Delivery of RIPK4 small interfering RNA for bladder cancer therapy using natural halloysite nanotubes

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Abstract

HNTs/siRIPK4 nanoparticles have been shown to be an effective treatment for bladder cancer.

Abstract

RNA interference (RNAi) technology can specifically silence the expression of a target gene and has emerged as a promising therapeutic method to treat cancer. In the present study, we showed that natural halloysite nanotube (HNT)–assisted delivery of an active small interfering RNA (siRNA) targeting receptor-interacting protein kinase 4 ( RIPK4 ) efficiently silenced its expression to treat bladder cancer. The HNTs/siRNA complex increased the serum stability of the siRNA, increased its circulation lifetime in blood, and promoted the cellular uptake and tumor accumulation of the siRNA. The siRNA markedly down-regulated RIPK4 expression in bladder cancer cells and bladder tumors, thus inhibiting tumorigenesis and progression in three bladder tumor models (a subcutaneous model, an in situ bladder tumor model, and a lung metastasis model), with no adverse effects. Thus, we revealed a simple but effective method to inhibit bladder cancer using RIPK4 silencing, indicating a promising therapeutic method for bladder cancer.

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A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.

Y Matsumura, H. Maeda (1986)

We previously found that a polymer conjugated to the anticancer protein neocarzinostatin, named smancs, accumulated more in tumor tissues than did neocarzinostatin. To determine the general mechanism of this tumoritropic accumulation of smancs and other proteins, we used radioactive (51Cr-labeled) proteins of various molecular sizes (Mr 12,000 to 160,000) and other properties. In addition, we used dye-complexed serum albumin to visualize the accumulation in tumors of tumor-bearing mice. Many proteins progressively accumulated in the tumor tissues of these mice, and a ratio of the protein concentration in the tumor to that in the blood of 5 was obtained within 19 to 72 h. A large protein like immunoglobulin G required a longer time to reach this value of 5. The protein concentration ratio in the tumor to that in the blood of neither 1 nor 5 was achieved with neocarzinostatin, a representative of a small protein (Mr 12,000) in all time. We speculate that the tumoritropic accumulation of these proteins resulted because of the hypervasculature, an enhanced permeability to even macromolecules, and little recovery through either blood vessels or lymphatic vessels. This accumulation of macromolecules in the tumor was also found after i.v. injection of an albumin-dye complex (Mr 69,000), as well as after injection into normal and tumor tissues. The complex was retained only by tumor tissue for prolonged periods. There was little lymphatic recovery of macromolecules from tumor tissue. The present finding is of potential value in macromolecular tumor therapeutics and diagnosis.

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Knocking down barriers: advances in siRNA delivery

Kathryn Whitehead, Róbert Miklós Langer, Daniel Anderson (2009)

Key Points RNA interference (RNAi) is a fundamental pathway in eukaryotic cells by which sequence-specific small interfering RNA (siRNA) is able to silence genes through the destruction of complementary mRNA. RNAi is an important therapeutic tool that can be used to silence aberrant endogenous genes or to knockdown genes essential to the proliferation of infectious organisms. Delivery remains the central challenge to the therapeutic application of RNAi technology. Before siRNA can take effect in the cytoplasm of a target cell, it must be transported through the body to the target site without undergoing clearance or degradation. Currently, the most effective synthetic, non-viral delivery agents of siRNA are lipids, lipid-like materials and polymers. Various cationic agents including stable nucleic acid–lipid particles, lipidoids, cyclodextrin polymers and polyethyleneimine polymers have been used to achieve the successful systemic delivery of siRNA in mammals without inducing significant toxicity. Direct conjugation of delivery agents to siRNA can facilitate delivery. For example, cholesterol-modified siRNA enables targeting to the liver. RNAi therapeutics have progressed to the clinic, where studies are being conducted to determine siRNA efficacy in treating several diseases, including age-related macular degeneration and respiratory syncytial virus. Moving forward, it will be important to pay close attention to the potential nonspecific immunostimulatory effects of siRNA. Modifications to siRNA can be used to minimize stimulation of the immune system, and an increased emphasis must be placed on performing proper controls to ensure that therapeutic effects are sequence-specific.

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Engineered nanoparticles for drug delivery in cancer therapy.

Tianmeng Sun, Yu Zhang, Bo Pang … (2014)

In medicine, nanotechnology has sparked a rapidly growing interest as it promises to solve a number of issues associated with conventional therapeutic agents, including their poor water solubility (at least, for most anticancer drugs), lack of targeting capability, nonspecific distribution, systemic toxicity, and low therapeutic index. Over the past several decades, remarkable progress has been made in the development and application of engineered nanoparticles to treat cancer more effectively. For example, therapeutic agents have been integrated with nanoparticles engineered with optimal sizes, shapes, and surface properties to increase their solubility, prolong their circulation half-life, improve their biodistribution, and reduce their immunogenicity. Nanoparticles and their payloads have also been favorably delivered into tumors by taking advantage of the pathophysiological conditions, such as the enhanced permeability and retention effect, and the spatial variations in the pH value. Additionally, targeting ligands (e.g., small organic molecules, peptides, antibodies, and nucleic acids) have been added to the surface of nanoparticles to specifically target cancerous cells through selective binding to the receptors overexpressed on their surface. Furthermore, it has been demonstrated that multiple types of therapeutic drugs and/or diagnostic agents (e.g., contrast agents) could be delivered through the same carrier to enable combination therapy with a potential to overcome multidrug resistance, and real-time readout on the treatment efficacy. It is anticipated that precisely engineered nanoparticles will emerge as the next-generation platform for cancer therapy and many other biomedical applications.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): SciAdv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: September 2019

Publication date (Electronic): 25 September 2019

Volume: 5

Issue: 9

Electronic Location Identifier: eaaw6499

Affiliations

[1 ]Department of Urology, The Third Xiangya Hospital of Central South University, Changsha 410013, China.

[2 ]Institute of Prostate Disease of Central South University, Changsha 410013, China.

[3 ]School of Minerals Processing and Bioengineering, Central South University, Changsha 410083, China.

[4 ]Department of Dermatology, The Third Xiangya Hospital of Central South University, Changsha 410013, China.

[5 ]Hunan Key Laboratory of Pharmacodynamics and Safety Evaluation of New Drugs, Changsha 410331, China.

[6 ]Department of Digestive, The Third Xiangya Hospital of Central South University, Changsha 410013, China.

[7 ]Department of Operation Center, The Second Xiangya Hospital of Central South University, Changsha 410011, China.

[8 ]Department of Urology, Hunan Aerospace Hospital, Changsha 410205, China.

[9 ]Department of Onology, The Third Xiangya Hospital of Central South University, Changsha 410013, China.

[10 ]Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha 410008, China.

Author notes

[*]

These authors contributed equally to this work.

[† ]Corresponding author. Email: csucaoke@ 123456163.com

Author information

Jianye Liu http://orcid.org/0000-0002-7953-3672

Yi Zhang http://orcid.org/0000-0003-0391-7159

Qinghai Zeng http://orcid.org/0000-0002-3489-2057

Ke Cao http://orcid.org/0000-0001-5392-2306

Article

Publisher ID: aaw6499

DOI: 10.1126/sciadv.aaw6499

PMC ID: 6760933

PubMed ID: 31579820

SO-VID: 5c5918cf-0773-4baf-9b54-270a2dc64008

Copyright © Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 12 January 2019

Date accepted : 03 September 2019

Funding

Funded by: doi http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81802556

Funded by: doi http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81874137

Funded by: The Natural Science Foundation of Hunan Province;

Award ID: 2019JJ30039

Funded by: the New Xiangya Talent Projects of the Third Xiangya Hospital of Central South University;

Award ID: JY201615

Funded by: the Scientific Projects of Health and Family Planning Commision of Hunan Province;

Award ID: B2017034

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Copyeditor Monica Bilog

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Delivery of RIPK4 small interfering RNA for bladder cancer therapy using natural halloysite nanotubes

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RNA drug delivery

Most cited references 35

A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.

Knocking down barriers: advances in siRNA delivery

Engineered nanoparticles for drug delivery in cancer therapy.

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