A 3-in-1 polymeric micelle nanocontainer for poorly water-soluble drugs

Shin, Ho-Chul; Alani, Adam W. G.; Cho, Hyunah; Bae, Younsoo; Kolesar, Jill M.; Kwon, Glen S.

doi:10.1021/mp2000549

Cited by 126Nanoparticle-Based Drug DeliveryDrug Solubulity and Delivery SystemsAdvanced Drug Delivery Systems

A 3-in-1 polymeric micelle nanocontainer for poorly water-soluble drugs

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Shin, Ho-Chul, Alani, Adam W. G., Cho, Hyunah, Bae, Younsoo, Kolesar, Jill M., Kwon, Glen S.·2011·Molecular Pharmaceutics

DOI 10.1021/mp2000549PMC PMC4896148

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Abstract

Poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA) micelles have a proven capacity for drug solubilization and have entered phase III clinical trials as a substitute for Cremophor EL in the delivery of paclitaxel in cancer therapy. PEG-b-PLA is less toxic than Cremophor EL, enabling a doubling of paclitaxel dose in clinical trials. We show that PEG-b-PLA micelles act as a 3-in-1 nanocontainer for paclitaxel, 17-allylamino-17-demethoxygeldanamycin (17-AAG), and rapamycin for multiple drug solubilization. 3-in-1 PEG-b-PLA micelles were ca. 40 nm in diameter; dissolved paclitaxel, 17-AAG, and rapamycin in water at 9.0 mg/mL; and were stable for 24 h at 25 °C. The half-life for in vitro drug release (t(1/2)) for 3-in-1 PEG-b-PLA micelles was 1-15 h under sink conditions and increased in the order of 17-AAG, paclitaxel, and rapamycin. The t(1/2) values correlated with log P(o/w) values, implicating a diffusion-controlled mechanism for drug release. The IC(50) value of 3-in-1 PEG-b-PLA micelles for MCF-7 and 4T1 breast cancer cell lines was 114 ± 10 and 25 ± 1 nM, respectively; combination index (CI) analysis showed that 3-in-1 PEG-b-PLA micelles exert strong synergy in MCF-7 and 4T1 breast cancer cell lines. Notably, concurrent intravenous (iv) injection of paclitaxel, 17-AAG, and rapamycin using 3-in-1 PEG-b-PLA micelles was well-tolerated by FVB albino mice. Collectively, these results suggest that PEG-b-PLA micelles carrying paclitaxel, 17-AAG, and rapamycin will provide a simple yet safe and efficacious 3-in-1 nanomedicine for cancer therapy.

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For effective and safe delivery of drug combinations, the drugs should be well-solubilized in the polymeric micelle so that excipient amount and injection volume can be minimized for parenteral injection.
“For the effective and safe delivery of drug combinations, the combination drugs should be well-solubilized in the polymeric micelle so that the amount of the excipient and injection volume can be minimized for parenteral injection [114, 188, 240].”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [240]
The Introduction and Discussion (pages not provided) identify sufficient solubility for IV infusion and lower toxicity from avoiding conventional solubilizing vehicles as goals for micelle delivery. The Discussion also reports high drug loading for combinations. Our copy does not say that this minimizes excipient amount or injection volume for parenteral injection; the injection volume mentioned in Methods is for an analytical assay. (LLM, conf=0.86)
Experimental — accuracy not yet measured
3-in-1 PEG-b-PDLLA micelles containing 17-AAG, paclitaxel, and rapamycin had a hydrodynamic size of about 40 nm and improved drug solubility to approximately 3 mg/mL in aqueous solution.
“The 3-in-1 micelle featured 40 nm hydrodynamic size and improved drug solubility (approximately up to 3 mg/mL in aqueous solution).”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [240]
In vitro cytotoxicity and combination index analysis showed synergistic effects of the drug components in 3-in-1 micelles against MCF-7 and 4T1 breast cancer cell lines.
“In vitro cytotoxicity studies and combination index (CI) analysis displayed a synergistic effect of drug components in 3-in-1 micelles for MCF-7 and 4T1 breast cancer cell lines.”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [240]

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Authors: Shin, H.-C., Alani, A. W. G., Cho, H., Bae, Y., Kolesar, J. M., & Kwon, G. S.
Affiliations: University of Wisconsin–Madison (US)
Oregon State University (US)
University of Kentucky (US)
Corresponding author: Kwon, Glen S.
ORCID: Shin, Ho-Chul
Alani, Adam W. G.
Cho, Hyunah
Bae, Younsoo
Kolesar, Jill M.
Kwon, Glen S.
Venue: Molecular Pharmaceutics
Publisher: American Chemical Society (ACS)
Published: 2011-06-23
Volume: 8
Issue: 4
Pages: 1257-1265
ISSN: 1543-8384 (ISSN-L)
1543-8392
DOI: 10.1021/mp2000549
PMC: PMC4896148
OpenAlex: W2318913758
Cited by: 126
References: 32
Citations by year: 2026: 1 · 2025: 6 · 2024: 3 · 2023: 2 · 2022: 6 · 2021: 3 · 2020: 9 · 2019: 9 · 2018: 7 · 2017: 10 · 2016: 17 · 2015: 15 · 2014: 8 · 2013: 12 · 2012: 17
FWCI: 4.98
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Molecular Pharmaceutics (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: University of Wisconsin-Madison
National Institute of Allergy and Infectious Diseases (R01AI043346)
Topics: Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
Keywords: polymeric micelles, poorly water-soluble drugs, paclitaxel, 17-AAG, rapamycin, drug solubilization, drug release kinetics, diffusion-controlled release, combination index, synergistic drug delivery, breast cancer, nanomedicine
MeSH terms: Humans, Micelles, Models, Theoretical, Polyesters, Polyethylene Glycols, Polymers, Solubility, Water, Benzoquinones, Paclitaxel, HSP90 Heat-Shock Proteins, Lactic Acid, Sirolimus, Cell Line, Tumor, Lactams, Macrocyclic, TOR Serine-Threonine Kinases

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A 3-in-1 polymeric micelle nanocontainer for poorly water-soluble drugs

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