The blood clearance kinetics and pathway of polymeric micelles in cancer drug delivery
Abstract
Polymer micelles are one of the most investigated nanocarriers for drug delivery; many have entered clinical trials and some are in clinic use, but their delivery systems have not yet shown the expected high therapeutic efficacy in clinics. Further understanding their in vivo behaviors, particularly how quickly and by what mechanism polymer micelles are cleared ( i. e., via micelles or unimers) once injected, is key to solving this dilemma. Herein, we hope to answer these questions for the clinically relevant polyethylene glycol- block-poly(ε-caprolactone) (PEG-PCL) and PEG- block-poly(d,l-lactide) (PEG-PDLLA) micelles. A small fraction of the hydrophobic chain ends was conjugated with a pair of fluorescence resonance energy transfer (FRET) dyes, Cy5 and Cy5.5, and used to fabricate FRET micelles whose FRET efficiency was correlated to the percentage of polymer chains in the micelles, the micelle degree. In vitro, serum proteins induced PEG-PCL micelle dissociation to some extent; mouse serum or blood surprisingly did not induce micelle dissociation but once with shear applied by a microfluidic channel caused most PEG-PCL micelles dissociated. After intravenous administration in mice, the PEG-PCL or PEG-PDLLA micelles were quickly sequestered into the liver as unimers, and the micelle degree in the blood quickly decreased to about 20%. The FRET-imaging experiments showed that in blood vessels the micelles quickly dissociated into unimers, which were found associated with albumin in blood and in liver. Thus, it is concluded that, upon intravenous injection, the shear and the bloodborne proteins (particularly albumin) induced the most (∼80%) PEG-PCL and PEG-PDLLA micelles to quickly dissociate into unimers, which were sequestered by Kupffer cells, while intact micelles were difficult to clear. These micelles were able to penetrate tumors and were very stable with cell membranes, but dissociated gradually inside cells. These findings on in vivo micelle fate and the clearance mechanism are directional for the rational design of polymer micelles for improved therapeutics; particularly, improving micelle stability in blood is the prerequisite for surface functionalizations such as introducing targeting ligands.
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In vivo real-time FRET after intravenous injection of DiO/DiI-loaded PEG-PDLLA micelles in mice showed emission signals at 15 min, 1 h, and 3 h, with spectra showing increasing DiO emission around 501 nm and decreasing DiI emission at higher wavelengths, indicating quick release of the compounds from the micellar core.
“The spectra recorded (Fig. 13B) showed a peak with increasing intensity around 501 nm caused by DiO emission and a peak with decreasing intensity at higher wavelengths originated from DiI emission (FRET), indicating the quick release of the compounds from the micellar core.”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [235]
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- Authors
- Sun, X., Wang, G., Zhang, H., Hu, S., Liu, X., Tang, J., & Shen, Y.
- Affiliations
- Zhejiang University of Technology (CN)
- Zhejiang University (CN)
- Corresponding author
- Shen, Youqing
- Venue
- ACS Nano
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-05-30
- Volume
- 12
- Issue
- 6
- Pages
- 6179-6192
- ISSN
- 1936-0851 (ISSN-L)
- 1936-086X
- OpenAlex
- W2805861692
- Cited by
- 253
- References
- 64
- Citations by year
- 2026: 14 · 2025: 27 · 2024: 23 · 2023: 32 · 2022: 45 · 2021: 35 · 2020: 40 · 2019: 28 · 2018: 9
- FWCI
- 9.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ACS Nano (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Science and Technology of the People's Republic of China (2014CB931900)
- National Natural Science Foundation of China (21506192, U1501243, 51390481)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- polymeric micelles, blood clearance, PEG-PCL, micelle dissociation, serum albumin, Kupffer cells, tumor penetration, FRET imaging, nanocarriers, anticancer drug delivery
- MeSH terms
- Animals, Antineoplastic Agents, Female, Humans, Kinetics, Lactones, Mice, Inbred ICR, Micelles, Neoplasms, Polyethylene Glycols, Tumor Cells, Cultured, Drug Delivery Systems, Fluorescence Resonance Energy Transfer, Mice, Hep G2 Cells
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