Killing cancer cells by targeted drug-carrying phage nanomedicines
Open accessAbstract
Background: Systemic administration of chemotherapeutic agents, in addition to its anti-tumor benefits, results in indiscriminate drug distribution and severe toxicity. This shortcoming may be overcome by targeted drug-carrying platforms that ferry the drug to the tumor site while limiting exposure to non-target tissues and organs. Results: We present a new form of targeted anti-cancer therapy in the form of targeted drug-carrying phage nanoparticles. Our approach is based on genetically-modified and chemically manipulated filamentous bacteriophages. The genetic manipulation endows the phages with the ability to display a host-specificity-conferring ligand. The phages are loaded with a large payload of a cytotoxic drug by chemical conjugation. In the presented examples we used anti ErbB2 and anti ERGR antibodies as targeting moieties, the drug hygromycin conjugated to the phages by a covalent amide bond, or the drug doxorubicin conjugated to genetically-engineered cathepsin-B sites on the phage coat. We show that targeting of phage nanomedicines via specific antibodies to receptors on cancer cell membranes results in endocytosis, intracellular degradation, and drug release, resulting in growth inhibition of the target cells in vitro with a potentiation factor of >1000 over the corresponding free drugs. Conclusion: The results of the proof-of concept study presented here reveal important features regarding the potential of filamentous phages to serve as drug-delivery platform, on the affect of drug solubility or hydrophobicity on the target specificity of the platform and on the effect of drug release mechanism on the potency of the platform. These results define targeted drug-carrying filamentous phage nanoparticles as a unique type of antibody-drug conjugates.
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Two-dimensional monolayer cultures of human or murine cancer cell lines serve as preliminary models to evaluate phage targeting, transduction efficiency, and cytotoxic effects.
“Two-dimensional (2D) monolayer cultures of human or murine cancer cell lines serve as preliminary models to evaluate phage targeting, transduction efficiency, and cytotoxic effects [93,95,104,105]”
From Phage therapy in oncology: opportunities for cancer prevention and treatment (2026) · cites this paper as [93]
The Methods (Cell lines and Cell viability assay; page not provided) describe human cancer cell lines grown in culture and tested for phage-mediated cell killing. The Results (Binding analysis; page not provided) assess phage targeting. The paper does not report murine cancer cell cultures or measure transduction efficiency; its confocal microscopy method examines phage internalization, which is not the same measure. (LLM, conf=0.88)
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Cites
Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review
Maeda, H., Wu, J., Sawa, T., Matsumura, Y., & Hori, K. (2000) · Journal of Controlled Release · doi:10.1016/s0168-3659(99)00248-5 · Cited by 6,565 · see citing works
Cancer nanotechnology: opportunities and challenges
Ferrari, M. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1566 · Cited by 4,558 · see citing works
Nanoparticle and targeted systems for cancer therapy
Brannon‐Peppas, L., & Blanchette, J. O. (2004) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2004.02.014 · Cited by 2,335 · see citing works
Polymer conjugates as anticancer nanomedicines
Duncan, R. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1958 · Cited by 1,956 · see citing works
Virus-Enabled Synthesis and Assembly of Nanowires for Lithium Ion Battery Electrodes
Nam, K. T., Kim, D., Yoo, P. J., Chiang, C. ‐., Meethong, N., Hammond, P. T., Chiang, Y., & Belcher, A. M. (2006) · Science · doi:10.1126/science.1122716 · Cited by 1,854 · see citing works
Exploiting the enhanced permeability and retention effect for tumor targeting
Iyer, A. K., Khaled, G., Fang, J., & Maeda, H. (2006) · Drug Discovery Today · doi:10.1016/j.drudis.2006.07.005 · Cited by 1,846 · see citing works
Molecular biomimetics: nanotechnology through biology
Sarıkaya, M., Tamerler, C., Jen, A. K. ‐., Schulten, K. J., & Baneyx, F. (2003) · Nature Materials · doi:10.1038/nmat964 · Cited by 1,597 · see citing works
Torchilin, V. P. (2006) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2006.09.009 · Cited by 1,274 · see citing works
Arming antibodies: prospects and challenges for immunoconjugates
Wu, A. M., & Senter, P. D. (2005) · Nature Biotechnology · doi:10.1038/nbt1141 · Cited by 1,053 · see citing works
Enhancement by N-hydroxysulfosuccinimide of water-soluble carbodiimide-mediated coupling reactions
Staros, J. V., Wright, R. W., & Swingle, D. M. (1986) · Analytical Biochemistry · doi:10.1016/0003-2697(86)90176-4 · Cited by 901 · see citing works
Antibody targeted drugs as cancer therapeutics
Schrama, D., Reisfeld, R. A., & Becker, J. C. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd1957 · Cited by 769 · see citing works
Erickson, H. K., Park, P. U., Widdison, W. C., Kovtun, Y., Garrett, L. M., Hoffman, K. L., Lutz, R. J., Goldmacher, V. S., & Blättler, W. A. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-4489 · Cited by 586 · see citing works
Doronina, S. O., Mendelsohn, B. A., Bovee, T. D., Cerveny, C. G., Alley, S. C., Meyer, D. L., Oflazoglu, E., Toki, B. E., Sanderson, R. J., Zabinski, R. F., et al. (2005) · Bioconjugate Chemistry · doi:10.1021/bc0502917 · Cited by 515 · see citing works
Long-circulating bacteriophage as antibacterial agents.
Merril, C. R., Biswas, B. K., Carlton, R. M., Jensen, N., Creed, G. J., Zullo, S. J., & Adhya, S. L. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.8.3188 · Cited by 513 · see citing works
Polymeric anticancer drugs with pH-controlled activation
Ulbrich, K. (2004) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2003.10.040 · Cited by 495 · see citing works
MacDiarmid, J. A., Amaro-Mugridge, N. B., Weiss, J., Phillips, L., Burn, A. L., Paulin, R. P., Haasdyk, J. E., Dickson, K.-A., Brahmbhatt, V. N., Pattison, S. T., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.03.012 · Cited by 307 · see citing works
A Hybrid Vector for Ligand-Directed Tumor Targeting and Molecular Imaging
Hajitou, A., Trepel, M., Lilley, C. E., Soghomonyan, S., Alauddin, M. M., Marini, F. C., Restel, B. H., Ozawa, M. G., Moya, C. A., Rangel, R., et al. (2006) · Cell · doi:10.1016/j.cell.2006.02.042 · Cited by 283 · see citing works
Networks of gold nanoparticles and bacteriophage as biological sensors and cell-targeting agents
Souza, G. R., Christianson, D. R., Staquicini, F. I., Ozawa, M. G., Snyder, E. Y., Sidman, R. L., Miller, J. H., Arap, W., & Pasqualini, R. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509739103 · Cited by 262 · see citing works
Cell killing by antibody–drug conjugates
Kovtun, Y., & Goldmacher, V. S. (2007) · Cancer Letters · doi:10.1016/j.canlet.2007.04.010 · Cited by 244 · see citing works
Austin, C. D., Wen, X., Gazzard, L. J., Nelson, C. D., Scheller, R. H., & Scales, S. J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509035102 · Cited by 237 · see citing works
Targeted delivery of chemotherapeutics: tumor-activated prodrug therapy
Chari, R. V. J. (1998) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(97)00095-1 · Cited by 235 · see citing works
Engineering M13 for phage display
Sidhu, S. S. (2001) · Biomolecular Engineering · doi:10.1016/s1389-0344(01)00087-9 · Cited by 224 · see citing works
Immunotoxins in cancer therapy
Kreitman, R. J. (1999) · Current Opinion in Immunology · doi:10.1016/s0952-7915(99)00005-9 · Cited by 215 · see citing works
Targeted Liposomal Drug Delivery in Cancer
Medina, O. P., Zhu, Y., & Kairemo, K. (2004) · Current Pharmaceutical Design · doi:10.2174/1381612043383467 · Cited by 200 · see citing works
Muro, S., Dziubla, T. D., Qiu, W., Leferovich, J. M., Cui, X., Berk, E., & Muzykantov, V. R. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.098970 · Cited by 192 · see citing works
Selection of tumor-specific internalizing human antibodies from phage libraries
Poul, M., Becerril, B., Nielsen, U. B., Morisson, P., & Marks, J. D. (2000) · Journal of Molecular Biology · doi:10.1006/jmbi.2000.4026 · Cited by 192 · see citing works
Dubowchik, G. M., & Firestone, R. A. (1998) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(98)00609-x · Cited by 189 · see citing works
Wels, W. S., Harwerth, I. M., Mueller, M., Groner, B., & Ne, H. (1992) · PubMed · Cited by 186 · see citing works
Wu, G. J., Barth, R. F., Yang, W., Kawabata, S., Zhang, L., & Green‐Church, K. B. (2006) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0325 · Cited by 177 · see citing works
Biotechnological exploitation of bacteriophage research
Petty, N. K., Evans, T. J., Fineran, P. C., & Salmond, G. P. C. (2006) · Trends in biotechnology · doi:10.1016/j.tibtech.2006.11.003 · Cited by 156 · see citing works
Targeted Drug-Carrying Bacteriophages as Antibacterial Nanomedicines
Yacoby, I., Bar, H., & Benhar, I. (2007) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00163-07 · Cited by 152 · see citing works
Self-citationTargeting Antibacterial Agents by Using Drug-Carrying Filamentous Bacteriophages
Yacoby, I., Shamis, M., Bar, H., Shabat, D., & Benhar, I. (2006) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00169-06 · Cited by 151 · see citing works
Self-citationToward Selection of Internalizing Antibodies from Phage Libraries
Becerril, B., Poul, M., & Marks, J. D. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.0177 · Cited by 148 · see citing works
Cancer-Targeted Polymeric Drugs
Luo, Y., & Prestwich, G. (2002) · Current Cancer Drug Targets · doi:10.2174/1568009023333836 · Cited by 147 · see citing works
Gallois, L., Fiallo, M. M. L., & Garnier‐Suillerot, A. (1998) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/s0005-2736(97)00241-1 · Cited by 146 · see citing works
Targeted gene delivery to mammalian cells by filamentous bacteriophage
Poul, M., & Marks, J. D. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.2678 · Cited by 145 · see citing works
King, D., Dubowchik, G. M., Mastalerz, H. A., Willner, D., Hofstead, S. J., Firestone, R. A., Lasch, S. J., & Trail, P. A. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm020149g · Cited by 135 · see citing works
Endothelial targeting of semi-permeable polymer nanocarriers for enzyme therapies
Dziubla, T. D., Shuvaev, V. V., Hong, N. K., Hawkins, B. J., Madesh, M., Takano, H., Simone, E. A., Nakada, M. T., Fisher, A. B., Albelda, S. Μ., et al. (2007) · Biomaterials · doi:10.1016/j.biomaterials.2007.09.023 · Cited by 114 · see citing works
Design and construction of targeted AAVP vectors for mammalian cell transduction
Hajitou, A., Rangel, R., Trepel, M., Soghomonyan, S., Gelovani, J. G., Alauddin, M. M., Pasqualini, R., & Arap, W. (2007) · Nature Protocols · doi:10.1038/nprot.2007.51 · Cited by 109 · see citing works
von Minckwitz, G., Harder, S., Hövelmann, S., Jäger, E., Al‐Batran, S., Loibl, S., Atmaca, A., Cimpoiasu, C., Antje, N., Abera, A., et al. (2005) · Breast Cancer Research · doi:10.1186/bcr1264 · Cited by 101 · see citing works
Yip, W. L., Weyergang, A., Berg, K., Tønnesen, H. H., & Selbo, P. K. (2007) · Molecular Pharmaceutics · doi:10.1021/mp060105u · Cited by 101 · see citing works
Albright, C. F., Graciani, N. R., Han, W., Yue, E. W., Stein, R. L., Lai, Z., Diamond, M. A., Dowling, R. L., Grimminger, L. C., Zhang, S., et al. (2005) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0006 · Cited by 101 · see citing works
Kobayashi, H., Shirakawa, K., Kawamoto, S., Saga, T., Sato, N., Hiraga, A., Watanabe, I., Heike, Y., Togashi, K., Konishi, J., et al. (2002) · PubMed · Cited by 99 · see citing works
Biodistribution of filamentous phage peptide libraries in mice
Zou, J., Dickerson, M. T., Owen, N. K., Landon, L. A., & Deutscher, S. L. (2004) · Molecular Biology Reports · doi:10.1023/b:mole.0000031459.14448.af · Cited by 80 · see citing works
Receptor-Targeted Gene Delivery Using Multivalent Phagemid Particles
LaRocca, D., Jensen-Pergakes, K., Burg, M. A., & Baird, A. (2001) · Molecular Therapy · doi:10.1006/mthe.2001.0284 · Cited by 80 · see citing works
King, D., Yurgaitis, D., Willner, D., Firestone, R. A., Yang, M. B., Lasch, S. J., Hellström, K. E., & Trail, P. A. (1999) · Bioconjugate Chemistry · doi:10.1021/bc980100i · Cited by 73 · see citing works
Enshell‐Seijffers, D. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.10.e50 · Cited by 70 · see citing works
Genetic Selection of Phage Engineered for Receptor-Mediated Gene Transfer to Mammalian Cells
Kassner, P. D., Burg, M. A., Baird, A., & LaRocca, D. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.1603 · Cited by 70 · see citing works
Engineering antibodies for imaging and therapy
Carter, P. M., & Merchant, A. M. (1997) · Current Opinion in Biotechnology · doi:10.1016/s0958-1669(97)80067-5 · Cited by 67 · see citing works
Antibody internalization studied using a novel IgG binding toxin fusion
Mazor, Y., Barnea, I., Keydar, I., & Benhar, I. (2007) · Journal of Immunological Methods · doi:10.1016/j.jim.2007.01.008 · Cited by 66 · see citing works
Self-citationInternalizing antibodies and targeted cancer therapy: direct selection from phage display libraries
Nielsen, U. B., & Marks, J. D. (2000) · Pharmaceutical Science & Technology Today · doi:10.1016/s1461-5347(00)00280-7 · Cited by 61 · see citing works
Andersson, L. I., Davies, J., Duncan, R., Ferruti, P., Ford, J., Kneller, S., Mendichi, R., Pasut, G., Schiavon, O., Summerford, C., et al. (2005) · Biomacromolecules · doi:10.1021/bm049381p · Cited by 52 · see citing works
Folate Receptor-Mediated Targeting of Liposomal Drugs to Cancer Cells
Stephenson, S. M., Low, P. S., & Lee, R. J. (2004) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(04)87003-4 · Cited by 50 · see citing works
Urbanelli, L., Ronchini, C., Fontana, L., Ménard, S., Orlandi, R., & Monaci, P. (2001) · Journal of Molecular Biology · doi:10.1006/jmbi.2001.5111 · Cited by 46 · see citing works
LaRocca, D., & Baird, A. (2001) · Drug Discovery Today · doi:10.1016/s1359-6446(01)01837-2 · Cited by 45 · see citing works
Gao, C., Mao, S., Ronca, F., Zhuang, S., Quaranta, V., Wirsching, P., & Janda, K. D. (2003) · Journal of Immunological Methods · doi:10.1016/s0022-1759(02)00522-7 · Cited by 41 · see citing works
Endo, N., Umemoto, N., Katō, Y., Takeda, Y., & Hara, T. (1987) · Journal of Immunological Methods · doi:10.1016/0022-1759(87)90512-6 · Cited by 41 · see citing works
Recombinant full-length human IgG1s targeting hormone-refractory prostate cancer
Liu, B., Conrad, F., Roth, A., Drummond, D. C., Simko, J. P., & Marks, J. D. (2007) · Journal of Molecular Medicine · doi:10.1007/s00109-007-0208-z · Cited by 39 · see citing works
Assembly of multimeric phage nanostructures through leucine zipper interactions
Sweeney, R. Y., Park, E. Y., Iverson, B. L., & Georgiou, G. (2006) · Biotechnology and Bioengineering · doi:10.1002/bit.20886 · Cited by 21 · see citing works
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Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases
Dheer, D., Nicolas, J., & Shankar, R. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.01.010 · Cited by 144 · see citing works
Phage therapy in oncology: opportunities for cancer prevention and treatment
Mutalik, V. K., Inman, J. L., Chang, H., Arkin, A., & Mao, J.-H. (2026) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2026.02.001 · Cited by 5 · see citing works
- Authors
- Bar, H., Yacoby, I., & Benhar, I.
- Affiliations
- Tel Aviv University (IL)
- Corresponding author
- Benhar, Itai
- Venue
- BMC Biotechnology
- Published
- 2008-04-03
- Volume
- 8
- Issue
- 1
- Pages
- 37-37
- ISSN
- 1472-6750 (ISSN-L)
- PMC
- PMC2323368
- OpenAlex
- W2083473010
- Cited by
- 149
- References
- 59
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 10 · 2023: 11 · 2022: 6 · 2021: 9 · 2020: 7 · 2019: 6 · 2018: 5 · 2017: 4 · 2016: 17 · 2015: 6 · 2014: 10 · 2013: 5 · 2012: 13
- FWCI
- 4.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- BMC Biotechnology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Israel Cancer Association
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Environmental Science › Ecology › Bacteriophages and microbial interactions
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Keywords
- filamentous bacteriophage, targeted drug delivery, antibody-drug conjugates, ERBB2, hygromycin, doxorubicin, cathepsin B, phage display, endocytosis, intracellular drug release, tumor targeting, drug potency
- MeSH terms
- Bacteriophages, Carcinoma, Cell Survival, Humans, Viral Proteins, Drug Delivery Systems, Cell Line, Tumor, Nanostructures, Nanomedicine
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