CD44 targeted delivery of siRNA by using HA-decorated nanotechnologies for KRAS silencing in cancer treatment
Open accessAbstract
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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).”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [202]
Cites
Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer
Kamerkar, S., LeBleu, V. S., Sugimoto, H., Yang, S., Ruivo, C. F., Melo, S. A., Lee, J. J., & Kalluri, R. (2017) · Nature · doi:10.1038/nature22341 · Cited by 2,639 · see citing works
CD44: From adhesion molecules to signalling regulators
Ponta, H., Sherman, L. S., & Herrlich, P. A. (2003) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1004 · Cited by 2,393 · see citing works
Drugging the undruggable RAS: Mission Possible?
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4389 · Cited by 1,997 · see citing works
Essential role for oncogenic Ras in tumour maintenance
Chin, L., Tam, A., Pomerantz, J. H., Wong, M., Holash, J., Bardeesy, N., Shen, Q., O'Hagan, R., Pantginis, J., Zhou, H., et al. (1999) · Nature · doi:10.1038/22788 · Cited by 928 · see citing works
Stephen, A. G., Esposito, D., Bagni, R. K., & McCormick, F. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.02.017 · Cited by 795 · see citing works
Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice
Collins, M. A., Bednar, F., Zhang, Y., Brisset, J.-C., Galbán, S., Galbán, C. J., Rakshit, S., Flannagan, K. S., Adsay, N. V., & Pasca di Magliano, M. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59227 · Cited by 770 · see citing works
Chitosan nanoparticles as delivery systems for doxorubicin
Janes, K. A., Fresneau, M. P., Marazuela, A., Fabra, À., & Alonso, M. J. (2001) · Journal of Controlled Release · doi:10.1016/s0168-3659(01)00294-2 · Cited by 721 · see citing works
Hyaluronic acid targeting of CD44 for cancer therapy: from receptor biology to nanomedicine
Mattheolabakis, G., Milane, L., Singh, A., & Amiji, M. M. (2015) · Journal of Drug Targeting · doi:10.3109/1061186x.2015.1052072 · Cited by 597 · see citing works
Deng, X., Cao, M., Zhang, J., Hu, K., Yin, Z., Zhou, Z., Xiao, X., Yang, Y., Sheng, W., Wu, Y. F., et al. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2014.02.006 · Cited by 515 · see citing works
Hyaluronan–CD44 interactions as potential targets for cancer therapy
Misra, S., Heldin, P., Hascall, V. C., Karamanos, N. K., Skandalis, S. S., Markwald, R. R., & Ghatak, S. (2011) · The FEBS Journal · doi:10.1111/j.1742-4658.2011.08071.x · Cited by 494 · see citing works
The hyaluronan receptor (CD44) participates in the uptake and degradation of hyaluronan.
Culty, M., Nguyen, H., & Underhill, C. B. (1992) · The Journal of Cell Biology · doi:10.1083/jcb.116.4.1055 · Cited by 399 · see citing works
The depolymerization of chitosan: effects on physicochemical and biological properties
Mao, S., Shuai, X., Unger, F. T., Simon, M. W., Bi, D., & Kissel, T. (2004) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2004.05.019 · Cited by 376 · see citing works
Ganesh, S., Iyer, A. K., Morrissey, D. V., & Amiji, M. M. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.01.077 · Cited by 361 · see citing works
Yu, M., Jambhrunkar, S., Thorn, P., Chen, J., Gu, W., & Yu, C. (2012) · Nanoscale · doi:10.1039/c2nr32145a · Cited by 336 · see citing works
A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma
Collisson, E. A., Trejo, C. L., Silva, J. M., Gu, S., Korkola, J. E., Heiser, L. M., Charles, R., Rabinovich, B. A., Hann, B. C., Dankort, D. L., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0347 · Cited by 320 · see citing works
Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers
Hatzivassiliou, G., Haling, J. R., Chen, H., Song, K. W., Price, S., Heald, R. A., Hewitt, J. F. M., Zak, M., Peck, A., Orr, C., et al. (2013) · Nature · doi:10.1038/nature12441 · Cited by 317 · see citing works
Blasco, R. B., Francoz, S., Santamaría, D., Cañamero, M., Dubus, P., Charron, J., Baccarini, M., & Barbacid, M. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.04.002 · Cited by 302 · see citing works
Mutant KRAS is a druggable target for pancreatic cancer
Zorde Khvalevsky, E., Gabai, R., Rachmut, I. H., Horwitz, E., Brunschwig, Z., Orbach, A., Shemi, A., Golan, T., Domb, A. J., Yavin, E., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1314307110 · Cited by 295 · see citing works
Design considerations for nanotherapeutics in oncology
Stylianopoulos, T., & Jain, R. K. (2015) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2015.07.015 · Cited by 283 · see citing works
Development of Farnesyl Transferase Inhibitors: A Review
Appels, N. M. G. M., Beijnen, J. H., & Schellens, J. H. M. (2005) · The Oncologist · doi:10.1634/theoncologist.10-8-565 · Cited by 272 · see citing works
A Hyaluronic Acid−Taxol Antitumor Bioconjugate Targeted to Cancer Cells
Luo, Y., Ziebell, M. R., & Prestwich, G. D. (2000) · Biomacromolecules · doi:10.1021/bm000283n · Cited by 262 · see citing works
The antimicrobial polymer PHMB enters cells and selectively condenses bacterial chromosomes
Chindera, K., Mahato, M., Sharma, A. K., Horsley, H., Kloc-Muniak, K., Kamaruzzaman, N. F., Kumar, S., McFarlane, A., Stach, J., Bentin, T., et al. (2016) · Scientific Reports · doi:10.1038/srep23121 · Cited by 253 · see citing works
Self-citationThe CD44‐Mediated Uptake of Hyaluronic Acid‐Based Carriers in Macrophages
Rosa, J. M. R. D. L., Tirella, A., Gennari, A., Stratford, I. J., & Tirelli, N. (2016) · Advanced Healthcare Materials · doi:10.1002/adhm.201601012 · Cited by 213 · see citing works
Self-citationRoles and targeting of the HAS/hyaluronan/CD44 molecular system in cancer
Karousou, E. G., Misra, S., Ghatak, S., Dobra, K., Götte, M., Vigetti, D., Passi, A. G., Karamanos, N. K., & Skandalis, S. S. (2016) · Matrix Biology · doi:10.1016/j.matbio.2016.10.001 · Cited by 202 · see citing works
Ross, S. J., Revenko, A. S., Hanson, L. L., Ellston, R., Staniszewska, A., Whalley, N., Pandey, S. K., Revill, M., Rooney, C., Buckett, L. K., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aal5253 · Cited by 177 · see citing works
Li, F., Park, S., Ling, D., et al. (2013) · Journal of Materials Chemistry B · doi:10.1039/c3tb00506b · Cited by 175 · see citing works
Targeted Delivery of Doxorubicin by HPMA Copolymer-Hyaluronan Bioconjugates
Luo, Y., Bernshaw, N. J., Lu, Z., Kopec̆ek, J., & Prestwich, G. D. (2002) · Pharmaceutical Research · doi:10.1023/a:1015170907274 · Cited by 172 · see citing works
Surace, C., Arpicco, S., Dufaÿ-Wojcicki, A., et al. (2009) · Molecular Pharmaceutics · doi:10.1021/mp800215d · Cited by 160 · see citing works
Hyaluronic Acid- Paclitaxel: Antitumor Efficacy against CD44(+) Human Ovarian Carcinoma Xenografts
Auzenne, E. J., Ghosh, S. C., Khodadadian, M., Rivera, B., Farquhar, D., Price, R. E., Ravoori, M. K., Kundra, V., Freedman, R. S., & Klostergaard, J. (2007) · Neoplasia · doi:10.1593/neo.07229 · Cited by 159 · see citing works
Chitosan/Hyaluronic Acid Nanoparticles: Rational Design Revisited for RNA Delivery
Lallana, E., Rosa, J. M. R. D. L., Tirella, A., Pelliccia, M., Gennari, A., Stratford, I. J., Puri, S., Ashford, M. B., & Tirelli, N. (2017) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.7b00320 · Cited by 146 · see citing works
Self-citationEllis, C. A., & Clark, G. (2000) · Cellular Signalling · doi:10.1016/s0898-6568(00)00084-x · Cited by 145 · see citing works
Almalik, A., Karimi, S., Ouasti, S., Donno, R., Wandrey, C., Day, P. J., & Tirelli, N. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.03.065 · Cited by 138 · see citing works
Self-citationTargeting Mutant KRAS for Anticancer Therapeutics: A Review of Novel Small Molecule Modulators
Wang, Y., Kaiser, C. E., Frett, B., & Li, H. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm3017706 · Cited by 121 · see citing works
Bassi, P. F., Volpe, A., D’Agostino, D., et al. (2010) · The Journal of Urology · doi:10.1016/j.juro.2010.09.073 · Cited by 104 · see citing works
Ma, M., Chen, H., Chen, Y., Zhang, K., Wang, X., Cui, X., & Shi, J. (2012) · Journal of Materials Chemistry · doi:10.1039/c2jm15489g · Cited by 93 · see citing works
The status and role of ErbB receptors in human cancer
Überall, I., Kolář, Z., Trojanec, R., Berkovcová, J., & Hajdúch, M. (2008) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2007.12.002 · Cited by 92 · see citing works
Hyaluronic acid/Chitosan nanoparticles as delivery vehicles for VEGF and PDGF-BB
Parajó, Y., d’Angelo, I., Welle, A., et al. (2010) · Drug Delivery · doi:10.3109/10717544.2010.509357 · Cited by 89 · see citing works
Kim, H., Yang, X., Rosada, C., et al. (1994) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1994.1199 · Cited by 81 · see citing works
Hyaluronan, CD44, and Cyclooxygenase-2 in Colon Cancer
Misra, S., Hascall, V., Berger, F. G., Markwald, R. R., & Ghatak, S. (2008) · Connective Tissue Research · doi:10.1080/03008200802143356 · Cited by 63 · see citing works
Colorectal cancer-related mutant KRAS alleles function as positive regulators of autophagy
Alves, S., Castro, L., Fernandes, M. S., Francisco, R., Castro, P. J. T. D., Priault, M., Chaves, S. R., Moyer, M. P., Oliveíra, C., Seruca, R., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5021 · Cited by 60 · see citing works
HA ‐ C oated Chitosan Nanoparticles for CD 44‐ M ediated Nucleic Acid Delivery
Almalik, A., Day, P. J., & Tirelli, N. (2013) · Macromolecular Bioscience · doi:10.1002/mabi.201300302 · Cited by 58 · see citing works
Self-citationCD44 promotes Kras-dependent lung adenocarcinoma
Zhao, P., Damerow, M. S., Stern, P., et al. (2012) · Oncogene · doi:10.1038/onc.2012.542 · Cited by 58 · see citing works
CD44 Isoform Status Predicts Response to Treatment with Anti-CD44 Antibody in Cancer Patients
Birzele, F., Voß, E., Nopora, A., Honold, K., Heil, F., Lohmann, S., Verheul, H. M. W., Tourneau, C. L., Delord, J., van Herpen, C., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2141 · Cited by 56 · see citing works
Asati, V., Mahapatra, D. K., & Bharti, S. K. (2016) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2016.09.049 · Cited by 55 · see citing works
Zhang, Z., Jiang, G., Yang, F., & Wang, J. (2006) · Cancer Biology & Therapy · doi:10.4161/cbt.5.11.3297 · Cited by 54 · see citing works
Rosa, J. M. R. D. L., Wubetu, J., Tirelli, N., & Tirella, A. (2018) · Biomedical Physics & Engineering Express · doi:10.1088/2057-1976/aac1c9 · Cited by 47 · see citing works
Self-citationRosa, J. M. R. D. L., Tirella, A., & Tirelli, N. (2018) · Advanced Biosystems · doi:10.1002/adbi.201800049 · Cited by 35 · see citing works
Self-citationGosling, M., & Cox, B. (2014) · Royal Society of Chemistry eBooks · doi:10.1039/9781849735087 · Cited by 26 · see citing works
Shin, W., Lee, S.-K., Hwang, J.-H., Park, J.-C., Cho, Y.-H., Ro, E. J., Song, Y., Seo, H. R., & Choi, K.-Y. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0102-5 · Cited by 10 · see citing works
Magnusson (1999) · doi:10.1002/(sici)1097-0215(19990505)81:3
Flagged first, then by citations
Cited by
Sorted by citations
The current state of the art and future trends in RAS-targeted cancer therapies
Punekar, S. R., Velcheti, V., Neel, B. G., & Wong, K.-K. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00671-9 · Cited by 549 · see citing works
- 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
- bronze
- doi.org
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review