Correlation between in vitro stability and pharmacokinetics of poly(ε-caprolactone)-based micelles loaded with a photosensitizer
Open accessAbstract
Polymeric micelles are extensively investigated as drug delivery systems for hydrophobic drugs including photosensitizers (PSs). In order to benefit from micelles as targeted delivery systems for PS, rather than only solubilizers, the stability and cargo retention of the (PS-loaded) micelles should be properly assessed in biologically relevant media to get insight into the essential parameters predicting their in vivo performance (i.e., pharmacokinetics). In the present study, asymmetric flow field-flow fractionation (AF4) was used to investigate the in vitro stability in human plasma of empty and meta-tetra(hydroxyphenyl)chlorin (mTHPC)-loaded dithiolane-crosslinked micelles based on poly(ɛ-caprolactone)-co-poly(1,2-dithiolane‑carbonate)-b-poly(ethylene glycol) (p(CL-co-DTC)-PEG) and non (covalently)-crosslinked micelles composed of poly(ε-caprolactone)-b-poly(ethylene glycol) (pCL-PEG). AF4 allows separation of the micelles from plasma proteins, which showed that small non (covalently)-crosslinked pCL9-PEG (17 nm) and pCL15-PEG (22 nm) micelles had lower stability in plasma than pCL23-PEG micelles with larger size (43 nm) and higher degree of crystallinity of pCL, and had also lower stability than covalently crosslinked p(CL9-DTC3.9)-PEG and p(CL18-DTC7.5)-PEG micelles with similar small sizes (~20 nm). In addition, PS (re)distribution to specific plasma proteins was observed by AF4, giving strong indications for the (in)stability of PS-loaded micelles in plasma. Nevertheless, fluorescence spectroscopy in human plasma showed that the retention of mTHPC in non (covalently)-crosslinked but semi-crystalline pCL23-PEG micelles (>8 h) was much longer than that in covalently crosslinked p(CL18-DTC7.5)-PEG micelles (~4 h). In line with this, in vivo circulation kinetics showed that pCL23-PEG micelles loaded with mTHPC had significantly longer half-life values (t½-β of micelles and mTHPC was 14 and 18 h, respectively) than covalently crosslinked p(CL18-DTC7.5)-PEG micelles (t½-β of both micelles and mTHPC was ~2 h). As a consequence, long circulating pCL23-PEG micelles resulted in significantly higher tumor accumulation of both the micelles and loaded mTHPC as compared to short circulating p(CL18-DTC7.5)-PEG micelles. These in vivo data were in good agreement with the in vitro stability studies. In conclusion, the present study points out that AF4 and fluorescence spectroscopy are excellent tools to evaluate the (in)stability of nanoparticles in biological media and thus predict the (in)stability of drug loaded nanoparticles after i.v. administration, which is favorable to screen promising delivery systems with reduced experimental time and costs and without excessive use of animals.
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AF4's more interesting application concerns the study of micelles stability in complex biological matrices, since it can separate intact micelles from unimers and from biological fluid components without the inconveniences of chromatographic techniques.
“Its more interesting application concerns the study of micelles stability in complex biological matrices [241], since it is possible to separate intact micelles from unimers and from biological fluid components, without the inconveniencies of the chromatographic techniques.”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [241]
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Ghezzi, M., Pescina, S., Padula, C., Santi, P., Del Favero, E., Cantù, L., & Nicoli, S. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.02.031 · Cited by 1,135 · see citing works
- Authors
- Liu, Y., Fens, M. H. A. M., Capomaccio, R. B., Mehn, D., Scrivano, L., Kok, R. J., Oliveira, S., Hennink, W. E., & van Nostrum, C. F.
- Affiliations
- Utrecht University (NL)
- Joint Research Centre (IT)
- ORCID
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 328
- Pages
- 942-951
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W3093855272
- Cited by
- 25
- References
- 47
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 2 · 2023: 3 · 2022: 7 · 2021: 3
- FWCI
- 0.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Controlled Release (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Joint Research Centre (European Commission) (submittedVersion)
- Funders
- Chinese Government Scholarship
- European Commission
- China Scholarship Council
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Photodynamic Therapy Research Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- photosensitizer delivery, pharmacokinetics, asymmetrical flow field-flow fractionation, circulation half-life
- MeSH terms
- Animals, Caproates, Drug Carriers, Humans, Lactones, Micelles, Polyesters, Polyethylene Glycols, Photosensitizing Agents
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