Hyaluronic acid-based hydrogels as 3D matrices for in vitro evaluation of chemotherapeutic drugs using poorly adherent prostate cancer cells
Open accessAbstract
The current investigation aimed to develop a biomimetic, three-dimensional (3D) culture system for poorly adherent bone metastatic prostate cancer cells (C4-2B) for use as an in vitro platform for anti-cancer drug screening. To this end, hyaluronic acid (HA) derivatives carrying complementary aldehyde (HAALD) and hydrazide (HAADH) groups were synthesized and characterized. In situ encapsulation of C4-2B cells was achieved by simple mixing of HAALD and HAADH in the presence of the cells. Unlike two-dimensional (2D) monolayer culture in which cells adopt an atypical spread morphology, cells residing in the HA matrix formed distinct clustered structures which grew and merged, reminiscent of real tumors. Anti-cancer drugs added to the media surrounding the cell/gel construct diffused into the gel and killed the embedded cells. The HA hydrogel system was used successfully to test the efficacy of anti-cancer drugs including camptothecin, docetaxel, and rapamycin, alone and in combination, including specificity, dose and time responses. Responses of cells to anti-neoplastics differed between the 3D HA hydrogel and 2D monolayer systems. We suggest that the data obtained from 3D HA systems is superior to that from conventional 2D monolayers as the 3D system better reflects the bone metastatic microenvironment of the cancer cells.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Most studies have shown that cell viability in 3D cultures during the first few days (1-5 days) was not significantly different compared to 2D culture.
“Most studies have shown that the cell viability in 3D cultures during the first few days (1-5 days) was not significantly different when compared to that in 2D culture. 30,34”
From Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors (2014) · cites this paper as [34]
Results §3.1.2 reports approximately the same percentage of dead C4-2B cells in 3D hydrogel and 2D culture on days 1–3. By day 5, however, the percentage increased dramatically in 2D relative to the hydrogel. This single study does not establish what most studies found, and it does not support comparable viability throughout days 1–5. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The NCI60 human tumour cell line anticancer drug screen
Shoemaker, R. H. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1951 · Cited by 2,644 · see citing works
Modeling Tissue Morphogenesis and Cancer in 3D
Yamada, K. M., & Cukierman, E. (2007) · Cell · doi:10.1016/j.cell.2007.08.006 · Cited by 1,751 · see citing works
Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo
Farokhzad, O. C., Cheng, J., Teply, B. A., Sherifi, I., Jon, S., Kantoff, P. W., Richie, J. P., & Langer, R. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601755103 · Cited by 1,667 · see citing works
Boyd, M. R., & Paull, K. D. (1995) · Drug Development Research · doi:10.1002/ddr.430340203 · Cited by 1,572 · see citing works
Modelling glandular epithelial cancers in three-dimensional cultures
Debnath, J., & Brugge, J. S. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1695 · Cited by 1,014 · see citing works
Focal adhesion regulation of cell behavior
Wozniak, M. A., Modzelewska, K., Kwong, L., & Keely, P. J. (2004) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2004.04.007 · Cited by 995 · see citing works
Engineering tumors with 3D scaffolds
Fischbach, C., Chen, R., Matsumoto, T., Schmelzle, T., Brugge, J. S., Polverini, P. J., & Mooney, D. J. (2007) · Nature Methods · doi:10.1038/nmeth1085 · Cited by 823 · see citing works
Three-dimensional tissue culture models in cancer biology
Kim, J. B. (2005) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2005.05.002 · Cited by 613 · see citing works
The many ways to cleave hyaluronan
Stern, R., Kogan, G., Jedrzejas, M. J., & Šoltés, L. (2007) · Biotechnology Advances · doi:10.1016/j.biotechadv.2007.07.001 · Cited by 420 · see citing works
LIFE ISN'T FLAT: TAKING CANCER BIOLOGY TO THE NEXT DIMENSION
Smalley, K. S. M., Lioni, M., & Herlyn, M. (2006) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1290/0604027.1 · Cited by 303 · see citing works
3-D Tumor Model forIn VitroEvaluation of Anticancer Drugs
Horning, J. L., Sahoo, S. K., Vijayaraghavalu, S., Dimitrijevic, S., Vasir, J. K., Jain, T. K., Panda, A. K., & Labhasetwar, V. D. (2008) · Molecular Pharmaceutics · doi:10.1021/mp800047v · Cited by 292 · see citing works
The Mammalian Target of Rapamycin Signaling Pathway: Twists and Turns in the Road to Cancer Therapy
Abraham, R. T., & Gibbons, J. J. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-2798 · Cited by 244 · see citing works
Lin, J., Adam, R. M., Santiestevan, E., & Freeman, M. R. (1999) · PubMed · Cited by 241 · see citing works
Bourguignon, L., Singleton, P. A., Zhu, H., & Diedrich, F. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301885200 · Cited by 237 · see citing works
Hyaluronic Acid-Based Microgels and Microgel Networks for Vocal Fold Regeneration
Jia, X., Yeo, Y., Clifton, R. J., Jiao, T., Kohane, D. S., Kobler, J. B., Zeitels, S. M., & Langer, R. (2006) · Biomacromolecules · doi:10.1021/bm0604956 · Cited by 236 · see citing works
Self-citationBourguignon, L., Singleton, P. A., Zhu, H., & Zhou, B. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204320200 · Cited by 224 · see citing works
Hyaluronan: A constitutive regulator of chemoresistance and malignancy in cancer cells
Toole, B. P., & Slomiany, M. G. (2008) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2008.03.009 · Cited by 219 · see citing works
Simamora, P., Alvarez, J. M., & Yalkowsky, S. H. (2001) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(00)00617-7 · Cited by 211 · see citing works
Cragg, G. M. L., & Newman, D. J. (2003) · Journal of Natural Products · doi:10.1021/np030420c · Cited by 210 · see citing works
Sahoo, S. K., Panda, A. K., & Labhasetwar, V. D. (2005) · Biomacromolecules · doi:10.1021/bm0492632 · Cited by 191 · see citing works
Prolongation of sciatic nerve blockade by in situ cross-linked hyaluronic acid
Jia, X., Colombo, G., Padera, R. F., Langer, R., & Kohane, D. S. (2004) · Biomaterials · doi:10.1016/j.biomaterials.2003.12.012 · Cited by 191 · see citing works
Self-citationSerebriiskii, I. G., Castelló-Cros, R., Lamb, A., Golemis, E. A., & Cukierman, E. (2008) · Matrix Biology · doi:10.1016/j.matbio.2008.02.008 · Cited by 176 · see citing works
Prestwich, G. D. (2007) · Accounts of Chemical Research · doi:10.1021/ar7000827 · Cited by 176 · see citing works
CLARK, B. R., & Keating, A. (1995) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1995.tb31044.x · Cited by 176 · see citing works
Qiu, Y., Gao, Y., Hu, K., & Li, F. (2008) · Journal of Controlled Release · doi:10.1016/j.jconrel.2008.04.019 · Cited by 161 · see citing works
Hicks, K. O., Pruijn, F. B., Secomb, T. W., Hay, M. P., Hsu, R., Brown, J. M., Denny, W. A., Dewhirst, M. W., & Wilson, W. R. (2006) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djj306 · Cited by 152 · see citing works
Microenvironmental regulation of biomacromolecular therapies
Kong, H. J., & Mooney, D. J. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2309 · Cited by 147 · see citing works
Spontaneous Metastasis of Prostate Cancer Is Promoted by Excess Hyaluronan Synthesis and Processing
Bharadwaj, A. G., Kovar, J. L., Loughman, E., Elowsky, C. G., Oakley, G. G., & Simpson, M. A. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.080501 · Cited by 141 · see citing works
Molecular mechanisms and treatment of bone metastasis
Clines, G. A., & Guise, T. A. (2008) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399408000616 · Cited by 135 · see citing works
Jha, A. K., Hule, R. A., Jiao, T., Teller, S. S., Clifton, R. J., Duncan, R. L., Pochan, D. J., & Jia, X. (2009) · Macromolecules · doi:10.1021/ma8019442 · Cited by 124 · see citing works
Self-citationCD44 signaling through focal adhesion kinase and its anti‐apoptotic effect
Fujita, Y., Kitagawa, M., Nakamura, S., Azuma, K., Ishii, G., Higashi, M., Kishi, H., Hiwasa, T., Koda, K., Nakajima, N., et al. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)03262-3 · Cited by 112 · see citing works
Gayet, J.-C., & Fortier, G. (1996) · Journal of Controlled Release · doi:10.1016/0168-3659(95)00118-2 · Cited by 105 · see citing works
Watanabe, M., Kawano, K., Toma, K., et al. (2008) · Journal of Controlled Release · doi:10.1016/j.jconrel.2008.02.005 · Cited by 91 · see citing works
David, L., Dulong, V., Cerf, D. L., et al. (2007) · Acta Biomaterialia · doi:10.1016/j.actbio.2007.08.012 · Cited by 91 · see citing works
Chemical structure of hyaluronic acid.
MEYER, K. (1958) · PubMed · Cited by 80 · see citing works
Drug Delivery Systems in Cancer Therapy
Brown, D. (2003) · Humana Press eBooks · doi:10.1385/1592594271 · Cited by 78 · see citing works
Leung, S. Y. L., Jackson, J. K., Miyake, H., Burt, H. M., & Gleave, M. E. (2000) · The Prostate · doi:10.1002/1097-0045(20000701)44:2 · Cited by 67 · see citing works
Morgan, T. M., Pitts, T. E. M., Gross, T. S., Poliachik, S. L., Vessella, R. L., & Corey, E. (2008) · The Prostate · doi:10.1002/pros.20752 · Cited by 59 · see citing works
Doillon, C. J., Gagnon, É., Paradis, R., et al. (2004) · PubMed · Cited by 57 · see citing works
Laplanche, R., Meno‐Tetang, G. M. L., & Kawai, R. (2007) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-007-9051-7 · Cited by 36 · see citing works
Biology and clinical management of prostate cancer bone metastasis
Ye, X.-C. (2007) · Frontiers in bioscience · doi:10.2741/2311 · Cited by 35 · see citing works
Steady-state fluorescence study on release of camptothecin from agar hydrogel
Liu, J., Chen, L., Li, L., Hu, X., & Cai, Y. (2004) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2004.08.010 · Cited by 31 · see citing works
Manipulation of the C(22)-C(27) region of rapamycin: Stability issues and biological implications
Nelson, F. C., Stachel, S. J., Eng, C. P., et al. (1999) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(98)00735-5 · Cited by 28 · see citing works
Docetaxel in the management of prostate cancer: current standard of care and future directions
Dosso, S. D., & Berthold, D. (2008) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.9.11.1969 · Cited by 19 · see citing works
Opdenaker, L. M., & Farach‐Carson, M. C. (2009) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22145 · Cited by 6 · see citing works
Self-citationHyaluronate and its receptors in bone marrow
Schade, U. M., Nehmann, N., Horny, H.-P., et al. (2006) · Acta Histochemica · doi:10.1016/j.acthis.2006.03.018 · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Edmondson, R., Broglie, J. J., Adcock, A. F., & Yang, L. (2014) · ASSAY and Drug Development Technologies · doi:10.1089/adt.2014.573 · Cited by 2,515 · see citing works
pH-Sensitive nano-systems for drug delivery in cancer therapy
Liu, J., Huang, Y., Kumar, A., Tan, A., Jin, S., Mozhi, A., & Liang, X.-J. (2014) · Biotechnology Advances · doi:10.1016/j.biotechadv.2013.11.009 · Cited by 1,121 · see citing works
Challenges of applying multicellular tumor spheroids in preclinical phase
Han, S. J., Kwon, S., & Kim, K. S. (2021) · Cancer Cell International · doi:10.1186/s12935-021-01853-8 · Cited by 428 · see citing works
Organ-on-a-chip platforms for studying drug delivery systems
Bhise, N. S., Ribas, J., Manoharan, V., Zhang, Y. S., Polini, A., Massa, S., Dokmeci, M. R., & Khademhosseini, A. (2014) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.05.004 · Cited by 381 · see citing works
Costa, E. C., de Melo‐Diogo, D., Moreira, A. F., Carvalho, M. P., & Correia, I. J. (2018) · Biotechnology Journal · doi:10.1002/biot.201700417 · Cited by 224 · see citing works
Hongisto, V., Jernström, S., Fey, V., Mpindi, J.-P., Kleivi Sahlberg, K., Kallioniemi, O., & Perälä, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077232 · Cited by 181 · see citing works
Hydrogels to model 3D in vitro microenvironment of tumor vascularization
Song, H.-H. G., Park, K. M., & Gerecht, S. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.06.002 · Cited by 153 · see citing works
3D Matrices for Anti-Cancer Drug Testing and Development
Gurski, L. A., Petrelli, N. J., Jia, X., & Farach-Carson, M. C. (2010) · Oncology Issues · doi:10.1080/10463356.2010.11883480 · Cited by 130 · see citing works
Self-citationDereli-Korkut, Z., Akaydin, H. D., Ahmed, A. H. R., Jiang, X., & Wang, S. (2014) · Analytical Chemistry · doi:10.1021/ac403899j · Cited by 62 · see citing works
Heylman, C., Sobrino, A., Shirure, V. S., Hughes, C. C., & George, S. C. (2014) · Experimental Biology and Medicine · doi:10.1177/1535370214525295 · Cited by 53 · see citing works
A study of electrochemical biosensor for analysis of three-dimensional (3D) cell culture
Jeong, S. H., Lee, D. W., Kim, S., Kim, J., & Ku, B. (2012) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2012.02.039 · Cited by 33 · see citing works
- Authors
- Gurski, L. A., Jha, A. K., Zhang, C., Jia, X., & Farach-Carson, M. C.
- Affiliations
- University of Delaware (US)
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 30
- Issue
- 30
- Pages
- 6076-6085
- ISSN
- 0142-9612 (ISSN-L)
- PMC
- PMC2782556
- OpenAlex
- W2083443762
- Cited by
- 269
- References
- 46
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 12 · 2022: 25 · 2021: 17 · 2020: 20 · 2019: 15 · 2018: 17 · 2017: 25 · 2016: 18 · 2015: 30 · 2014: 27 · 2013: 18 · 2012: 13
- FWCI
- 5.12
- Type
- journal article
- Language
- en
- Update notices
- erratum (2010-05-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P01CA098912)
- National Institute on Deafness and Other Communication Disorders (R01DC008965)
- National Center for Research Resources (P20RR016472)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- hyaluronic acid hydrogel, 3D cell culture, prostate cancer, bone metastasis, C4-2B cells, drug screening, camptothecin, docetaxel, rapamycin, combination therapy, tumor microenvironment, 2D vs 3D culture comparison
- MeSH terms
- Aldehydes, Antineoplastic Agents, Cell Adhesion, Diffusion, Drug Screening Assays, Antitumor, Humans, Hyaluronic Acid, Hydrazines, Male, Neoplasm Metastasis, Prostatic Neoplasms, Drug Delivery Systems, Cell Culture Techniques, Hydrogels, Hydrogel, Polyethylene Glycol Dimethacrylate
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
