown, viral construct mediated gene silencing has been hindered in the clinical setting due to toxic immune responses and potential integration into the host genome, leading to the widespread development of nonviral carriers.…”

Section: Introductionmentioning

confidence: 99%

Targeted Delivery of MicroRNA125a-5p by Engineered Lipid Nanoparticles for the Treatment of HER2 Positive Metastatic Breast Cancer

Hayward

Francis

Kholmatov

et al. 2016

j biomed nanotechnol

View full text Add to dashboard Cite

MicroRNAs (miRNAs) are endogenous regulators of gene expression that play a pivotal role in biological processes spanning from global homeostasis to disease onset and progression. The ability to manipulate and induce cellular reequilibrium of deregulated miRNA expression profiles by inhibition of oncogenic miRNA or overexpression of tumor suppressor miRNA is a promising cancer strategy, but is currently hindered in application by the lack of nonviral delivery systems. Here we present a lipid nanoparticle (LNP) platform surface coated with Hyaluronic Acid (HA) for the delivery of mature tumor suppressor MicroRNA125a-5p to treat HER2 positive metastatic breast cancer. The delivery platform actively targets patient-derived metastatic breast cancer cells (21MT-1) isolated from the metastatic pleural effusion over normal breast tissue via an intrinsic HA-CD44 mediated endocytosis event, and has the ability to escape from the intracellular endolysosomal pathway for potent gene silencing. Knockdown of the HER2 proto-oncogene at the level of transcription and translation was achieved following HA-LNP mediated transfection with MicroRNA125a-5p. In addition, the PI3K/AKT and MAPK hyperactivated signaling pathways, cellular proliferation, and migration potential were also potently suppressed. Furthermore, the therapeutic efficacy of MicroRNA125a-5p by the HA-LNP platform was demonstrated to be significantly improved as compared to a commercial transfection reagent. This study highlights the therapeutic potential of MicroRNA125a-5p as a standalone treatment of HER2+ metastatic breast cancer via a translational nonviral delivery platform. These findings have major implications on future gene therapy regimens for breast cancer.

show abstract

“…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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Versatile RNA Interference Nanoplatform for Systemic Delivery of RNAs

Cited by 97 publications

References 36 publications

Lipophilic siRNA targets albumin in situ and promotes bioavailability, tumor penetration, and carrier-free gene silencing

Lipophilic siRNA targets albumin in situ and promotes bioavailability, tumor penetration, and carrier-free gene silencing

Targeted Delivery of MicroRNA125a-5p by Engineered Lipid Nanoparticles for the Treatment of HER2 Positive Metastatic Breast Cancer

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

Contact Info

Product

Resources

About