The DOI matches its Crossref record; 127 of the 140 references it cites were found in a registry or an index.
Doxil® — The first FDA-approved nano-drug: Lessons learned
Abstract
Doxil®, the first FDA-approved nano-drug (1995), is based on three unrelated principles: (i) prolonged drug circulation time and avoidance of the RES due to the use of PEGylated nano-liposomes; (ii) high and stable remote loading of doxorubicin driven by a transmembrane ammonium sulfate gradient, which also allows for drug release at the tumor; and (iii) having the liposome lipid bilayer in a "liquid ordered" phase composed of the high-T(m) (53 °C) phosphatidylcholine, and cholesterol. Due to the EPR effect, Doxil is "passively targeted" to tumors and its doxorubicin is released and becomes available to tumor cells by as yet unknown means. This review summarizes historical and scientific perspectives of Doxil development and lessons learned from its development and 20 years of its use. It demonstrates the obligatory need for applying an understanding of the cross talk between physicochemical, nano-technological, and biological principles. However, in spite of the large reward, ~2 years after Doxil-related patents expired, there is still no FDA-approved generic "Doxil" available.
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In the citing paper
“Among such attempts, polyethylene glycol (PEG) coating on liposomes is a successful attempt to avoid RES recognition of nanocarrier system (Barenholz, 2012; Wong et al., 2012).”
From Nanotechnology: A Promising Approach for Delivery of Neuroprotective Drugs (2020) · cites this paper as Barenholz, 2012
In the citing paper
“The successful listing of pegylated liposome Doxil, the first nanoparticle therapeutic drug, in 1995 proved the feasibility of this technology.292”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [292]
In the citing paper
“Doxil, a PEG functionalized liposomal doxorubicin, was the first nanomedicine that has been approved for anticancer medications (FDA in 1995).292”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [292]
Citations
Cites
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13 of the 140 references couldn’t be matched to a known paper.
Research works printed but not linked: 3
- Amselem, 1993, A large-scale method for the preparation of sterile and nonpyrogenic liposomal formulations of defined size distributions for clinical use, vol. 1, 501
- Barenholz, 1993, Quality control assays in the development and clinical use of liposome-based formulations, vol. 1, 527
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Li, T., Nowell, C. J., Cipolla, D., Rades, T., & Boyd, B. J. (2019) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.8b01308 · Cited by 57
Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease
Woitok, M. M., Zoubek, M. E., Doleschel, D., Bartneck, M., Mohamed, M. R., Kießling, F., Lederle, W., Trautwein, C., & Cubero, F. J. (2020) · Cell Death & Disease · doi:10.1038/s41419-020-2571-4 · Cited by 53
Joy, R., George, J., & John, F. (2022) · ChemistrySelect · doi:10.1002/slct.202104045 · Cited by 50
Qiu, M., Ouyang, J., Sun, H., Meng, F., Cheng, R., Zhang, J., Cheng, L., Lan, Q., Deng, C., & Zhong, Z. (2017) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.7b10533 · Cited by 45
Jung, F., Nothnagel, L., Gao, F., Thurn, M., Vogel, V., & Wacker, M. G. (2018) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2018.03.010 · Cited by 42
Hu, X., Dong, M., Liang, X., Liu, Z., & Li, Q. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s280187 · Cited by 29
A review on Stimuli-pH responsive liposomal formulation in cancer therapy
Jayapriya, P., Pardhi, E., Vasave, R., Guru, S. K., Madan, J., & Mehra, N. K. (2023) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2023.105172 · Cited by 24
Wang, C., Siriwardane, D. A., Jiang, W., & Mudalige, T. (2019) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2019.118576 · Cited by 24
Metadata
- Authors
- Barenholz, Y. (.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Barenholz, Yechezkel (Chezy)
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 160
- Issue
- 2
- Pages
- 117-134
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W1989230986
- Cited by
- 4,792
- References
- 140
- Citations by year
- 2026: 415 · 2025: 541 · 2024: 462 · 2023: 405 · 2022: 444 · 2021: 441 · 2020: 436 · 2019: 303 · 2018: 324 · 2017: 284 · 2016: 243 · 2015: 188 · 2014: 174 · 2013: 106 · 2012: 23
- FWCI
- 8.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- pegylated liposomal doxorubicin, PEGylated liposomes, nanotherapeutics, doxorubicin, enhanced permeability and retention effect, passive tumor targeting, liposome circulation time, remote loading, phosphatidylcholine, cholesterol, drug release, generic drug availability
- MeSH terms
- Antibiotics, Antineoplastic, Chemistry, Pharmaceutical, Delayed-Action Preparations, Doxorubicin, Drug Carriers, Drug Compounding, Humans, Liposomes, Solubility, United States, United States Food and Drug Administration, Drug Design, Drug Approval, Nanoparticles
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