Enhancing Drug Delivery Efficacy Through Bilayer Coating of Zirconium-Based Metal-Organic Frameworks: Sustained Release and Improved Chemical Stability and Cellular Uptake for Cancer Therapy

Our plain-English summary of Enhancing Drug Delivery Efficacy Through Bilayer Coating of Zirconium-Based Metal-Organic Frameworks: Sustained Release and Improved Chemical Stability and Cellular Uptake for Cancer Therapy, by X. Liu, J. Obacz, G. Emanuelli, et al (Chemistry of Materials, 2024).

The study

• Authors: X. Liu, J. Obacz, G. Emanuelli, J.E. Chambers, S. Abreu, X. Chen, E. Linnane, J.P. Mehta, A.E.H. Wheatley, S.J. Marciniak, D. Fairen-Jimenez
• Journal: Chemistry of Materials
• Published: 2024;36(8):3588-3603
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The development of nanoparticle (NP)-based drug carriers has presented an exciting opportunity to address challenges in oncology. Among the 100,000 available possibilities, zirconium-based metal-organic frameworks (MOFs) have emerged as promising candidates in biomedical applications. Zr-MOFs can be easily synthesized as small-size NPs compatible with intravenous injection, whereas the ease of decorating their external surfaces with functional groups allows for targeted treatment. Despite these benefits, Zr-MOFs suffer degradation and aggregation in real, in vivo conditions, whereas the loaded drugs will suffer the burst effect-i.e., the fast release of drugs in less than 48 h. To tackle these issues, we developed a simple but effective bilayer coating strategy in a generic, two-step process. In this work, bilayer-coated MOF NU-901 remained well dispersed in biologically relevant fluids such as buffers and cell growth media. Additionally, the coating enhances the long-term stability of drug-loaded MOFs in water by simultaneously preventing sustained leakage of the drug and aggregation of the MOF particles. We evaluated our materials for the encapsulation and transport of pemetrexed, the standard-of-care chemotherapy in mesothelioma. The bilayer coating allowed for a slowed release of pemetrexed over 7 days, superior to the typical 48 h release found in bare MOFs. This slow release and the related performance were studied in vitro using both A549 lung cancer and 3T mesothelioma cells. Using high-resolution microscopy, we found the successful uptake of bilayer-coated MOFs by the cells with an accumulation in the lysosomes. The pemetrex-loaded NU-901 was indeed cytotoxic to 3T and A549 cancer cells. Finally, we demonstrated the general approach by extending the coating strategy using two additional lipids and four surfactants. This research highlights how a simple yet effective bilayer coating provides new insights into the design of promising MOF-based drug delivery systems.

© 2024 The Authors. Published by American Chemical Society.

In plain English

This laboratory study did not examine asbestos or exposed people, and no patients or animals were studied. The authors loaded pemetrexed, a standard mesothelioma chemotherapy drug, into zirconium-based particles (a metal-organic framework called NU-901), then coated them with asolectin, a soybean phospholipid mixture, and a surfactant, Pluronic F-127, to improve stability and slow release. In a salt solution (PBS), uncoated particles released 98% of their pemetrexed in the first 6 hours. Coated particles released 20% in that time and about 95% by day 7. Uncoated particles clumped together in laboratory fluids, while coated ones stayed dispersed. The coating lowered drug loading from 25.1 to 15.0 percent by weight. The authors tested the particles on a lung cancer cell line (A549) and an epithelioid pleural mesothelioma cell line (3T). In both, coated and uncoated particles ended up inside lysosomes, and the coating raised uptake in A549 cells. Drug-loaded coated particles showed a delayed toxic effect on both cell lines. The authors concluded that the method is a convenient and economical way to modify drug-loaded particles, which they described as promising for biomedical applications.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: pemetrexed was loaded into NU-901 particles, which were then given a two-layer coating. The particles were tested in cell culture, with no human or animal subjects.
• Who was studied: Two human cancer cell lines: A549 (non-small cell lung cancer, from ATCC) and 3T (a low-passage primary cell line from epithelioid pleural mesothelioma, obtained from MesobanK)
• Exposure: No asbestos exposure was studied. Cells were exposed to NU-901 zirconium metal-organic framework particles that were either uncoated or coated with asolectin (a soybean phospholipid mixture) and Pluronic F-127. The particles were either empty or loaded with the chemotherapy drug pemetrexed, and were compared with free pemetrexed.
• Main results:
  • In PBS, uncoated particles released 98% of their pemetrexed in the first 6 hours.
  • In PBS, coated particles (NU-901-A-F) released 20% of their pemetrexed in the first 6 hours and reached about 95% on day 7.
  • In water, uncoated particles released 32% of their pemetrexed in the first 2 hours and then plateaued. Coated particles released 8% in the first 2 hours and 14% after 7 days.
  • In PBS, uncoated particles released more than 80% of their framework building blocks (ligands) in about 48 hours. Coated particles released no detectable ligand for at least 140 hours.
  • In three biological media, uncoated particles clumped immediately, with sizes of 412, 1020 and 986 nm. Coated particles measured 168, 199 and 191 nm.
  • Drug loading was 25.1 wt % for uncoated pemetrexed-loaded particles and 15.0 wt % for coated pemetrexed-loaded particles.
  • In A549 lung cancer cells, uptake of coated particles (signal intensity 1750 au) was significantly higher than uptake of uncoated particles (500 au).
  • In 3T mesothelioma cells, uptake was high for both particle types, with only a small tendency toward higher uptake of coated particles.
  • In both cell lines, coated and uncoated particles were found inside lysosomes.
  • Empty particles of both types were tolerated by the cells up to 10 micrograms per mL.
  • Uncoated pemetrexed-loaded particles were as toxic to the cells as an equivalent dose of free pemetrexed. Coated pemetrexed-loaded particles showed a delayed toxic effect in both cell lines.
  • Eight coating variants made with two other lipids and four other surfactants stayed dispersed at around 200 nm over 3 days in PBS. Uncoated particles grew from 1311 to 1532 nm over the same period.
• The authors' conclusion: The authors concluded that the bilayer method provides a convenient and economical way to modify drug-loaded metal-organic framework nanocarriers, which they described as promising for biomedical applications. They suggested that the slower release could enable less frequent dosing.
• Limitations the authors state:
  • Optical resolution limited the authors' ability to assess how the particles interacted with lysosomes in standard confocal imaging, so they moved to super-resolution microscopy.
  • Drug loading decreased after the coating was applied.

Topics

Medical terms in this study, explained in our Lexicon: Encapsulation, Pemetrexed (Alimta), Chemotherapy, Mesothelioma, Lung Cancer.

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