Liposomes with Different Sizes Drug Delivery Commercially Available

Liposomes are now a foundation of high-tech drug delivery because they are biocompatible, have the ability to transport both hydrophilic and hydrophobic molecules, and are capable of optimizing therapeutic effects with minimum side effects. They possess their multipurpose structure, which consists of bilayers of lipids surrounding a aqueous center and can be used for the encapsulation and controlled release of many different pharmaceutical molecules. Size directly determines pharmacokinetics, biodistribution and cell uptake, which in turn allows for a tailoring of liposomes to the clinical applications.

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What is the Effect of Particle Size on Liposomes?

Liposome particle size also dictates the way that liposomes are regulated in terms of time of circulation, biodistribution, cellular uptake, and crossing biological boundaries. These properties directly influence liposomal drug delivery system efficacy, safety and pharmacokinetics.

Circulation Time in the Bloodstream

• Smaller Liposomes (20–200 nm): These particles tend to avoid rapid clearance by the mononuclear phagocyte system (MPS) due to their small size and surface properties, particularly when PEGylated. This results in extended blood circulation times, allowing greater accumulation in target tissues, such as tumors, via the enhanced permeability and retention (EPR) effect.
• Larger Liposomes (>200 nm): Larger liposomes are more readily taken up by the MPS, leading to shorter circulation times. This effect can be beneficial in certain applications, such as targeting macrophage-rich tissues in inflammatory or infectious diseases.

Tissue Penetration and Accumulation

• Smaller Liposomes (20–200 nm): Their nanoscale size allows for better penetration into tissues with tight endothelial junctions, such as solid tumors. This is facilitated by the enhanced permeability and retention (EPR) effect, where small liposomes passively accumulate in tumor tissues with leaky vasculature.
• Larger Liposomes (>200 nm): While larger liposomes may not penetrate deep into dense tissues, they can accumulate in areas with fenestrated vasculature or in tissues where phagocytic uptake is desired.

Cellular Uptake and Internalization

• Smaller Liposomes (20–200 nm): Nano-sized liposomes are often internalized more efficiently by cells through endocytosis, which is advantageous for delivering drugs to intracellular targets. Their smaller size also enhances the ability to cross biological barriers, such as the blood-brain barrier in certain cases.
• Larger Liposomes (>200 nm): Larger liposomes are less likely to be internalized by non-phagocytic cells. However, their size makes them suitable for targeting phagocytic cells like macrophages, dendritic cells, or Kupffer cells, as in the case of liposomal formulations for treating infections or activating immune responses.

Drug Encapsulation Efficiency

• Smaller Liposomes (20–200 nm): While smaller liposomes have higher surface area-to-volume ratios, their limited internal aqueous core restricts the encapsulation capacity for hydrophilic drugs.
• Larger Liposomes (>200 nm): Larger liposomes, particularly large unilamellar vesicles (LUVs) or multilamellar vesicles (MLVs), provide a higher encapsulation capacity for both hydrophilic and hydrophobic drugs, making them ideal for formulations requiring high drug loads.

Biodistribution

The biodistribution of liposomes is heavily size-dependent. Smaller liposomes can target a wider range of tissues due to enhanced mobility in biological systems. Larger liposomes are often localized in organs with higher phagocytic activity, such as the liver and spleen.

Liposomes with Different Sizes for Drug Delivery

Liposomes are spherical vesicles composed of one or more phospholipid bilayers, with an aqueous core that can encapsulate both hydrophilic and hydrophobic drugs. The size and structural properties of liposomes significantly influence their therapeutic applications, particularly in targeted drug delivery. Liposomes can range in size from nanometers to micrometers, and their classification into different categories—small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs), multilamellar vesicles (MLVs), and giant unilamellar vesicles (GUVs)—offers varying benefits in drug delivery systems. These different liposome types are used to enhance drug bioavailability, improve stability, and enable controlled release.

Small Unilamellar Vesicles

Small Unilamellar Vesicles (SUVs) are a type of liposome typically ranging from 20 nm to 100 nm in diameter. These vesicles consist of a single lipid bilayer surrounding an aqueous core. Due to their small size, SUVs possess a high surface-area-to-volume ratio, which enhances their potential for drug encapsulation.

• The key advantage of SUVs lies in their ability to effectively deliver a wide range of drugs, particularly hydrophobic compounds, while minimizing the systemic side effects often seen with traditional drug delivery methods. Furthermore, the small size of SUVs allows them to evade the mononuclear phagocyte system (MPS), thereby extending their circulation time and improving the targeting efficiency to specific tissues, especially tumors, via the enhanced permeability and retention (EPR) effect.
• Examples of marketed products using SUVs include Doxil, a PEGylated liposomal formulation of doxorubicin. Doxil utilizes small unilamellar vesicles to enhance drug delivery while significantly reducing cardiotoxicity and other side effects associated with free doxorubicin, providing a successful treatment for various cancers, including Kaposi's sarcoma and ovarian cancer.

Large Unilamellar Vesicles

Large Unilamellar Vesicles (LUVs) are liposomes with a size range from 100 nm to 500 nm in diameter, composed of a single lipid bilayer. LUVs are capable of encapsulating a significantly higher volume of aqueous content compared to SUVs due to their larger core, making them an ideal vehicle for delivering both hydrophobic and hydrophilic drugs.

• The larger size of LUVs enhances their capacity for sustained drug release and increased drug loading, which is crucial in therapies requiring higher doses or prolonged drug action. Moreover, LUVs' size helps with targeting specific tissues more effectively and can be used to encapsulate biomolecules like proteins and RNA for gene therapies.
• Onivyde, a PEGylated liposomal formulation of irinotecan, is a notable example of LUVs in clinical use. Onivyde has demonstrated enhanced efficacy and reduced side effects in the treatment of metastatic pancreatic cancer, leveraging LUVs to ensure a controlled release of the chemotherapeutic agent.

Multilamellar Vesicles

Multilamellar Vesicles (MLVs) are larger, more complex liposomes that contain multiple lipid bilayers, each separated by an aqueous phase. Ranging from 500 nm to several micrometers in diameter, MLVs offer the advantage of encapsulating both hydrophobic and hydrophilic substances within the different layers.

• The multi-layered structure provides greater stability, protecting the encapsulated drug from premature degradation. MLVs also enable controlled and prolonged release, which is especially beneficial in therapies that require a slow and steady delivery of the active ingredient over an extended period.
• DepoDur, a sustained-release formulation of morphine sulfate, is an example of an MLV-based drug delivery system. DepoDur utilizes multilamellar vesicles to release morphine gradually, significantly improving pain management in post-operative patients and offering a longer duration of effect with fewer administrations.

Giant Unilamellar Vesicles

Giant Unilamellar Vesicles (GUVs) are liposomes with diameters ranging from 1 to 100 micrometers, significantly larger than SUVs, LUVs, or MLVs. GUVs consist of a single lipid bilayer surrounding a large aqueous core. They are primarily used in research and development, particularly for studies related to cell interactions, drug encapsulation, and the design of drug delivery systems targeting specific cells or tissues.

While GUVs are less commonly used in routine drug delivery due to their size, they hold promise for gene and RNA delivery, where large molecules or multiple types of payloads need to be incorporated. Their size also makes them an attractive option for modeling the cell membrane and studying cellular processes on a larger scale.

In recent developments, GUV-based technology has been adapted for nucleic acid delivery, inspired by the need for scalable, efficient vehicles capable of delivering large RNA or DNA molecules. However, their clinical use remains limited compared to other liposomal forms like SUVs and LUVs.

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Commercially Available Liposome Formulations for Drug Delivery

Numerous liposomal formulations are already commercially available, addressing a wide range of medical conditions, from cancer to infections, pain management, and more. These formulations are designed with specific sizes and structures to optimize the therapeutic effect of the encapsulated drug while minimizing side effects.

Doxil

Doxil (also known as Caelyx in Europe) is a liposomal formulation of doxorubicin, one of the most commonly used chemotherapy drugs. This PEGylated liposomal formulation is designed to reduce the cardiotoxicity and other systemic side effects associated with conventional doxorubicin administration. The liposome encapsulates the drug and extends its circulation time in the bloodstream, enhancing its delivery to tumor cells through the enhanced permeability and retention (EPR) effect.

Doxil is primarily used in the treatment of cancers such as Kaposi's sarcoma, ovarian cancer, and multiple myeloma. It has become a benchmark in liposomal drug delivery systems, demonstrating significant improvements in therapeutic efficacy while reducing adverse effects.

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Onivyde

Onivyde is a PEGylated liposomal formulation of irinotecan, a chemotherapy agent used in the treatment of metastatic pancreatic cancer. Developed by Merrimack Pharmaceuticals, Onivyde enhances the solubility and stability of irinotecan, which is poorly water-soluble in its free form, thereby reducing its toxicity and improving its pharmacokinetics.

Onivyde works by encapsulating the drug within liposomes, allowing for sustained release and reduced side effects such as nausea, vomiting, and diarrhea. It is often used in combination with other chemotherapeutic agents, such as fluorouracil and leucovorin, for more effective treatmen

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Ambisome

Ambisome is a liposomal formulation of amphotericin B, an antifungal agent used to treat severe fungal infections, such as those caused by Candida, Aspergillus, and Cryptococcus species. Conventional amphotericin B is highly toxic, particularly to the kidneys. However, Ambisome encapsulates the drug in liposomes, significantly reducing its nephrotoxicity while maintaining its potent antifungal activity.

Ambisome is often used in the treatment of invasive fungal infections in immunocompromised patients, such as those with HIV/AIDS or cancer undergoing chemotherapy.

Fungisome

Fungisome is another liposomal formulation of amphotericin B developed by Lifecare Innovations. Similar to Ambisome, Fungisome is designed to reduce the toxicity of amphotericin B, particularly nephrotoxicity, and improve its pharmacokinetic profile.

Fungisome has shown excellent results in treating severe systemic fungal infections, with fewer side effects and greater tolerability compared to the conventional formulation. It is particularly beneficial in managing infections in immunocompromised patients.

Onpattro

Onpattro is the first FDA-approved siRNA-based liposomal drug for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR). Developed by Alnylam Pharmaceuticals, Onpattro uses lipid nanoparticles similar to liposomes to deliver patisiran, a small interfering RNA (siRNA) that targets and silences the production of abnormal transthyretin protein. This protein causes the amyloidosis associated with hATTR.

Onpattro is a groundbreaking treatment in the realm of RNA therapeutics, and its liposomal delivery system ensures the stability of the fragile RNA molecules and promotes their efficient uptake into target cells, resulting in a reduction in amyloid deposits.

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DepoDur

DepoDur is a liposomal formulation of morphine sulfate, a potent opioid used for pain management. DepoDur uses DepoFoam technology, which encapsulates morphine in multilamellar liposomes for sustained release. This formulation enables the extended delivery of morphine, providing prolonged pain relief for up to 48 hours after a single epidural injection.

DepoDur is primarily used for managing post-surgical pain, particularly in patients undergoing major orthopedic procedures or abdominal surgery. Its extended-release profile reduces the need for frequent dosing and minimizes the risk of opioid-related side effects.

Visudyne

Visudyne is a liposomal formulation of verteporfin, a photosensitizing agent used in photodynamic therapy (PDT) for age-related macular degeneration (AMD) and other retinal disorders. Verteporfin, when activated by light, generates reactive oxygen species that selectively damage abnormal blood vessels in the eye, thereby preventing vision loss.

Visudyne is designed to improve the stability and targeted delivery of verteporfin, allowing for effective treatment of retinal diseases without causing significant systemic toxicity. The liposomal formulation facilitates the controlled release and precise localization of the drug to the site of action.

Marqibo

Marqibo is a liposomal formulation of vincristine, an anticancer agent commonly used to treat leukemia and lymphoma. Vincristine, when encapsulated in liposomes, has improved pharmacokinetics, including prolonged circulation time and enhanced accumulation in target tissues. This formulation is particularly useful in treating hematologic malignancies like acute lymphoblastic leukemia.

Marqibo provides a safer and more effective alternative to free vincristine by reducing the risk of neurotoxicity and other side effects. It is marketed by Merrimack Pharmaceuticals and approved for the treatment of ALL and non-Hodgkin lymphoma.