ABSTRACT
In the research on cancer theranostics, most environment-sensitive drug delivery systems can only achieve unidirectional and irreversible responsive changes under pathological conditions, thereby improving the targeting effect and drug release performance of the delivery system. However, such irreversible changes pose potential safety hazards when the dynamically distributed delivery system returns to the blood circulation or transports to the normal physiological environment. Intelligent reversible drug delivery systems can respond to normal physiological and pathological microenvironments to achieve bidirectional and reversible structural changes. This feature will help to precisely control the drug release of the delivery system, prolong the blood circulation time, improve the targeting efficiency, and avoid the potential safety hazards of the irreversible drug delivery system. In this review, we describe the research progress of intelligent reversible drug delivery system from two main aspects: controlled drug release and prolonged blood circulation time/enhanced cellular internalization of drug.
ABSTRACT
Ribonucleic acid (RNA) medicines have strong therapeutic potential for numerous rare genetic illnesses and malignancies because of its exact programmability based on Watson-Crick base pairing principle and unique ability to regulate gene expression. However, RNA medicines still have limitations in many areas, including stability, half-life time, immunogenicity, organ selectivity, cellular uptake and endosomal escape efficiency despite their great therapeutic potentials. This review briefly introduced numerous RNA medications [mostly messenger RNA (mRNA), small interfering RNA (siRNA), microRNA (miRNA) and antisense oligonucleotide (ASO)] that have intrigued of researchers in recent years, as well as their action mechanism in vivo. A number of delivery techniques, such as chemical modification, ligands coupling and nanocarriers have been proposed. The manufacture and applications of lipid nanoparticle, polymer nanoparticle and exosomes were discussed in depth. The goal of this work is to give a theoretical foundation and design concepts for the development of effective and safe RNA delivery technology, as well as to facilitate RNA therapeutic clinical translation.
ABSTRACT
Lung is susceptible to external disturbance, resulting in a variety of acute and chronic lung diseases. Functionalized nanoparticles as carriers can carry drugs through multiple biological barriers of lung into lung lesions, but there are some problems such as poor targeting and low therapeutic efficiency. As a drug carrier, membrane-coated biomimetic nanoparticles have the characteristics of immune system escape, active targeting, inflammatory chemotaxis and crossing physiological barriers due to the retention of the characteristics of the source cells. Therefore, it has been widely used in the treatment of lung diseases in recent years. In this review, the application of membrane-coated biomimetic nanoparticles in the treatment of lung diseases in the recent years was summarized and classified. Cell membrane sources include erythrocyte membrane, platelet membrane, macrophage membrane, neutrophil membrane, lung epithelial membrane, lung surfactant, endothelial membrane, cancer cell membrane, bacterial membrane, hybrid membrane and so on. The purpose of this review is to provide a new idea for treating lung diseases with membrane-coated biomimetic nanoparticles.
ABSTRACT
Cancer is still one of the major diseases threatening human life and health. At present, how to achieve precise diagnosis and treatment of tumors is the biggest challenge in cancer treatment. Prodrugs use the tumor specificity of targeting molecules to deliver anticancer drugs to tumor sites, which can effectively improve drug bioavailability, therapeutic efficacy and safety, and are currently a hot spot in the research and development of anticancer drugs. The targeting molecules of prodrugs mainly include nucleic acid aptamers, polymers, antibodies, polypeptides, etc. Among them, polypeptides have the advantages of good biocompatibility, controllable degradation performance, high in vivo responsiveness, and simple and easy preparation methods, and are widely used. It is used to construct peptide-drug conjugates (PDC) prodrugs to achieve targeted therapy of tumors. In recent years, with the development of phage peptide library technology and peptide standard solid-phase synthesis technology, more and more targeted peptides have been discovered and effectively synthesized and modified, providing strong support for the development of PDC. This review briefly introduces the types and functions of functional peptides and linkers in PDC, and discusses the application of PDC in chemotherapy, immunotherapy and photodynamic therapy in tumor targeted diagnosis and treatment, and finally summarizes the difficulties faced by PDC drug development.
ABSTRACT
Cancer is the most important leading cause of death worldwide, with about 10 million deaths caused by cancer in 2020. In situ gel drug delivery systems have attracted much attention in the field of pharmacy and biotechnology due to their good histo-compatibility, excellent injectability, high drug delivery capacity, slow-release drug delivery, and less influence by the in vivo environment. Meanwhile, in situ gel can be combined with chemotherapy, photo-thermal therapy, chemokinetic therapy, immunotherapy and so on to deliver drugs into the tumor site in a less invasive way without surgical operation, forming a semi-solid gel reservoir in the tumor site to realize in situ tumor combined therapy. In this paper, the author summarized the research progress of anti-tumor in situ gel delivery system in the past 10 years, introduced its commonly used polymer materials, classification principles and specific application examples, and finally summarized and discussed the key issues, in order to provide reference for the development of new anti-tumor drug delivery system in the future.
ABSTRACT
The neonatal Fc receptor (FcRn) was first found to be a membrane protein that maternal antibodies transmitted to fetuses and newborns, and also expressed in multiple organs and tissues for whole life in adults. It plays a significant role to central regulate the lifespan of immunoglobulin G and serum albumin, as well as its involvement in innate and adaptive immune responses. In modern biopharmaceuticals, FcRn is a great potential drug delivery target and a highlighted subject for current research. This paper briefly describes the basic biological properties and action mechanism of FcRn, as well as the commonly used drug carrier design strategies of FcRn, especially the functional applications of prolonging half-life, targeted drug delivery, transmembrane and antigen presentation and so on. We propose that these distribution in different tissues and the diverse biological activities may have significant implications of targeting FcRn for novel drug delivery systems and immunotherapy.
ABSTRACT
Exosomes are one of the most important ways of cell-to-cell communication in living lives. They are involved in major physiological and pathological processes, including drug resistance, infection propagation, cancer development and cardiovascular diseases. The biological functions of exosomes made it possess characteristics of low immunogenicity, high delivery efficiency, ability to cross multiple biological barriers and targeting capacity, which also encourage people to try to use it as a drug carrier to overcome the disadvantages of poor stability, low solubility, low bioavailability and high toxicity of some drugs. In this paper, the latest progress of exosomes in the delivery of antitumor drugs, including small chemotherapeutic drugs, biological macromolecules and nucleic acid drugs, is reviewed. In addition, the isolation, drug loading, and modification method and the application prospect of exosomes are also discussed.
ABSTRACT
Cancer is considered as one of the major diseases endangering human health in the world, it is urgent to find a safer and more efficient treatment for cancer therapy. Gene therapy with ribonucleic acid (RNA) drugs could regulate the expression of tumor related genes, and exhibit good anti-tumor therapeutic potential in preclinical and clinical trials. Based on the differences between tumor tissues and normal tissues in microenvironment signal characteristics such as pH, specific enzyme concentration or redox gradient, various microenvironment responsive nanocarriers had been studied and developed to deliver RNA drugs to tumor tissues and cells, improving the anti-tumor efficacy of RNA drugs and reducing toxic and side effects. This paper reviews the pathophysiological characteristics of tumor microenvironment and various strategies of tumor microenvironment responsive nanocarriers, in order to provide reference for the design of safe and efficient RNA drug delivery system for cancer therapy.
ABSTRACT
Photothermal therapy (PTT) is a highly effective anti-tumor method. However, when laser radiation was used to ablate tumors, it usually triggers a series of inflammatory reactions, promoting the further development of tumors and affecting the effect of anti-tumor therapy. Therefore, it is an effective method to improve the anti-tumor effect by suppressing the inflammatory response through the precise targeted delivery of anti-inflammatory drug while realizing the photothermal treatment of tumors. To this end, the redox-responsive linker 3,3'-dithiodipropionic acid was used to bond the classic hydrophobic anti-inflammatory drug 18β-glycyrrhetinic acid (18β-GA) and the hydrophilic fragment methoxy-polyethylene glycol (mPEG-NH2) to obtain redox-responsive amphiphilic polymer PEG-DA-GA in this study. Then, photothermal agent IR-780 was encapsulated to prepare redox-responsive polymer micelle PDG/IR-780 NPs. The PDG/IR-780 NPs exhibited uniform particle size of 80.2 ± 5.3 nm and the polydispersity index (PDI) was 0.215 ± 0.079. All animal experiments followed the ethical requirements formulated by the Ethics Committee of Sichuan University. The results showed that PDG/IR-780 NPs could respond to the abundant glutathione (GSH) in tumor cells to promote the disintegration of nanoparticle and the release of 18β-GA, thus significantly improved the killing efficiency on 4T1 cells, when compared with the non-redox-responsive control PSG/IR-780 NPs. When the concentration of 18β-GA was 50 μg·mL-1, the cell viability of 4T1 cells in the PDG/IR-780 NPs group was only (19.29 ± 1.80) %, which was significantly lower than the result of in PSG/IR-780 NPs group (29.30 ± 1.37) %. The results of frozen sections of tumor tissues showed that the designed PDG NPs can promote the tumor-targeted distribution of drugs compared with the free drug group. Eventually, PDG/IR-780 NPs achieved wonderful anti-tumor efficacy on 4T1 triple-negative breast cancer model, revealing the new possibility of the combined therapy strategy of photothermal and anti-inflammatory therapy.
ABSTRACT
The development of nanotechnology has made it possible to develop safe, efficient, precise and controllable drug delivery system (DDS). Among them, organic or inorganic synthetic nanocarriers have been widely reported and used for the delivery of tumor therapeutic agents. However, some of carriers have several problems, such as easily eliminated by the body's immune system, difficult to preparation or poor safety in vivo. In recent years, with the development of biomedicine, biomimetic technology based biomembrane-mediated nanodrug delivery has organically integrated the low immunogenicity of natural biomembrane, cancer targeting, and the controllable and multifunctional of smart nanocarrier design. It will achieve a new breakthrough of nanotechnology in cancer targeted therapy. Based on the recent advances of cell membrane-derived biomimetic nanotechnology and the nanomedicine in the field of cancer therapy, this review discusses the three aspects including the experimental basis of cell membrane-derived biomimetic nanotechnology, the classification of biomimetic nanodrug delivery platforms, and the application in cancer targeted therapy. Therefore, the review will provide reference for the design of smart drug delivery system and its development in cancer targeted treatment.
ABSTRACT
As a basic amino acid, histidine has a pKa close to the acidity of the tumor microenvironment, thus the charge and solubility of histidine are able to vary as the pH changes. Under a neutral environment, histidine is not charged and exhibits hydrophobic properties, while it can be protonated and becomes hydrophilic when exposed to mildly acidic pH, such as tumor microenvironment. Therefore, histidine is widely used in the design of drug delivery systems to target the mildly acidic pH of tumor microenvironment. This article reviews the recent progresses of histidine-based tumor-targeting drug delivery systems, and summarizes the principles on promoting internalization and tuning drug release by taking advantage of histidine. Finally, we point out the common issues on histidine application and illustrate its future prospects.
ABSTRACT
In recent years, immunotherapy has made great progress in clinical cancer therapy. However, the poor tumor specificity, low intra-tumoral penetration, and low cellular uptake in the systemic delivery of immunotherapeutic drugs lead to low efficacy and poor safety, limiting the development of immunotherapy. Active tumor-targeting nano drug delivery systems (aNDDS) can enhance the concentration of drugs in target cells through the interaction between surface-conjugated antibodies or ligands and the receptors on target cell membranes, providing a viable strategy for specific and efficient drug delivery. In addition, some specific types of cell membranes with the natural targeting ability have been exploited for the construction of biomimetic nanocarriers to improve the drug delivery efficiency. In view of the many advantages of active tumor-targeting nanocarriers, researchers also have designed a series of aNDDS for promoting antitumor immune responses and proved that they improved the efficacy and safety of immunotherapy. In this review, we summarize the recent progress on aNDDS for improving the tumor immunotherapy and look forward to the main challenges and future directions in this field.
ABSTRACT
Polydopamine (PDA) is a novel type of polymer synthesized inspired by adhesion proteins in mussels. It has been widely used in tumor-targeting drug delivery systems due to its natural advantages such as good biocompatibility, excellent photothermal conversion performance, adhesion, high chemical reactivity and multiple drug release response mechanisms. This review summarizes the applications of PDA-based tumor-targeting drug delivery in recent years, hoping to provide references for designing a more reasonable and effective PDA-based multifunctional collaborative tumor therapy platform.
ABSTRACT
Tumor immune checkpoint therapy is a clinical treatment strategy developed based on the new principle of the inhibition of negative immune regulation. In this article, the tumor immune checkpoint therapy and the drug delivery strategies were reviewed, mainly including immunity and tumor therapy, tumor immune checkpoint therapy and its mechanism of action, clinical application of tumor immune checkpoint therapy and therapeutic drugs, immune resistance of programmed cell death protein 1 (PD1)/programmed cell death ligand 1 (PDL1) treatment and countermeasures, drug delivery strategies for tumor immune checkpoint therapeutic agents, etc. As a revolutionary new immunotherapy strategy, tumor immune checkpoint therapy has shown obvious superior therapeutic efficacy in a variety types of tumor. However, tumor immune checkpoint therapy is also faced with a big challenge, namely, immunotherapy resistance. With the discovery of new mechanism, the continuous development of new therapeutic drugs and delivery strategies, tumor immune checkpoint therapy is expected to further improve the clinical efficacy of tumor.
ABSTRACT
Due to the complexity of tumor pathology, the demand for the combined use of multiple drugs in clinical treatment has become increasingly clear-cut. Multi-drug combination can act on multiple pathways and multiple targets simultaneously to exert synergistic effects. However, the current delivery strategy for multi-drug combination still needs to be optimized. Nano-drug delivery systems can carry drugs to overcome physiological and pathological barrier to target tumor tissues and cells, achieve the goal of continuous, controllable, and targeted delivery, and enhance the efficacy of anti-tumor synergism and detoxification. To meet the new requirements for smarter and more accurate antitumor multi-drug combinational therapy, the nano-drug delivery system has been well-designed to realize more functions. For instance, delivery of multiple drugs in accurate proportions and doses can make the multi-drug synergistic effect more precise; stimulus-responsive drug release can improve selectivity and reduce side effects; controlling the time-course relationship of multiple drugs can realize sequential drug combination effect. It has shown broad prospects in the field of tumor multidrug therapy and has become one of the new directions of research and development. This article reviews the recent developments in the application of tumor drug combination therapy strategies and their delivery systems, and analyzes the new requirements and challenges of multidrug combination for the development of nano-drug delivery systems.
ABSTRACT
With the in-depth study on the gut microflora, the impact of intestinal bacteria on human health has attracted more and more attention. It has become a research hotspot in life science and medicine, and is considered as an important target of disease control. Prebiotics can regulate the composition and function of intestinal flora and then improve host health. Carbohydrate is the most basic prebiotic. Its unique physiochemical characteristics and gut microbiota-regulating ability make it a promising ingredient for achieving drug target delivery and intestinal health promotion. In this paper, different kinds of prebiotics and their regulation mechanism of intestinal bacteria were illuminated. Moreover, the research progress of carbohydrate prebiotics in drug delivery system was elucidated, and its application prospect is prospected, so as to provide reference for related research.
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Peptide drugs exhibit an irreplaceable role in clinics due to their high specificity, efficiency and low toxicity. At present, more than 80 peptide drugs have been approved for marketing with global sales exceeding $50 billion in 2019. However, with large molecular weights, high hydrophilicity and instability in digestive tract, oral peptide drugs encounter substantial physiological barriers leading to low oral bioavailability. Therefore, peptide drugs are mostly administered by parenteral routes. Although parenteral delivery of peptide drugs achieves high bioavailability, this is associated with inconvenience and discomfort, even causing severe side effects compared with the oral route possessing a high degree of patient compliance. Therefore, numerous studies concentrate on novel strategies to improve the oral bioavailability of peptide drugs. Some delivery technologies such as Eligen™ and Axcess™ have been successfully applied to the oral dosage form of therapeutic peptides and have accelerated relevant oral formulations for Food and Drug Administration (FDA) approval and clinical treatment. In this review, we focus on the oral peptide delivery, mainly summarizing the progress of recent strategies used to overcome oral barriers and the commercialization applications of related patents, which could facilitate the research and development (R&D) of clinical applications of oral delivery techniques for peptide drugs.
ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. The prevalence of NAFLD is increasing year by year in the world, which seriously threaten the public health. The pathogenesis of NAFLD is complex, and there is no specific treatment for NAFLD. Natural-derived compounds have the characteristics of multi-target and multi-mechanism, which can improve the curative effect and reduce the toxic and side effects by regulating multiple factors of the disease. They are ideal drugs for treating complex diseases and have unique advantages in improving NAFLD. However, low intestinal absorption, poor bioavailability, and single medicine efficiency limit the utilization of many compounds, and further drug development and clinical application are challenging. This paper reviews the research progress of natural-derived compounds in the prevention and treatment of NAFLD in recent years, analyzes the existing problems, and discusses the improvement strategies, so as to provide reference for related research.
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Ionic liquids (ILs) are liquid mixtures formed by anions and cations in a certain stoichiometric ratio under certain conditions. They are widely used in various fields because of their simple preparation process, low volatility, high stability, high conductivity and non-flammability. Here, we firstly introduce their formation principles, classification, and physical and chemical properties in detail. Then, we summarize their functions in pharmaceutical preparations, such as improving the solubility of insoluble drugs, enhancing the stability of drugs, and promoting the permeability of drugs, as well as their role as active pharmaceutical ingredients (API) to fabricate new drug delivery systems of API-ILs. Finally, we reviewed the applications of ILs in different administration routes, including oral, transdermal, mucosal, and injection routes, and meanwhile offer perspectives for the further use of ILs.
ABSTRACT
Mitochondria is involved in many important physiological activities such as energy supply, signal transduction, cell differentiation, etc., and plays an significant role in the occurrence and development of diseases. Using mitochondria as a target is a new strategy for cancer treatment. The use of nanotechnology to construct a mitochondrial targeted nano-drug delivery system can improve the solubility of traditional drugs, prolong the half-life of drugs in the body, increase the bioavailability and concentration of drugs at the tumor site, and reduce the toxic and side effects of drugs. It is expected to solve the resistance in the process of tumor treatment. This review focuses on the field of cancer treatment. Firstly, it introduces the mechanism of mitochondrial targeted nano-drug delivery system for cancer treatment. Secondly, it outlines the design ideas, classification and application research of mitochondrial targeted nano-drug delivery systems in the past five years. Finally, it expands the analysis of other studies that target mitochondria, such as bionic vectors, and presents its advantages and disadvantages, which provide a basis for in-depth research on drug delivery systems in the future.