Cited by 60RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryDendrimers and Hyperbranched Polymers

CD44 targeted delivery of siRNA by using HA-decorated nanotechnologies for KRAS silencing in cancer treatment

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Tirella, A., Kloc-Muniak, K., Good, L., Ridden, J., Ashford, M., Puri, S., Tirelli, N.·2019·International Journal of Pharmaceutics

Abstract

KRAS is a small GTPase that regulates cell proliferation and survival. In tumors, the KRAS gene is mutated, and leading to unregulated tumor growth. Despite the recognized importance of KRAS in cancer, attempts to develop small molecule inhibitors have proved unsuccessful. An alternative strategy is gene silencing and the use of small nucleic acid sequences (e.g. siRNA, shRNA), has been reported to successfully downregulate KRAS. In this study we developed ternary nanocomplexes to deliver an anti-KRAS siRNA to colorectal cancer cells, exploiting the interaction of hyaluronic acid (HA) with CD44 as a means to achieve selective targeting of CD44-positive cancer cells. Two different polycations, poly(hexamethylene biguanide) and chitosan, were complexed with siRNA and coated with HA. Physico-chemical properties and stability of nanoparticles were characterized, including size, surface charge, and degree of siRNA protection. We demonstrate nanoparticle internalization (flow cytometry), siRNA cytosolic release (confocal microscopy) and KRAS silencing (RT-qPCR) in CD44+/KRAS+ colorectal cancer cell line, HCT-116. Further we demonstrate that the uptake of HA-decorated nanoparticles in cancer cells is higher when co-cultured with fibroblasts.

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Crossref · 10.1016/j.ijpharm.2019.02.032

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  • Nanoparticle-based platforms delivering KRAS-specific siRNAs have been shown to reach cancer cells, decrease KRAS levels and produce anticancer activity.

    “This technology has been shown to be adequately delivered to cancer cells and to effectively decrease their KRAS levels, resulting in anticancer activity200–202 (Table 1).”

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Authors
Tirella, A., Kloc-Muniak, K., Good, L., Ridden, J., Ashford, M., Puri, S., & Tirelli, N.
Affiliations
  • Manchester Academic Health Science Centre (GB)
  • Tecrea (United Kingdom) (GB)
  • Royal Veterinary College (GB)
  • AstraZeneca (United Kingdom) (GB)
Corresponding author
Tirella, A.
Venue
International Journal of Pharmaceutics
Publisher
Elsevier BV
Published
2019-04
Volume
561
Pages
114-123
ISSN
0378-5173 (ISSN-L)
OpenAlex
W2917735202
Cited by
60
References
50
Citations by year
2026: 3 · 2025: 9 · 2024: 7 · 2023: 7 · 2022: 10 · 2021: 8 · 2020: 8 · 2019: 8
FWCI
2.81
Type
journal article
Language
en
Open access
Locations
  • International Journal of Pharmaceutics (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
  • RVC Research Online (Royal Veterinary College) (submittedVersion, cc-by)
  • Institutional Research Information System (Università degli Studi di Trento) (submittedVersion, cc-by-nc-nd)
Funders
  • University of Manchester
  • Wellcome Trust
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Physical Sciences › Materials Science › Polymers and Plastics › Dendrimers and Hyperbranched Polymers
Keywords
CD44, hyaluronic acid, siRNA delivery, colorectal cancer, chitosan, targeted nanoparticle delivery, nanoparticle uptake, tumor microenvironment, fibroblast co-culture, gene silencing
MeSH terms
Biguanides, Drug Stability, Fibroblasts, Humans, Hyaluronic Acid, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Drug Delivery Systems, Coculture Techniques, Hyaluronan Receptors, Gene Silencing, RNA, Small Interfering, Cell Line, Tumor, Chitosan, Nanomedicine, Nanoparticles, Chemical Phenomena, Drug Liberation

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