Lipid Nanomedicine Delivery In Vivo

In the past few decades, the advent of lipid-based nano-delivery systems has brought research in the field of nanomedicines to new heights. Nanocarriers can encapsulate different types of drug molecules and have the advantages of improving drug solubility, extending circulation, achieving sustained and controlled drug release and targeted delivery. Lipids are important components of organisms, including fats, phospholipids, sterols, etc. Among them, phospholipids and sterols are the main components of biological membranes.

Compared with other nanoformulations, lipid-based nanocarriers have good biocompatibility and complete biodegradability, low carrier toxicity and immunogenicity, and have great potential in clinical practice for the treatment of various diseases. Most of the nanomedicines currently on the market are lipid-based nano-delivery systems represented by liposomes and lipid nanoparticles (LNP), which are widely used in many fields such as cancer treatment, viral or fungal infections, analgesia, and gene delivery. Although lipid nanomedicines have been studied for decades, their in vivo delivery process and interactions with organisms have not yet been elucidated.

Most of the clinical applications of lipid nanomedicines or products under development are administered by injection. Lipid nanocarriers carry drugs into the systemic blood circulation (or enter the systemic blood circulation through lymphatic reflux) and then transport them to the lesion site. The in vivo processes involved It is extremely complex. Not only can it affect the in vivo performance of the drug by changing the pharmacokinetics, biodistribution, intracellular delivery, release, metabolism and excretion of the encapsulated drug, but the carrier, as an exogenous “particle”, can also interact with the body to create mechanisms. Complex biological effects affect the clinical transformation and precise medication of lipid nanomedicines. For example, long-circulating doxorubicin liposomes can effectively reduce the myocardial toxicity associated with free doxorubicin injection, but long-term injection can produce hand-foot syndrome, injection reactions and other unidentified adverse reactions; a variety of lipid nanomedicines ( Hypersensitivity reactions during clinical use, including the mRNA COVID-19 vaccine, are all related to the interaction of lipid nanocarriers with the body. With the widespread vaccination of the COVID-19 mRNA vaccine, clinical data show that the vaccine can induce autoimmune hepatitis, but the relevant mechanism is still unclear. During the transport process in the body, lipid nanocarriers adsorb endogenous macromolecules (proteins, lipids, etc.) in blood, tissue fluid or cytosol to form a “biological corona”, which greatly affects the interaction between lipid nanocarriers and the body. And because the composition of the biological corona is extremely complex, it increases the uncertainty of the biological effects of lipid nanocarriers in vivo. Compared with other inorganic nanocarriers, most lipid nanocarriers are self-assembly systems, and their integrity in the body is difficult to track dynamically in real time. The main components (phospholipids, cholesterol, etc.) are similar to cell membranes. Explore their relationship with cells and tissues. The interaction is even more difficult, and there is a lack of in-depth systematic research so far.

Therefore, it is necessary to clarify the in vivo process of lipid nanomedicine and reveal the biological effects related to the process, and then based on the in vivo process and biological effect mechanism, through lipid nanocarrier design and the regulation of the body’s physiological and pathological environment, we can actively and accurately regulate the lipid nanocarrier in vivo. performance will greatly promote the clinical transformation and precise medication of lipid nanomedicines.

Lipid Nanomedicine Delivery Process In Vivo

Absorbed Into Blood

In addition to the most common intravenous administration routes (intravenous injection, bolus injection), lipid nanomedicines are also widely used in oral administration, intramuscular injection (subcutaneous, intradermal, intramuscular), nasal inhalation, eye drops, etc., but regardless of the Regardless of the route of administration, lipid nanomedicines will enter target and off-target tissues through blood or lymph circulation. Orally administered lipid nanomedicines adhere to the intestinal mucosa and are translocated across the mucus layer, and then are endocytosed by Peyer’s node M cells and enter the blood circulation via lymph. A small amount of intramuscularly injected lipid nanomedicine enters the blood circulation through capillary penetration, and most of it is absorbed by the lymphatic capillaries at the injection site. The lipid nanomedicine that is not captured by lymph nodes will enter the bloodstream through lymphatic circulation. Although most of the lipid nanomedicines administered through mucous membranes such as nasal inhalation and eye drops exert their medicinal effects locally, a small amount of them may also enter the bloodstream through the nasal mucosa and retina.

Blood Circulation

After lipid nanomedicines enter the blood circulation through different absorption pathways or direct intravenous infusion, the Gibbs free energy on the surface is relatively high, causing biomolecules (proteins, lipids, sugars) in the plasma to adsorb on them along the potential energy gradient, and forms biological crown on the surface. The protein content in plasma is high, and the biomolecules adsorbed by lipid nanoparticles in the blood circulation are mainly proteins. Plasma proteins with higher abundance quickly bind to the surface of lipid nanoparticles within 30 s and are gradually replaced by proteins with higher affinity to the particle surface over time. After adsorbing the protein corona, some nanomedicines are engulfed by circulating leukocytes and migrate to other areas with the cells, while the remaining nanomedicines circulate throughout the body with the blood.

Blood Vessel Penetration

Lipid nanomedicines circulating in the blood have multiple vascular extravasation pathways. 1. Passive transport: Under physiological conditions, there are gaps of different sizes in the capillaries of different organs, allowing nanoparticles of specific sizes to escape from the blood; 2. Active transport: direct modification by ligands or indirect adsorption of functional plasma After protein synthesis, lipid nanomedicines can be transported out of blood vessels through mediated endocytosis and transport through membrane receptors corresponding to vascular endothelial cells; 3. Mediated by leukocytes: Since circulating leukocytes have phagocytosis and chemotactic abilities, they can directly capture lipids in peripheral blood. material nanoparticles and carry them out of blood vessels into tissues. At the same time, during the extravasation of leukocytes, the blood vessel wall is briefly opened, causing the nanoparticles to extravasate along the concentration gradient. Vascular penetration is crucial for the accumulation and efficacy of lipid nanomedicines in target tissues (such as tumors), but penetration at non-target sites may also cause unexpected adverse reactions (such as liposomal doxorubicin Clinical skin toxicity).

Interstitial Transport

After extravasation from blood vessels, lipid nanomedicines enter the extracellular matrix (ECM) filled with interstitial fluid. ECM is a non-cellular three-dimensional macromolecular network composed of collagen, glycosaminoglycans, fibronectin, laminin and other glycoproteins. Its network structure prevents the penetration of large-sized lipid nanoparticles and further interaction with cells.

Cell Binding

The structure and composition of lipid nanomedicines are similar to those of cell membranes, so they can directly enter cells through membrane fusion and release the encapsulated drugs or genes. After their surface is modified with target molecules and adsorbed with functional plasma proteins or opsonins, lipid nanomedicines can Drugs can enter cells through receptor-mediated pinocytosis (clathrin-dependent, caveolin-dependent, macropinocytosis, etc.), and then exert drug effects or produce immune responses.

Intracellular Transport

Lipid nanomedicines that are imported through clathrin will initially enter early endosomal vesicles, and then fuse to form endosomal sorting and transport complexes and transfer to lysosomes; and through caveolin-dependent endocytosis Nanomedicines entering the cell will initially enter non-lysosomal subcellular compartments, eventually diffuse into the cytoplasm and enter the Golgi apparatus and endoplasmic reticulum. Lipid nanomedicines internalized through the macropinocytosis pathway have two transport pathways: a small amount of lipid nanomedicines are transported from macrophages to the endocytic recycling compartment and finally secreted out of the cell; while most drugs directly enter late endosomes, and are degraded by lysosomes or transported out of the cell through the endoplasmic reticulum-Golgi pathway and the exosome secretion pathway.

Body Clearance

Lipid nanomedicines in peripheral blood are mainly excreted from the body through renal excretion and hepatobiliary excretion. During the blood circulation process, some lipid nanoparticles are degraded by biological enzymes, filtered by the kidneys, and excreted from the body in the urine; while undegraded lipid nanoparticles adsorb opsonin proteins in the blood circulation and are quickly eliminated by the liver. It is endocytosed by non-parenchymal cells (liver sinusoidal endothelial cells, Kupffer cells), then degraded by hydrolases in lysosomes and finally excreted into the intestine with bile.