Lipidomics in biomedical research: chance and challenges

Lipids are essential for numerous functions in the human body. They are not only components of cell membranes, extracellular vesicles and hormones, but also store energy, facilitate metabolism, mediate cell signalling pathways, and much more. This incredibly diverse class of molecules encompasses at least 100,000 distinct species in humans.1 Due to their great complexity and importance in human physiology, disturbances in any mechanism involving lipids may lead to diseases. It is therefore not surprising that lipid biology has attracted increasing interest in the fields of medicine and pharmacology, with the goal of advancing the diagnosis of human diseases, as well as developing novel therapies and drug targets.

Rise of lipidomics

In recent years, the importance and application of lipidomics has grown dramatically, thanks to advances in scientific techniques such as mass spectrometry. We are now able to understand the causes of the physiological processes of diseases by identifying and quantifying their biomarkers, and examine how molecular and biochemical aspects of lipids play a role. While the application of mass spectrometry in lipidomics is not new, it has progressed dramatically in recent years through the support of state-of-the-art biostatistical, bioinformatic and high-throughput data analysis methods.

Metabolomics research

One area where modern lipidomics has helped tremendously is in the study of metabolism. Since metabolism is central to numerous physiological functions, lipids are not only involved in metabolic ailments, but also in diseases of the cardiovascular, renal and nervous systems, as well as of the liver, gallbladder, bile, and pancreas.2 Consequently, the growing ability to study the effect of lipid metabolism at the cellular and physiological levels has greatly facilitated clinical diagnostics of a vast variety of diseases.

Study of extracellular vesicles

As previously mentioned, lipids are also important constituents of extracellular vesicles. Made of a lipid bilayer, extracellular vesicles separate and safeguard the material inside cells, such as proteins, metabolites, nucleic acids and lipids, from the environment outside. Lipidomics is now allowing the study of extracellular vesicles to deepen the understanding of the biological structure of membranes and the mechanisms participating in vesicular trafficking. Extracellular vesicles are also being investigated as potential biomarkers for a variety of diseases, and as biological nanoparticles for drug delivery.3 While the application of lipidomics in extracellular vesicle research is still emerging, its growing interest and practice hold great potential for disease diagnostics and drug development.

Cancer research

Lipidomics is also helping to considerably advance cancer research, treatments and immunotherapy approaches. As cancer development is known to be associated with alterations in cellular signalling pathways and regulating mechanisms, the ability to detect changes in physio-pathological conditions in cells through lipidomics is increasingly enabling effective and personalised cancer-targeting therapies. Cell membranes are being used as biomimetic nanocarriers for anticancer drugs, the host immune system is being activated to kill cancer cells, and smart nanomaterials are being designed to achieve simultaneous cancer radiosensitisation and precise antiangiogenesis by encapsulating nanoparticles with cell membranes.

Examples of the latest applications of lipidomics in cancer research include the achievement of in-vivo anti-tumour efficacy, by He et al., through the use of red blood cell (RBC) MoSe2-potentiated photothermal therapy (PTT) to prevent macrophage phagocytosis.4 In another study, Wang et al. have designed an NIR-triggered antigen-capturing nanoplatform using UCNP as a carrier, indocyanine green (ICG) as a light absorber, rose bengal (RB) as a photosensitiser, and a lipid molecule (DSPE-PEG-mal) as an antigen-capturing agent, for synergistic photo-immunotherapy in the treatment of metastasis cancer.5 Pinault et al. have designed a simple and cost-effective 1D high-performance thin layer chromatography (HPTLC) method validated to quantify lipid extracts of whole tumour cells or hepatocyte-isolated mitochondria.6 And Yeom et al. have shown that incorporating d-chirality into nanosystems enhances their uptake by cancer cells and prolongs in-vivo stability in circulation. Their research reveals that chiral nanosystems may have the potential to provide a new level of control for drug delivery systems, tumour detection markers, biosensors, and other biomaterial-based devices.7

Vaccine development

Liposomes have also become invaluable in the field of modern vaccine design due to their abilities to act as delivery vehicles. Although the theory and application of liposomes as a means of transporting drugs and genes is not new, more recent research has focused on the use of liposomes as vaccine adjuvants, not only for transporting antigens, but also as a means of increasing the immunogenicity of peptide and protein antigens.8 The rapid development of the field has been made possible through a combination of technological advances and a clearer knowledge of the immune system. Important progress in the field of liposomal vaccine adjuvants includes research by Henriksen-Lacey et al. into the development of liposomal systems that contain and deliver immunostimulators and antigens to target diseases that require stimulation of both humoral and cell-mediated immune responses.

Challenges of lipidomics

The rapid evolution of lipidomics has not come without its problems. Due to a current lack of standardisation, there are great discrepancies in methods, technologies, workflows, data analysis and reporting absolute lipid concentrations. Other difficulties include misidentifications, improper annotation of lipid species and over-reporting.

This has become a considerable challenge, undermining the reliability, reproducibility and comparability of progress in the field of liposome-based drug development. Overcoming these hurdles will require a combination of harmonised experimental protocols and high-quality lipid standards.

The future of lipidomics

For consistency and, thus, reliability in lipidomics, we need to ensure harmonisation. This is precisely the goal of the Lipidomics Standards Initiative (LSI) platform, which is part of the International Lipidomics Society (ILS). By defining minimal standardisation guidelines, the Initiative aims to enforce more consistency in the field of lipidomics.9 The hope is that as more lipidomic researchers perceive the current challenges and irregularities, there will be a stronger interest in adopting and adhering to harmonised guidelines that secure the reputability of their studies.

Another crucial means of ensuring the integrity of lipidomics is through the use of well-defined internal lipid standards in mass-spectrometry, which would ensure accurate identification of the structure or concentration of different molecular species. Chemically pure synthetic lipid standards, such as those from Avanti Polar Lipids, are optimal for lipidomics as they ensure precise quantisation or identification of numerous classes of lipids, including glycerolipids, glycerophospholipids, sphingolipids, and sterols. Researchers can choose between qualitative standards for general identification of lipids, and quantitative standards for identifying the structure and concentration of molecular species.

Another factor to consider when selecting lipid standards is globalisation. As demonstrated by the current pandemic, disease sees no borders. Thus, it is essential that internal standards used for drug or vaccine development are accessible quickly and easily worldwide. Presently, for example, Avanti monophosphoryl lipid A derivatives and adjuvants systems are used around the world for SARS-CoV-2 vaccine development.

About the author

Afrisha Anderson is a Product Manager at Merck KGaA.  She received her bachelor’s degree in Chemistry from University of Missouri in Columbia, Missouri, USA in 2005 and her MBA from Webster University in St. Louis, Missouri, USA in 2011.  Anderson has over 13 years of experience in the life science industry.

References

  1. A Shevchenko, K Simons. Lipidomics: Coming to Grips with Lipid Diversity. Nat Rev Mol Cell Biol. 11: 2010; 593–598
  2. Wu Z, Bagarolo GI, Thoröe-Boveleth S, Jankowski J. “Lipidomics”: Mass spectrometric and chemometric analyses of lipids. Adv Drug Deliv Rev. 2020;159:294-307. DOI: 10.1016/j.addr.2020.06.009. Epub 2020 Jun 14. PMID: 32553782.
  3. Skotland T, Sagini K, Sandvig K, Llorente A. An emerging focus on lipids in extracellular vesicles. Adv Drug Deliv Rev. 2020;159:308-321. DOI: 10.1016/j.addr.2020.03.002. Epub 2020 Mar 7. PMID: 32151658.
  4. L. He, T. Nie, X. Xia, T. Liu, Y. Huang, X. Wang, T. Chen; Designing Bioinspired 2D MoSe2 Nanosheet for Efficient Photothermal-Triggered Cancer Immunotherapy with Reprogramming Tumor-Associated Macrophages; Advanced Functional Materials; https://doi.org/10.1002/adfm.201901240; WILEY-VCH Verlag Lipidomics Vol. 2 2021; 20-26
  5. M. Wang, J. Song, F. Zhou, A. R. Hoover, C. Murray, B. Zhou, L. Wang, J. Qu, W. R. Chen; NIR-Triggered Phototherapy and Immunotherapy via an Antigen-Capturing Nanoplatform for Metastatic Cancer Treatment; Advanced Science; https://doi.org/10.1002/advs.201802157; WILEY-VCH Verlag Lipidomics Vol. 2 2021; 11-15
  6. M. Pinault, C. Guimaraes, J.-F. Dumas, S. Servais, S. Chevalier, P. Besson, C. Goupille; A 1D High Performance Thin Layer Chromatography Method Validated to Quantify Phospholipids Including Cardiolipin and Monolysocardiolipin from Biological Samples; European Journal of Lipid Science and Technology; https://doi.org/10.1002/ejlt.201900240; WILEY-VCH Verlag Lipidomics Vol. 2 2021; 27-32
  7. J. Yeom, P. P. G. Guimaraes, H. M. Ahn, B.-K. Jung, Q. Hu, K. McHugh, M. J. Mitchell, C.-O. Yun, R. Langer, and A. Jaklenec; Chiral Supraparticles for Controllable Nanomedicine; Advanced Materials; DOI: 1 0.1002/adma.201903878; WILEY-VCH Verlag Lipidomics Vol. 2 2021; 33-37
  8. Malou Henriksen-Lacey, Karen Smith Korsholm, Peter Andersen, Yvonne Perrie & Dennis Christensen(2011) Liposomal Vaccine Delivery Systems, Expert Opinion on Drug Delivery, 8:4, 505-519, DOI: 10.1517/17425247.2011.558081
  9. Ekroos, Kim; “Leaving the Wild West Era of Lipidomics”; Interview in WILEY-VCH Verlag Lipidomics Vol. 2 2021; 7-9

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