β-Lapachone-containing PEG–PLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells
Open accessAbstract
Beta-lapachone (beta-lap) is a novel anticancer agent that is bioactivated by NADP(H): quinone oxidoreductase 1 (NQO1), an enzyme overexpressed in a variety of tumors. Despite its therapeutic promise, the poor aqueous solubility of beta-lap hinders its preclinical evaluation and clinical translation. Our objective was to develop beta-lap-containing poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-PLA) polymer micelles for the treatment of NQO1-overexpressing tumors. Several micelle fabrication strategies were examined to maximize drug loading. A film sonication method yielded beta-lap micelles with relatively high loading density (4.7+/-1.0% to 6.5+/-1.0%) and optimal size (29.6+/-1.5 nm). Release studies in phosphate-buffered saline (pH 7.4) showed the time (t(1/2)) for 50% of drug release at 18 h. In vitro cytotoxicity assays were performed in NQO1-overexpressing (NQO1+) and NQO1-null (NQO1-) H596 lung, DU-145 prostate, and MDA-MB-231 breast cancer cells. Cytotoxicity data showed that after a 2 h incubation with beta-lap micelles, a marked increase in toxicity was shown in NQO1+ cells over NQO1- cells, resembling free drug both in efficacy and mechanism of cell death. In summary, these data demonstrate the potential of beta-lap micelles as an effective therapeutic strategy against NQO1-overexpressing tumor cells.
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?
Anticancer drugs encapsulated in polymeric micelles have shown better accumulation in the targeted site, reducing side effects on noncancerous tissues.
“Especially, anticancer drugs encapsulated in polymeric micelles have shown a better accumulation in the targeted site, thus reducing side effects on noncancerous tissues [46,47,48].”
From Recent Advances in Nanomicelles Delivery Systems. (2020) · cites this paper as [48]
Cites
Crank, J. (1956) · CERN Document Server (European Organization for Nuclear Research) · Cited by 18,281 · see citing works
Park, G. S. (1975) · Polymer · doi:10.1016/0032-3861(75)90130-5 · Cited by 15,035 · see citing works
Higuchi, T. (1963) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600521210 · Cited by 4,896 · see citing works
A simple, rapid, and sensitive DNA assay procedure
Labarca, C. G., & Paigen, K. (1980) · Analytical Biochemistry · doi:10.1016/0003-2697(80)90165-7 · Cited by 4,865 · see citing works
Ritger, P. L., & Peppas, N. A. (1987) · Journal of Controlled Release · doi:10.1016/0168-3659(87)90034-4 · Cited by 3,841 · see citing works
Maeda, H. (2001) · Advances in Enzyme Regulation · doi:10.1016/s0065-2571(00)00013-3 · Cited by 2,495 · see citing works
Micellar Nanocarriers: Pharmaceutical Perspectives
Torchilin, V. P. (2006) · Pharmaceutical Research · doi:10.1007/s11095-006-9132-0 · Cited by 1,910 · see citing works
Gref, R., Lück, M., Quellec, P., Marchand, M., Dellacherie, E., Harnisch, S., Blunk, T., & Müller, R. H. (2000) · Colloids and Surfaces B Biointerfaces · doi:10.1016/s0927-7765(99)00156-3 · Cited by 1,725 · see citing works
Openings Between Defective Endothelial Cells Explain Tumor Vessel Leakiness
Hashizume, H., Baluk, P., Morikawa, S., McLean, J. W., Thurston, G., Roberge, S., Jain, R. K., & McDonald, D. M. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65006-7 · Cited by 1,689 · see citing works
PEGylated nanoparticles for biological and pharmaceutical applications
Otsuka, H., Nagasaki, Y., & Kataoka, K. (2003) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(02)00226-0 · Cited by 1,587 · see citing works
Nano-engineering block copolymer aggregates for drug delivery
Allen, C., Maysinger, D., & Eisenberg, A. (1999) · Colloids and Surfaces B: Biointerfaces · doi:10.1016/s0927-7765(99)00058-2 · Cited by 1,358 · see citing works
Polymeric micelles—A new generation of colloidal drug carriers
Jones, M.-C., & Leroux, J.-C. (1999) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/s0939-6411(99)00039-9 · Cited by 1,256 · see citing works
Multifunctional polymeric micelles as cancer-targeted, MRI-ultrasensitive drug delivery systems
Nasongkla, N., Bey, E., Ren, J., Ai, H., Khemtong, C., Guthi, J. S., Chin, S.-F., Sherry, A. D., Boothman, D. A., & Gao, J. (2006) · Nano Letters · doi:10.1021/nl061412u · Cited by 1,238 · see citing works
Self-citationMicellar Nanocontainers Distribute to Defined Cytoplasmic Organelles
Savić, R., Luo, L., Eisenberg, A., & Maysinger, D. (2003) · Science · doi:10.1126/science.1078192 · Cited by 1,113 · see citing works
Olive, P. L., Banáth, J. P., Durand, R. E., & Banáth, J. P. (1990) · Radiation Research · doi:10.2307/3577587 · Cited by 1,095 · see citing works
Olive, P. L., Banáth, J. P., & Durand, R. E. (2012) · Radiation Research · doi:10.1667/rrav04.1 · Cited by 1,031 · see citing works
Kim, T.-Y., Kim, D.-W., Chung, J.-Y., Shin, S. G., Kim, S.-C., Heo, D. S., Kim, N. K., & Bang, Y.-J. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-03-0655 · Cited by 821 · see citing works
Peppas, N. A., Duncan, R., Wnek, G. E., Hoffman, A. S., Gao, G., Kim, S., Lee, D. S., Hadjiargyrou, M., Touítou, E., Ainbinder, D., et al. (2014) · Journal of Controlled Release · doi:10.1016/s0168-3659(14)00482-9 · Cited by 787 · see citing works
Self-citationShuai, X., Ai, H., Nasongkla, N., Kim, S., & Gao, J. (2004) · Journal of Controlled Release · doi:10.1016/j.jconrel.2004.06.003 · Cited by 695 · see citing works
Self-citationFunctionalized micellar systems for cancer targeted drug delivery
Sutton, D., Nasongkla, N., Blanco, E., & Gao, J. (2007) · Pharmaceutical Research · doi:10.1007/s11095-006-9223-y · Cited by 557 · see citing works
Self-citationTargeted polymeric micelles for delivery of poorly soluble drugs
Torchilin, V. P. (2004) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-004-4153-5 · Cited by 543 · see citing works
Logsdon, C. D., Simeone, D. M., Binkley, C. E., Arumugam, T., Greenson, J. K., Giordano, T. J., Misek, D. E., Kuick, R., & Hanash, S. (2003) · PubMed · Cited by 543 · see citing works
Immunomicelles: Targeted pharmaceutical carriers for poorly soluble drugs
Torchilin, V. P., Lukyanov, A. N., Gao, Z., & Papahadjopoulos‐Sternberg, B. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0931428100 · Cited by 538 · see citing works
Yamamoto, Y., Nagasaki, Y., Kato, Y., Sugiyama, Y., & Kataoka, K. (2001) · Journal of Controlled Release · doi:10.1016/s0168-3659(01)00451-5 · Cited by 441 · see citing works
NAD(P)H:Quinone Oxidoreductase Activity Is the Principal Determinant of β-Lapachone Cytotoxicity
Pink, J. J., Planchon, S. M., Tagliarino, C., Varnes, M. E., Siegel, D., & Boothman, D. A. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.8.5416 · Cited by 376 · see citing works
Self-citationBey, E. A., Srougi, M. C., Reinicke, K. E., Dong, Y., Yang, C., Girard, L., Minna, J. D., Bornmann, W. G., Gao, J., & Boothman, D. A. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702176104 · Cited by 355 · see citing works
Self-citationLi, C., Yu, D. F., Newman, R. A., Cabral, F., Stephens, L. C., Hunter, N. R., Milas, L., & Wallace, S. (1998) · PubMed · Cited by 339 · see citing works
Panyam, J., Williams, D. S., Dash, A. K., Leslie‐Pelecky, D. L., & Labhasetwar, V. D. (2004) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20094 · Cited by 320 · see citing works
Immunodetection of NAD(P)H:quinone oxidoreductase 1 (NQO1) in human tissues
Siegel, D. M., & Ross, D. (2000) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(00)00310-5 · Cited by 300 · see citing works
NAD(P)H:Quinone oxidoreductase1 (DT-diaphorase) expression in normal and tumor tissues
Belinsky, M. G., & Jaiswal, A. K. (1993) · Cancer and Metastasis Reviews · doi:10.1007/bf00689804 · Cited by 272 · see citing works
Planchon, S. M., Wuerzberger‐Davis, S. M., Frydman, B., Witiak, D. T., Hutson, P. R., Church, D. R., Wilding, G., & Boothman, D. A. (1995) · PubMed · Cited by 202 · see citing works
Self-citationHrkach, J. S., Peracchia, M. T., Bomb, A., Lotan, N., & Langer, R. (1997) · Biomaterials · doi:10.1016/s0142-9612(96)00077-4 · Cited by 201 · see citing works
HPMA copolymers with pH-controlled release of doxorubicin
Ulbrich, K., Etrych, T., Chytil, P., et al. (2003) · Journal of Controlled Release · doi:10.1016/s0168-3659(02)00348-6 · Cited by 198 · see citing works
Heald, C. R., Stolnik, S., Kujawinski, K. S., Matteis, C. D., Garnett, M. C., Illum, L., Davis, S. S., Purkiss, S. C., Barlow, R. J., & Gellert, P. R. (2002) · Langmuir · doi:10.1021/la011393y · Cited by 192 · see citing works
Ough, M., Lewis, A. M., Bey, E. A., Gao, J., Ritchie, J. M., Bornmann, W. G., Boothman, D. A., Oberley, L. W., & Cullen, J. J. (2005) · Cancer Biology & Therapy · doi:10.4161/cbt.4.1.1382 · Cited by 173 · see citing works
Self-citationLo, C.-L., Huang, C.-K., Lin, K.-M., & Hsiue, G. (2006) · Biomaterials · doi:10.1016/j.biomaterials.2006.09.050 · Cited by 156 · see citing works
Enhancement of Solubility and Bioavailability of β-Lapachone Using Cyclodextrin Inclusion Complexes
Nasongkla, N., Wiedmann, A. F., Bruening, A. J., Beman, M., Ray, D. G., Bornmann, W. G., Boothman, D. A., & Gao, J. (2003) · Pharmaceutical Research · doi:10.1023/a:1026143519395 · Cited by 150 · see citing works
Self-citationAmphiphilic block copolymer micelles for nanoscale drug delivery
Kwon, G. S., & Forrest, M. L. (2006) · Drug Development Research · doi:10.1002/ddr.20063 · Cited by 148 · see citing works
Calcium Is a Key Signaling Molecule in β-Lapachone-mediated Cell Death
Tagliarino, C., Pink, J. J., Dubyak, G., Nieminen, A., & Boothman, D. A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100730200 · Cited by 146 · see citing works
Self-citationSrougi, M. C., Reinicke, K. E., Bey, E. A., Spitz, D. R., & Boothman, D. A. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m603678200 · Cited by 128 · see citing works
Self-citationMitochondrial-derived free radicals mediate asbestos-induced alveolar epithelial cell apoptosis
Panduri, V., Weitzman, S. A., Chandel, N. S., & Kamp, D. W. (2004) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00371.2003 · Cited by 116 · see citing works
Gref, R., Quellec, P., Sánchez, A., Calvo, P., Dellacherie, E., & Alonso, M. J. (2001) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/s0939-6411(00)00143-0 · Cited by 115 · see citing works
μ-Calpain Activation in β-Lapachone-Mediated Apoptosis
Tagliarino, C., Pink, J. J., Reinicke, K. E., Simmers, S. M., & Boothman, D. A. (2003) · Cancer Biology & Therapy · doi:10.4161/cbt.2.2.237 · Cited by 90 · see citing works
Self-citationTargeting NAD(P)H:Quinone Oxidoreductase (NQO1) in Pancreatic Cancer
Lewis, A. M., Ough, M., Du, J., Tsao, M., Oberley, L. W., & Cullen, J. J. (2006) · Molecular Carcinogenesis · doi:10.1002/mc.20199 · Cited by 90 · see citing works
Reinicke, K. E., Bey, E. A., Srougi, M. C., Pink, J. J., Ingalls, S. T., Hoppel, C. L., Misico, R. I., Arzac, G. M., Burton, G., Bornmann, W. G., et al. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-2185 · Cited by 90 · see citing works
Self-citationTargeting NAD(P)H:quinone oxidoreductase (NQO1) in pancreatic cancer
Lewis, A. M., Ough, M., Hinkhouse, M. M., Tsao, M., Oberley, L. W., & Cullen, J. J. (2005) · Molecular Carcinogenesis · doi:10.1002/mc.20107 · Cited by 84 · see citing works
Quellec, P., Gref, R., Dellacherie, E., Sommer, F., Tran, M. D., & Alonso, M. J. (1999) · Journal of Biomedical Materials Research · doi:10.1002/(sici)1097-4636(19991205)47:3 · Cited by 64 · see citing works
Sutton, D. M., Wang, S., Nasongkla, N., Gao, J., & Dormidontova, E. E. (2007) · Experimental Biology and Medicine · doi:10.3181/0702-rm-31 · Cited by 62 · see citing works
Self-citationBouquet, W., Ceelen, W. P., Fritzinger, B., et al. (2006) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2006.11.025 · Cited by 59 · see citing works
Modulating β‐lapachone release from polymer millirods through cyclodextrin complexation
Wang, F., Blanco, E., Ai, H., Boothman, D. A., & Gao, J. (2006) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20721 · Cited by 42 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Multi-drug loaded polymeric micelles for simultaneous delivery of poorly soluble anticancer drugs
Shin, H.-C., Alani, A. W. G., Rao, D. A., Rockich, N. C., & Kwon, G. S. (2009) · Journal of Controlled Release · doi:10.1016/j.jconrel.2009.04.024 · Cited by 243 · see citing works
Recent Advances in Nanomicelles Delivery Systems.
Tawfik, S. M., Azizov, S., Elmasry, M. R., Sharipov, M., & Lee, Y.-I. (2020) · Nanomaterials · doi:10.3390/nano11010070 · Cited by 156 · see citing works
- Authors
- Blanco, E., Bey, E. A., Dong, Y., Weinberg, B. D., Sutton, D. M., Boothman, D. A., & Gao, J.
- Affiliations
- Harold C. Simmons Comprehensive Cancer Center (US)
- Case Western Reserve University (US)
- Corresponding author
- Gao, Jinming
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2007-10
- Volume
- 122
- Issue
- 3
- Pages
- 365-374
- ISSN
- 0168-3659 (ISSN-L)
- PMC
- PMC2064869
- OpenAlex
- W2107432760
- Cited by
- 165
- References
- 50
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 13 · 2021: 6 · 2020: 10 · 2019: 11 · 2018: 15 · 2017: 6 · 2016: 14 · 2015: 13 · 2014: 12 · 2013: 8 · 2012: 13
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Texas Southwestern Medical Center
- National Institutes of Health
- National Cancer Institute (R01CA090696, CA 102792, CA90696, R01CA102792, P30CA142543)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Keywords
- β-lapachone, NQO1, nanotherapeutics, enzyme-activated prodrugs, drug solubility enhancement, drug loading, controlled drug release, tumor cell killing, lung cancer, prostate cancer, breast cancer
- MeSH terms
- Antineoplastic Agents, Cell Survival, DNA Damage, Drug Carriers, Female, Humans, Male, Micelles, Naphthoquinones, Particle Size, Polyesters, Polyethylene Glycols, Solubility, NAD(P)H Dehydrogenase (Quinone), Cell Line, Tumor, Nanoparticles
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
