Liposomes are a traditional form of drug delivery with multiple benefits such as drug stability, enhanced bioavailability, and the potential to be encapsulated with hydrophilic and hydrophobic molecules. These are also enhanced when liposomes are made from niche lipids with distinct properties, like Cardiolipin (CL). CL is a phospholipid that's mainly present in the inner mitochondria membrane, where it regulates mitochondrial health, energy production, and apoptosis. As CL's biological value has been such a strong component of liposomal formulations, particularly for mitochondrial dysfunction therapy and diseases in which mitochondria are weakened. Not only do cardiolipin liposomes (CL liposomes) have all the standard benefits of liposomal delivery, but also some other features that improve targeting, stability and therapeutic potential. What differentiates Cardiolipin liposomes from regular liposomes is their particular liking to mitochondrial membranes. Because CL can't be far from the mitochondria, these liposomes are innately better equipped to kill cells' mitochondria. That skill comes in handy when dealing with mitochondrial dysregulation-related diseases (Alzheimer's, Parkinson's, mitochondrial myopathies, some cancers). There, diseased mitochondria are a major component, and medicines that go straight to the mitochondria would have better cure with fewer side effects. Through the use of the CL lipids' affinity for mitochondria, CL liposomes can be modified to carry drugs to these cells for treatment specificity and efficacy. And also, because the liposomes can attach themselves to mitochondrial membranes, the drug can be better delivered and targeted into the mitochondria. The structure of Cardiolipin is also a major factor in CL liposomes' efficacy in drug delivery. CL is a tetra-acyl lipid that gives the liposome shell a different rigidity and stability than other phospholipids typically found in liposomes. This architecture not only helps CL liposomes to be biocompatible but it's also what makes them such a good container for a wide array of molecules of drugs such as hydrophobic molecules and proteins, that would otherwise be difficult to deliver. CL liposomes are also better long-term stable, especially when other liposomal systems would degrade or spill their contents too early. CL liposomes high encapsulation rate allows longer release of capsulated drug so that the therapy stays in circulation for a longer duration and enhances its therapeutic index. The portability of CL liposome designs further allows for additional innovative drug delivery technologies like targeting ligands to ensure even more precise delivery of treatments at the targeted tissue or cell.
Figure 1. The structure of cardiolipin and the architecture of cardiolipin-based liposomes. (Grygorieva G, et al.; 2023)
Not only are Cardiolipin liposomes selective, they're also very diverse in the kind of drug delivery applications they support. CL liposomes' potential to treat mitochondrial dysfunction opens up new way for diseases that are difficult to treat with existing systems of drug delivery. Mitochondrial diseases such as Leber's hereditary optic neuropathy (LHON), Kearns-Sayre syndrome and myoclonus epilepsy, for instance, are triggered by DNA and protein mutations in mitochondria. The mitochondria are the target organelles for these conditions, because the malfunctions of mitochondria are at the centre of the disease. With CL liposomes, drugs can be carried directly to the mitochondria without the typical obstacle to drug absorption and with a greater likelihood of reaching therapeutic levels within these critical organelles. The treatment could be made more efficient for these debilitating disorders with a more direct and precise therapy. Cardiolipin liposomes' utility does not stop at mitochondrial disorders but also fields in which more precise drug delivery and modulation are needed. Most exciting potential uses are in cancer treatment where CL liposomes might aggregate in cancer cell mitochondria, where there is a tendency for damaged mitochondrial metabolism. Cancer cells have mitochondria – and they require a lot of energy to propel rapid growth, so they're an ideal candidate for therapy. The CL liposomes could deliver chemotherapeutics or other therapeutic molecules to the mitochondria of cancer cells, where they would show more cytotoxic while causing minimal damage to normal tissues. That would give chemotherapy much more selective power, limiting common side effects such as hair loss and immune suppression due to off-target drug effects. Beyond the cancer and mitochondrial disorders, Cardiolipin liposomes could be tapped for neurodegenerative disorders. For diseases such as Alzheimer's and Parkinson's, neurons degenerate with age, and sometimes the mitochondria of these cells become damaged. Targeting mitochondria in neurons is a growing field of research for scientists seeking more efficient treatments for neurodegenerative diseases. And maybe by sending drugs or genetic material right to mitochondria using CL liposomes, it is possible to bring back normal mitochondria, ameliorate cell stress, and delay or halt neuronal degeneration. And because CL liposomes shield delicate cargo from degradation in the circulation, the chances of the drug making it to the target without much loss are improved for therapeutic success.
Although Cardiolipin liposomes have much to be exciting about as drug carriers, there are still a few obstacles to get through before they are taken to the next level. These liposomes are among the most difficult ones to scale up and make. Liposomal matrices, especially matrices that include specialty lipids such as Cardiolipin, need to be handled delicately throughout synthesis so the liposomes stay stable, functional and predictable in drug encapsulation performance. The production of Cardiolipin liposomes in scale without degrading quality or efficacy is still a major challenge. Large-scale production processes, as well as improvements in liposome formulation consistency and reproducibility, would have to be found in order to keep up with the demands of clinical trials and commercial application. Cardiolipin liposome stability over time is another problem. CL liposomes, while more stable than most standard liposomal formulations, can still be degraded (especially because Cardiolipin is itself an oxidative compound). To be used in clinical settings, CL liposomes must be kept in storage and during administration able to preserve their structural integrity and drug delivery capacity. Stabilising molecules, antioxidants or the improvement of the liposomal membrane's lipid profile can solve these stability concerns, but more research is needed to determine the best strategies. Both the toxicity and immunogenicity of liposomal formulations are factors too, particularly with regards to mitochondria. Although Cardiolipin is a naturally occurring lipid, when delivered into the body as part of a liposomal drug delivery system, it can induce unwanted immune reactions or toxicity, especially if liposomes aren't designed correctly. Therefore, we still need to study CL liposomes' biocompatibility in vivo, so they don't incite harmful immune responses or migrate into non-target tissue over time. Also, it is possible to reduce these risks by controlling the size, charge and surface of the liposomes such that they don't come under the immune system's suspicion of foreignness and that they don't wander around in the bloodstream. Despite these obstacles, Cardiolipin liposomes have a very bright future in drug delivery, especially as demand for targeted treatments that treat cellular-based disease grows. While it's still to be determined if the capacity of these specialised liposomal systems can be fully exploited, there are sure to be more clinical situations in which Cardiolipin-based formulations yield better therapeutic outcomes — particularly for mitochondrial dysfunction disorders. With the right technologies and approvals, CL liposomes could soon be a standard part of next-generation drug delivery systems.
Alternate Names:
Diphosphatidylglycerol (DPG) Liposomes CL-Containing Liposomes
Mitochondrial Liposomes
Cardiolipin-Enhanced Liposomes
References:
1. Grygorieva G, et al.; Liposomes: from August Wassermann to vaccines against COVID-19. ADMET DMPK. 2023, 11(4):487-497.
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