Challenges in cell membrane-camouflaged drug delivery systems:Development strategies and future prospects

Extensive research has been performed on cell membrane camouflaged-based drug delivery systems in recent years.Herein,we provide an overview of the challenges in system preparation,functional design,continuous industrial production of these systems,and solution strategies for these challenges.Further,we analyze and discuss the frontier medical applications of cell membrane-camouflaged drug delivery systems in anti-inflammatory,anti-pathogenic microorganisms,and biological detoxification.This review takes a challenge-oriented perspective and seeks innovative strategies,provides a literature review of research into cell membrane-camouflaged drug delivery systems,and promotes the development of personalized clinical treatments.     

STING-activating drug delivery systems:Design strategies and biomedical applications

The stimulator of interferon genes(STING) shows promising clinical activity in infectious diseases and tumors.However,the lack of targeting capability and intracellular stability of STING agonists severely limits the therapeutic efficacy.Recently,drug delivery systems(DDSs) overcome these delivery barriers of STING agonists via passive or active cell targeting,prolonged blood circulation and drug release,and lysosome escape,etc.In this review,we will describe in detail how existing DDSs are designed to overcome delivery barriers and activate the STING pathway,and the current biomedical applications of STING-activating DDSs in the treatments of infectious diseases and tumors.Finally,the prospects and challenges of DDSs in STING activation are discussed.     

Hydrogel design strategies for drug delivery

Hydrogels are water-swollen three-dimensional networks made of polymers, proteins, small molecules or colloids. They constitute a versatile platform for drug delivery because of their capacity to encapsulate and protect drugs and provide sustained and/or remotely programmable spatial and temporal release and have thus generated a substantial amount of research for the delivery of either small active compounds or biopharmaceuticals. This article discusses the features that make hydrogels attractive as matrices for delivery and reviews a range of designs, focussing on studies from recent years, in particular: ‘smart’ hydrogels (responding to temperature, light, magnetic fields, ultrasounds or combined stimuli); recent technologies: 3D printing and microneedles; and closes by discussing polymer-free drug delivery systems: peptides, small molecules and colloids.     

Therapeutic systems and controlled drug delivery

Therapeutic systems can provide pre-programmed, unattended delivery of a drug at a rate, and for a time period, established to meet a specific therapeutic need. The system can be designed to minimize the patient's intervention and to optimize compliance with the prescribed regimen. The ocular therapeutic system described here for the control of intraocular pressure in glaucoma delivers pilocarpine at 20 or 40 μg/h for one week, and fits comfortably into the cul-de-sac of the eye. The intrauterine progesterone contraceptive system described here represents a new approach to steroidal contraception that localizes the effect of the hormone progesterone to the uterus, delivering the hormone at a rate of 65 μg/day for one year. Both of these systems are designed to deliver drug into their immediate locale, and are thus topical dosage forms. The transdermal therapeutic system described here has been designed to deliver scopolamine across intact skin and into systemic blood to achieve an antinausea effect. The pharmacokinetics of scopolamine are such that, to minimize the time required for the onset of drug action, drug should be presented at an initially high rate, i.e. as a priming dose, to attain the therapeutically effective drug level, and then at a constant rate, so as to maintain the therapeutically effective level. This system functions according to the priming dose/maintenance rate design requirement.     

Novel strategies to improve the anticancer action of 5-fluorouracil by using drug delivery systems

Because of the fundamental importance of new therapeutic routes for cancer treatment, a number of systems based on colloidal particles as vehicles for the delivery of the anticancer drug 5-fluorouracil have been devised. The target is always to provide the proper dose of the antitumor agent only at the desired locus of action, thus reducing the unwanted side effects. In this review, the main strategies and the more significant results in the development of 5-fluorouracil carriers for cancer treatment are discussed.     

Cyclodextrin based novel drug delivery systems

The versatile pharmaceutical material cyclodextrin’s (CDs) are classified into hydrophilic, hydrophobic, and ionic derivatives. By the early 1950s the basic physicochemical characteristics of cyclodextrins had been discovered, since than their use is a practical and economical way to improve the physicochemical and pharmaceutical properties such as solubility, stability, and bioavailability of administered drug molecules. These CDs can serve as multi-functional drug carriers, through the formation of inclusion complex or the form of CD/drug conjugate and, thereby potentially serving as novel drug carriers. This contribution outlines applications and comparative benefits of use of cyclodextrins (CDs) and their derivatives in the design of novel delivery systems like liposomes, microspheres, microcapsules, nanoparticles, cyclodextrin grafted cellulosic fabric, hydrogels, nanosponges, beads, nanogels/nanoassemblies and cyclodextrin-containing polymers. The article also focuses on the ability of CDs to enhance the drug absorption across biological barriers, the ability to control the rate and time profiles of drug release, drug safety, drug stability, and the ability to deliver a drug to targeted site. The article highlight’s on needs, limitations and advantages of CD based delivery systems. CDs, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes.     

NMR and MRI studies of drug delivery systems

Nuclear magnetic resonance imaging and spectroscopy are now commonplace in most academic and industrial research environments. The ability of magnetic resonance techniques to provide the researcher with non-invasive, quantitative, physicochemical information in the disciplines of chemistry, biology, materials science, chemical engineering and medicine is widely known. In the last 10–15 years a variety of magnetic resonance methods have provided the pharmaceutical research community with valuable information, especially in the important area of drug delivery using solid dosage forms. This review will highlight recent advances in magnetic resonance techniques and its specific applications to further our understanding of pharmaceutical drug delivery systems. The review is aimed at non-clinical research and development, and will focus on the behaviour and characterisation of drug release from pellets, tablets and capsules, which are the most commonly used drug delivery systems. In addition to magnetic resonance techniques a number of complementary analytical techniques are mentioned to illustrate the importance of adopting a multi-modal analytical approach to gain a better scientific understanding of the behaviour of drug delivery devices.     

Physicochemical aspects of drug delivery and release from polymer-based colloids

Recent advances in the preparation/loading, surface properties, and applications of polymer-based colloidal drug delivery and release systems, such as block copolymer micelles, polymer nano- and microparticles, polymer-modified liposomes, and chemical and physical hydrogels are presented. Drug release from polymer-based systems is affected by the drug–polymer interactions as well as the polymer microstructure and dissociation/erosion properties. Surface modification with poly(ethylene oxide) has become common in improving the biocompatibility and biodistribution of drug delivery carriers. Site-specific drug delivery can be achieved by polymer-based colloidal drug carriers when ligands of targeting information are attached on the carrier surface or when a phase transition is induced by an external stimulus. While significant progress in being made, many challenges remain in preserving the biological activity and attaining the desired drug release properties, especially for protein and DNA drugs.     

Colloidochemical aspects of transdermal drug delivery (review)

This review generalizes scientific information on factors that determine the efficacy of transdermal drug delivery, including the barrier functions of skin, the properties of drugs and enhancers of skin permeability, and the type of a transdermal therapeutic system, i.e., plaster. Colloidochemical aspects of transdermal drug delivery are considered in relation to the amphiphilic structure of drugs and action mechanisms of enhancers, among which nonionic surfactants prevail. Advantages of microreservoir-type transdermal therapeutic systems are shown, information on which is very scarce; the prospects of their development on the basis of oil-in-water and water-in-oil emulsions containing nonionic surfactants and polymer adhesives are outlined.     

Stimuli sensitive polymers for drug delivery systems

Temperature sensitive and electric field sensitive hydrogels were prepared for use in modulated drug release systems. Crosslinked poly(N-isopropyl-acrylamide) and its networks, modified with hydrophobic components by copolymerization or by interpenetrating polymer networks (IPNs) formation, were utilized as temperature sensitive hydrogels. Indomethacin (a model solute)-release from polymer matrix and permeation through polymer membrane demonstrated “on-off” regulation with temperature fluctuation. This was the result of polymer surface properties rather than bulk swelling, as temperature was changed past the swelling transition temperature range of the polymer. The on-off regulation in an electric field was also obtained with a positively charged solute (Edrophonium chloride) release in distilled-deionized water from a matrix of crosslinked poly(2-acrylamido-2-methylpropanesulfonic acid-co-butyl methacrylate). This was attributed to the ion exchange between Edrophonium ion and protons produced at the anode. The swelling changes produced by local pH or ionic strength changes affected non-charged solute release.     

Erythrocyte-derived drug delivery systems in cancer therapy

As natural blood components,erythrocytes were good candidates for being used as drug delive ry systems to improve the pharmacokinetics,biocompatibility and many other aspects of different drugs.The advantages brought by erythrocytes making erythrocyte-derived drug delivery systems,also known as erythrocyte carriers,suitable for various anti-cancer agents,especially newly invented agents like nanoparticles,which were characterized by their undesired systematic toxicity,anaphylactic reactions and poor biocompatibility.Current researches on erythrocyte carriers in ca ncer therapy showed inspiring results in four major aspects:cancer enzyme therapy,delivering chemotherapeutic agents,combining with nanoparticles,and several other anti-cancer agents for gene or immune therapy.This novel delivering system was now undergoing the translation process from laboratory to clinical practice.Erythrocyte carriers for cancer enzyme therapy have entered the stage of clinical trial and have showed promising outcomes,and others were still at pre-clinical stage.In summary,erythrocyte-derived drug delivery system might play an indispensable role in the management of cancer in the future.     

Intelligent drug delivery systems obtained by radiation

Radiation-induced polymerization of acryloyl-L-proline methyl ester, an -aminoacid-containing monomer, in the presence of a crosslinking agent and a hydrophilic monomer gave rise to polymer hydrogels whose water content at equilibrium was found to decrease as the swelling temperature increased. Some hydrogel samples were obtained with entrapped acetaminophen, an analgesic and antipyretic drug. It was ascertained that the release of the drug was controlled by both the hydrophilicity of the polymer matrices and the environmental temperature.     

Preparation and drug controlled-release of polyion complex micelles as drug delivery systems

Block copolymers, poly(N-vinylprrolidone)-block-poly(styrene-alter-maleic anhydride) (PVP-b-PSMA) and poly(N-vinylprrolidone)-block-poly(N,N-dimethylaminoethyl methacrylate) (PVP-b-PDMAEMA), were synthesized by reversible addition- fragmentation chain transfer (RAFT) polymerization. In aqueous media, this a pair of oppositely-charged diblock copolymers could self-assemble into stable and narrow distribution polyion complex micelles (PICMs). Transmission electron micrographs (TEM) and dynamic light scattering (DLS) analysis showed that the micelles to be spherically shaped with mean hydrodynamic diameter around 70 nm. In addition, the PICMs display ability to response to external stimuli. All of theses features are quite feasible for utilizing it as a novel intelligent drug delivery system. In order to assess its application in biomedical area, release profiles of coenzyme A (Co A) from PICMs were studied under both simulated gastric and intestinal pH conditions. The release was much quicker in pH 7.4 buffer than in pH 2.0 solution. Based on these results, these PICMs could be a potential pH-sensitive carrier for colon-specific drug delivery system.     

Two sides to supramolecular drug delivery systems

Although still in its infancy, there is a rapidly increasing interest in the development of supramolecular drug delivery systems (SDDSs). As chemists, the most challenging task ahead of us is to narrow the gap between SDDSs development in the lab, and clinical drug carriers. Only then will we achieve our ultimate goal of the successful translation of SDDSs to life saving medicines.     

Exosome-based drug delivery systems in cancer therapy

Exosome, which is a kind of extracellular vesicles with size around 40-160 nm, plays an important role in cell-to-cell communication in multiple diseases. Especially in tumor microenvironment, exosomes are the important pathway to transit proteins, nucleic acids and small molecules between different kinds of cells. Based on these characteristics, exosomes are served as both therapeutic agents and drug delivery systems in cancer therapy. In this review, the applications of exosomes as drug delive...     

Controlled drug delivery systems based on calixarenes

Recent advances on calixarene-based drug delivery systems in the form of inclusion complexes, amphiphilic self-assembly nanocarriers including micelles, hydrogels, vesicles and liposomes, and supramolecular nanovalves on mesoporous silicas, were reviewed and discussed.     

Lipid carrier systems for targeted drug and gene delivery

For effective chemotherapy, it is necessary to deliver therapeutic agents selectively to their target sites, since most drugs are associated with both beneficial effects and side effects. The use of lipid dispersion carrier systems, such as lipid emulsions and liposomes, as carriers of lipophilic drugs has attracted particular interest. A drug delivery system can be defined as a methodology for manipulating drug distribution in the body. Since drug distribution depends on the carrier, administration route, particle size of the carrier, lipid composition of the carrier, electric charge of the carrier and ligand density of the targeting carrier, these factors must be optimized. Recently, the lipid carrier system has also been applied to gene delivery systems for gene therapy. However, in both drug and gene medicine cases, a lack of cell-selectivity limits the wide application of this kind of drug and/or gene therapy. Therefore, lipid carrier systems for targeted drug and gene delivery must be developed for the rational therapy. In this review, we shall focus on the progress of research into lipid carrier systems for drug and gene delivery following systemic or local injection.     

Development of micro- and nanosystems for drug delivery

Methods for preparing colloidal delivery systems for drugs of different chemical structures have been developed and optimized. Proteins were encapsulated in bioadhesive biodegradable starch microparticles and liposomes from negatively charged and zwitter-ionic soybean phospholipids. Proteins and a poorly watersoluble anticancer drug-tamoxifen-were encapsulated in nanoparticles based on the amphiphilic graft block copolymer dextran-poly(?-caprolactone). In vitro release studies showed sustained release of proteins and tamoxifen in different media.     

Smart polymer grafted silica based drug delivery systems

Smart polymers are a special class of polymers, which respond to the various external stimuli by changing their properties. Recent developments in synthetic polymer chemistry have provided the possibility of designing and synthesis of various new stimuli-responsive polymers. These stimuli-responsive polymers can be used to prepare smart drug delivery systems (DDS) by grafting them on various nanomaterials. The main aim of this review is to present collective information on various stimuli-responsive polymers grafted on silica nanoparticles for the preparation of smart DDS. The stimuli covered are pH, temperature, redox, reactive oxygen species (ROS), glucose concentration, enzymes, magnetic field, and so forth. The structures of various stimuli-responsive polymers are shown with their relevance to the preparation of smart DDS. The crucial roles of macromolecular design and synthesis of smart polymers in the development of stimuli-responsive DDS are discussed with examples from literature and the challenges that still exist in this area of research are presented.