Drug delivery techniques have enabled the development of many undruggable drugs, through delivery systems that can enhance therapeutic drug delivery to target sites, minimize off-target accumulation, and facilitate patient compliance. As treatment modalities extend from small molecules to nucleic acids, peptides, proteins and antibodies to cellular gene therapies, this paper analyzes the challenges existing in drug delivery and the solutions to drug delivery techniques.
Small molecule drugs
Small-molecule drugs can rapidly spread through biofluids, across many biological barriers and cell membranes. These advantages allow small molecules to rapidly diffuse and enter into the systemic vasculature and interact with almost all tissues and cell types in the body. However, problems with small molecules include PK parameters (especially half-life, biodistribution and maximum drug concentration), solubility, permeability, and toxicity caused by off-target.
Response cases for drug delivery technology:
The absorption characteristics of nifedipine cause the phenomenon of blood concentration, which increases the risk of heart attack, and the long-acting nifedipine effectively reduces the toxic effects. Morphine is a powerful analgesic, but a short half-life is required every 4 hours, while slow-release morphine tablets can effectively control pain for 12 hours, fully demonstrating the advantages of slow-release morphine in pain relief. The solubility of paclitaxel is low, and the addition of castor oil produces allergic reaction. The delivery system of liposome, albumin and micelles not only solves the solubility problem, but also further improves the targeting, thus improving the efficacy and reducing the adverse reactions.
Protein, polypeptides, and antibodies
Compared with traditional chemical drugs, the advantages of proteins, peptides and antibodies are high targeting and good selectivity, so the curative effect and side effects are small. Biomacromolecular drug delivery challenges are not easy to enter cells, difficult to break through the blood-brain barrier, low structural stability, and frequent injection administration make poor patient compliance. And some drugs are immunogenic, etc.
Drug delivery technology response case: exenatide common injection twice a day, using microsphere delivery technology exenatide microsphere preparation of once a week can continue to provide steady-state exenopeptide concentration level, thus greatly reduce the frequency of administration, reduce the gastrointestinal tract, and increase the stability of the drug and improve patient compliance.
The absorption enhancer SNAC can locally raise pH to protect selmesiglutide from degradation by protease and promote simeaglutide transport across cells to enhance gastric absorption. Thus, oral simegallutide was successfully marketed. In addition, in response to the gastrointestinal environment for the development of oral protein has brought great challenges, microneedle delivery technology has also become a hot topic in protein drug delivery research.
The Shanghai Institute of Materia Medica, Chinese Academy of Sciences has developed a tumor microenvironment-activated immune-checkpoint antibody drug delivery system, which co-contains the photosensitizer molecule ICG and PD-L1 immune-checkpoint antibody (α PD-L1) through hydrophobic interaction, forming nanoparticles with a particle size of about 150 nm. The antibody nanoparticles containing PEG shell can stabilize circulation in the blood and shield the removal of macrophages and reticuloendothelial system, while avoiding the binding of α PD-L1 to normal tissue PD-L1 and inhibiting immune-related toxic side effects.
Nucleic acid drugs
Because nucleic acids are negatively charged biological macromolecules, it is difficult to pass through the negatively charged lipid bilayer cell membrane on the surface, and they are easy to be degraded by enzymes in plasma and tissues, and quickly cleared in the liver and kidney, the "card" cannot function in the endocytosome after recognition by the immune system. Therefore, an efficient, safe and accurately targeted delivery system is crucial for nucleic acid drugs.
Coping case for drug delivery technology: LNP is a highly personalized and designed nucleic acid delivery carrier, showing great potential in mRNA vaccine delivery. Ionizing lipids are crucial in LNP design, and LNP containing ionizing lipids is electroneutral and can avoid any unwanted electrostatic interactions on the negative charge of cell membrane surface, but obtain positive charge in the internal body acidic pH, promote mRNA release. With the mRNA vaccine approved for the prevention of novel coronavirus, LNP has become the most popular delivery technology for nucleic acid drugs. In addition, polymer nanoparticles (PNP), lipid multimeric complexes (LPP), infinite nanoparticles (INP) and other technologies are also widely used in nucleic acid drug delivery research.
Gene-cell therapeutic drugs
Gene therapy refers to the introduction of exogenous normal genes into target cells to correct or compensate for diseases caused by defects and abnormal genes. It can achieve long-term expression and tissue-specific expression of therapeutic proteins. It can solve a series of problems existing in traditional therapy from the root without drug intervention, radiotherapy or surgical treatment. However, gene therapy drugs are faced with problems such as poor persistence and viability in vivo, immunogenicity, and fixed in the focal location to maintain the therapeutic cell phenotype. Therefore, the development and optimization of novel gene delivery vector systems that enable more safe and efficient delivery of therapeutic genes to targeted cells or tissues will greatly facilitate the progress of gene therapy in clinical applications.
Case for drug delivery: Over decades, researchers have developed a variety of delivery vectors that can break through physiological barriers, including the most well studied viral vectors, lipid nanoparticles and virus-like particles. Viral vectors have high infection rate and high targeting, but high immunogenicity and the risk of random integration. Case: Lyfgenia Gene therapy for patients with sickle cell disease (SCD) with recurrent vaso-occlusive crisis (VOC) using lentiviral vectors for delivery of modified genes. LNP vector has good biocompatibility and no immunogenicity, but it has problems such as allergy and poor reproducibility. Case: NTLA-2002, a candidate for in vivo CRISPR gene editing therapy, targeted the KLKB 1 gene through lipid nanoparticle (LNP) delivery CRISPR-Cas 9 gene editing system in mRNA to permanently reduce the kallikrein activity in plasma, thus preventing the onset of hereditary angioedema (HAE). This greatly expands the application scope of CRISPR gene editing therapy, and direct injection of CRISPR components allows for efficient gene editing in vivo.
The drug delivery system can not only attenuate the existing mature drugs such as small molecules, and improve the compliance, but also play a role in improving the stability and delivery compliance of protein and peptide drugs. In addition, in terms of new technologies, such as PROTAC, nucleic acid drugs, mRNA vaccines, gene editing and cell therapy, with the delivery system, the drug is greatly improved, so that these emerging technologies ushered in rapid development, benefit patients. In the future, with the development of artificial intelligence and nanomaterials science, intelligent drug delivery system, nanometer robots and other drug delivery systems will become the focus of research, and bring new breakthroughs to pharmaceutical innovation and development.
reference documentation:
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