Transcellular Transport Of Enzyme-triggered Drug Delivery Systems For Deep Tumor Penetration In Hepatocellular Carcinom

At present,the traditional chemotherapy method not only produces many painful adverse reactions to the patient ’s body,but also is limited by the shortcomings of tumor multidrug resistance and toxic and side effects on the body.Nano drug delivery system is one of the main research directions of chemotherapy in the past five years.At present,many researchers are committed to the study of targeted drug delivery.By designing a series of tumor microenvironment stimuli-responsive nanocarrier systems to increase the absorption of drugs in tumor cells,improve the biological distribution and aggregation of tumor sites,and make targeted drug therapy possible.Although the advantages of nano-drug delivery systems in the direction of tumor treatment are gradually emerging,the low permeability of drugs still restricts the development of nano-drugs.In response to this problem,we have constructed two nano-drug delivery systems with gamma-glutamyltransferase(GGT)response in the tumor microenvironment.Its precise targeting ability,excellent biochemically stable structure and efficient active transport ability have achieved deep penetration and space-time controllable release of drugs,laying a solid foundation for targeted drug delivery for liver cancer treatment.(1)The advantage of enzyme-responsive nanocarriers is that they can carry anticancer drugs to be specifically recognized and degraded by enzymes on tumor cells,and accurately regulate drug release at a fixed time point.Using this feature,we prepared two GGT enzyme-responsive nano-drug delivery systems(*GGT-TAT-PEG-PCL@DOX/DGGTPEG-PCL@CPT).The targeted molecule GGT can enhance the targeting by triggering charge reversal,which can achieve efficient enrichment of drugs in the tumor site.Good dimensional stability can promote the blood circulation of the drug in the body.Sensitive charge reversal performance promotes endocytosis and transcytosis of tumor cells to achieve deep drug delivery.Controlled and sustained drug release performance can effectively improve the utilization rate of drugs and reduce the damage to the body.(2)The level of cell activity in vitro is an important basis for judging whether the drugloading system can be further applied in mice.The two drug delivery systems are internalized into HepG2 cells through the GGT-mediated signaling pathway overexpressed on the surface of cancer cell membranes to release anticancer drugs,which mainly depends on the high targeting of the drug delivery system and the selective release of drugs.The intracellular transport pathway from the endoplasmic reticulum to the Golgi apparatus and the unique cross-cellular transport mode improve the active transport capacity of the drugloading system and realize the deep delivery of nano-drugs.The drug-loading system has a strong killing effect on cancer cells and has low toxic and side effects on normal cells,showing good biocompatibility.(3)In vivo animal experiments are an important part of verifying the therapeutic effect and biosafety of the drug delivery system.Both systems can achieve specific enrichment at the tumor site,and significantly inhibit the mitosis of tumor cells in the tumor-bearing mouse model,showing excellent therapeutic effects.The important tissues and organs of the body will not be enriched for a long time,and can be metabolized and excreted through the kidney and liver.There is no obvious damage to normal tissues and organs in the mouse model,indicating that the drug-loading system has a good application prospect in the field of liver cancer treatment.In this paper,two nano-drug delivery platforms with hypersensitivity response were constructed.The overexpressed GGT on the surface of cancer cell membrane was used to control the charge reversal behavior of the drug-loading system,and the deep delivery and space-time controllable release of nano-drugs were realized.This method breaks the bottleneck of low permeability of drugs,provides a theoretical basis for targeted drug delivery,and also provides a possible path for the treatment of liver cancer.