Nanocarrier System Targeting Stromal Organelles

With the development of biomedicine, some diseases are clinically found to be caused by organelle lesions. And the drugs used to treat these diseases not only need to cross the cell membrane to enter the cell, but also need to target specific organelles to play a role. Therefore, in the development of drugs for these diseases, suitable carriers are needed to help the drugs target the target organelles. With the development of nanotechnology, researchers have found that nanosystems have obvious advantages in the field of organelle targeting. Therefore, more and more nanoparticles are used to target the endoplasmic reticulum, lysosomes and mitochondria.

Mitochondrial Targeting

Mitochondria play a very important role in cell apoptosis. A variety of drugs that induce apoptosis interact with mitochondrial membrane permeability transition pores. Drugs that have entered the cytoplasm still face two barriers before reaching the interior of the mitochondria: the protein skeleton in the cytoplasm and the membrane structure of the mitochondria themselves. Therefore, in order to further target active molecules to mitochondria, it is necessary to modify functional structures on nanocarriers that can specifically recognize and enter mitochondria, including non-peptide targeting sequences and polypeptide / protein targeting sequences.

Non-peptide targeting sequences are lipophilic cationic substances that rely on the high potential energy of the mitochondrial membrane to transport small molecule drugs or nanocarriers bound to them to mitochondrial matrices, such as triphenylphosphine (TPP) and lipophilic methyl groups Derivative TPMP. DQAsomes are liposomes containing the amphiphilic compound chloroquinoline, which release plasmid DNA after contact with the outer mitochondrial membrane. Cancer cells are more active than mitochondria of normal cells. Paclitaxel DQAsome can directly act on the mitochondrial membrane to induce apoptosis, which can prevent 50% of human colon cancer cells from growing in nude mice. DQAsome enters the endosome through endocytosis, and then destroys the endosomal membrane and transfers to the mitochondrial membrane. Once the DQAsome membrane contacts the mitochondrial membrane, it will be unstable and release paclitaxel, and acting on the mitochondrial membrane, the mitochondria release cytochrome C to induce cells Apoptosis eventually leads to cell death.

More than 99% of mitochondrial proteins are derived from cytoplasmic ribosomes, and synthetic precursor proteins are transported to mitochondria by means of targeting signals. The signal sequence is usually located at the N-terminus of the transporter protein and is rapidly hydrolyzed after entering the mitochondria. By combining these signal peptides / proteins with drugs and carriers, or integrating DNA sequences encoding mitochondrial targeting signal peptides (MTS) with therapeutic DNA, mitochondrial targeting of target molecules or carriers can be achieved.

Lysosomal Targeting

The lysosome is a cytoplasmic structure surrounded by a single layer of membrane, with an internal pH of 4-5, rich in hydrolase, and has intracellular digestion function. The newly formed primary lysosomes are repeatedly fused with various other structures to form membrane vesicles in various forms, and digest the wrapped molecules. Defects in lysosomal function will cause a variety of disorders. Lysosomal storage disease (LSD) includes more than 40 genetic diseases with single or multiple enzyme defects. These enzymes are involved in breaking down macromolecular substances that are swallowed into cells, such as lipids, sugars, and proteins. If the relevant hydrolase is missing, the substrate will not be degraded, and then the pathological reaction will be triggered. In addition, clinical studies have found that in addition to endocytosis mediated by cell-like cave-like depressions, other forms of endocytosis involve lysosomal processes, which is very beneficial for drugs that require lysosomal targeting. Clinically, enzyme supplement therapy is used to treat LSD with good results, but the enzyme is easily cleared in the blood circulation and difficult to reach the target site. Encapsulating the enzyme in the carrier can play a stabilizing role, and then passively target the enzyme to the lysosome through the endocytosis pathway, which improves the therapeutic effect.

Using liposomes can efficiently deliver β-fructofuranosidase, a-mannosidase, neuraminidase, and β-glucosidase to the lysosome to treat the corresponding LSD. Glucosidase and amyloglucosidase liposomes have achieved good results in clinical trials for the treatment of reticuloendothelial diseases Gaucher’s disease and Pompe’s disease. When the lipid-binding protein Saposin C is lacking, a large amount of multivesicular bodies accumulates in the cell, destroying the homeostasis of nerve cell growth and development, resulting in a complex LSD. After intravenous injection of SaposinC-loaded liposomes, it was found that the liposomes were concentrated in the lysosomes of nerve cells, returning the accumulated multivesicular bodies to normal levels.

Endoplasmic Reticulum Targeting

Endoplasmic reticulum (ER) is a closed network pipeline system composed of endometrium. Its main function is to synthesize proteins and lipids. The ER-synthesized protein may misfold or aggregate, leading to a series of diseases, such as Alzheimer’s disease and fibrous vesicle disease. Targeted drug delivery of ER has not received much attention at present. Preparation of endoplasmic reticulum N-glycosylation inhibitor N-butyl deoxynojirimycin pH-sensitive liposomes (composed of DOPE and cholesterol hemisuccinate), successfully inhibited mouse melanoma cell tyrosinase Activity and significantly reduced the dose administered.