Synergistic Enhancement of Cellular Uptake With CD44-Expressing Malignant Pleural Mesothelioma by Combining Cationic Liposome and Hyaluronic Acid-Lipid Conjugate

Our plain-English summary of Synergistic Enhancement of Cellular Uptake With CD44-Expressing Malignant Pleural Mesothelioma by Combining Cationic Liposome and Hyaluronic Acid-Lipid Conjugate, by Y. Sakurai, A. Kato, Y. Hida, et al (Journal of Pharmaceutical Sciences, 2019).

The study

• Authors: Y. Sakurai, A. Kato, Y. Hida, J. Hamada, N. Maishi, K. Hida, H. Harashima
• Journal: Journal of Pharmaceutical Sciences
• Published: 2019;108(10):3218-3224
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a highly aggressive form of cancer, with a median survival of less than 1 year. It is well known that the hyaluronan (HA) receptor CD44 is highly expressed by MPM cells and is reported to be correlated with a poor prognosis. We herein report on the development of a new type if drug delivery system against CD44 that involves the use of lipid nanoparticles (LNPs) equipped with a new type of HA derivative. In this study, we evaluated HA-lipid conjugation (HAL) via the end of the HA molecule through reductive amination, a process that allowed the carboxylate group to remain intact. As a result, the HAL-modified LNP appears to be a potent nanoparticle for dealing with MPM. Surprisingly, the use of a combination of a cationic lipid and HAL had a synergistic effect on cellular uptake in MPM and consequently permitted an anti-cancer drug such as cis-diamminedichloro-platinum(II) (CDDP). Intrapleural injection of CDDP-loaded HAL-LNP (1.5 mg/kg as CDDP) per week significantly suppressed the progression of this type of cancer in an MPM orthotopic model. These results suggest that HAL-modified LNP represents a potent delivery system for MPM cells that express high levels of CD44.

Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

In plain English

This laboratory study developed and tested a lipid nanoparticle (LNP) carrying a hyaluronic acid–lipid conjugate (HAL), made by linking lipid to the reducing end of hyaluronan so that its carboxylate groups stayed intact, to target CD44 on malignant pleural mesothelioma (MPM) cells. By flow cytometry, HMM3 and H226 cells expressed high CD44 and HMM1 moderate levels. Simply coating cationic LNPs with hyaluronan did not increase cellular uptake, whereas HAL modification increased uptake of cationic, but not neutral, liposomes; the synergy with the cationic lipid DOTAP was statistically significant (two-way ANOVA) up to 10 mol% DOTAP but not at 15 mol%, and 2.0 mol% HAL gave the highest uptake. CDDP-loaded HAL-LNP (262 ± 29 nm) matched free CDDP in cell killing. In H226 orthotopic mice, 24 h after intrapleural injection, tumour accumulation was 13.5 ± 10.2 %ID/organ for LNP versus 23.2 ± 7.8 %ID/organ for HAL-LNP. CDDP-loaded HAL-LNP (1.5 mg/kg CDDP, days 7, 14, 21, 28) suppressed MPM progression, with all treated mice alive at 45 days.

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: in vitro experiments in mesothelioma cell lines plus an orthotopic mouse model of malignant pleural mesothelioma
• Who was studied: Three human MPM cell lines (H226 from ATCC; HMM1 and HMM3 established from two patients aged 57 and 65) and athymic mice inoculated intrapleurally with 1.0 x 10^7 H226 cells; work performed in Japan
• Exposure: Lipid nanoparticles modified with a hyaluronic acid–lipid conjugate (HAL) and cationic lipids (DOTAP, DSTAP, DDAB, DC-chol), with or without encapsulated cisplatin (CDDP), given to cells or by intrapleural injection at 1.5 mg/kg CDDP
• Main results:
  • Hyaluronan simply coated on cationic LNPs did not raise cellular uptake in the MPM cells tested
  • HAL modification enhanced uptake of the cationic liposome but not the neutral liposome; synergy with DOTAP was significant up to 10 mol% but not 15 mol%
  • Optimum HAL density for cellular uptake was 2.0 mol% of total lipid
  • CDDP-loaded HAL-LNP equalled free CDDP in cell-killing activity, about 2-fold greater than CDDP-loaded unmodified LNP
  • Tumour accumulation 24 h after intrapleural injection: LNP 13.5 ± 10.2 %ID/organ versus HAL-LNP 23.2 ± 7.8 %ID/organ (described as a trend)
  • Treatment outcome in MPM-bearing mice: CDDP-loaded HAL-LNP suppressed progression, with all mice alive at 45 days; average survival printed for CDDP and PBS groups was 26.0 and 36.5 days
• The authors' conclusion: The authors concluded that combining HAL with a cationic LNP gave selective, synergistic uptake by CD44-positive MPM cells and that the optimized CDDP-loaded HAL-LNP achieved successful therapy in MPM-bearing mice
• Limitations the authors state:
  • The authors stated the mechanism of the synergistic uptake remains unknown and needs further study
  • Free hyaluronan inhibition of uptake could only be tested up to 10 mg/mL because higher concentrations made the medium too viscous
  • The in vivo enhancement of uptake was less marked than in vitro, possibly because MPM cells produce hyaluronan

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Hyaluronic Acid, Median Survival, Prognosis, Synergistic Effect.

Related studies

• Liposomal pemetrexed: formulation, characterization and in vitro cytotoxicity studies for effective management of malignant pleural mesothelioma — N. Essam Eldin, H.M. Elnahas, et al. (2015)
• Uptake-release by MSCs of a cationic platinum(II) complex active in vitro on human malignant cancer cell lines — I. Rimoldi, V. Coccè, et al. (2018)
• The effect of internalizing human single chain antibody fragment on liposome targeting to epithelioid and sarcomatoid mesothelioma — A.K. Iyer, Y. Su, et al. (2011)
• Histochemical demonstration of hyaluronic acid in pleural mesotheliomas — J.C. Wagner, D.E. Munday, et al. (1962)
• Pleural effusion hyaluronic acid as a prognostic marker in pleural malignant mesothelioma — J. Creaney, I.M. Dick, et al. (2013)
• Hyaluronic acid in the pleural fluid of patients with malignant pleural mesothelioma — N. Fujimoto, K. Gemba, et al. (2013)

Browse return to medical research.