Exosome-based drug delivery systems and their therapeutic applications

In the past few decades, scientists have actively worked on developing effective drug delivery systems (DDSs) as means to control life-threatening diseases and challenging illnesses. In order to develop such DDSs, nanobiotechnological strategies have been introduced, and many nanomaterial-based DDS platforms have been proposed. Among these nanomaterials, DDSs based on exosomes and hybrids of exosomes have been focused upon and developed due to their low toxicity, high bioactivity, and biocompatibility. In this review, we describe the processes involved in drug loading into exosomes and the surface modification of exosomes with treatment agents. Furthermore, we describe the synthesis methods of hybrid exosomes with organic or inorganic nanoparticles. Moreover, we focus on the effective therapeutic applications of exosome-based DDSs against various diseases. In conclusion, we show that exosomes and hybrids of exosomes show excellent drug carrier potential and capacity.

In the past few decades, scientists have actively worked on developing effective drug delivery systems (DDSs) as means to control life-threatening diseases and challenging illnesses.     

Novel drug delivery systems

Interest in pain management is growing, with the emerging demand by our patients and colleagues, for pain relief. To meet that need, pharmaceutical and medical technology companies have provided the medical field with a variety of choices and options to deliver medication for pain control. Examination and review of the present systemic options are introduced. A more detailed look at the intrathecal route is necessary because of the tremendous potential for receptor-targeted drug delivery. The ability to treat nociceptive and neuropathic pain with drug-specific therapy makes this system all the more exciting. Because of this future, a wealth of new and old drugs are being found or reexamined for their use.     

Neonatal drug monitoring and drug delivery systems

The problems associated with drug delivery and achievement of therapeutic blood levels in neonates are reviewed, using chloramphenicol as an example. Administration of small volumes, concentrated solutions and intravenous line filter chambers greatly affect the final dose delivered to the infant. Once delivered, variability in drug elimination caused by changing hepatic and renal function and protein binding necessitate careful drug monitoring and pharmacokinetic analysis especially with drugs like chloramphenicol that have a narrow therapeutic range. If one uses a team approach involving nurses, clinical chemists and clinical pharmacologists, optimal doses of chloramphenicol in the newborn are achieved more consistently.     

New biodegradable polymers for injectable drug delivery systems.

Many biodegradable polymers were used for drug delivery and some are successful for human application. There remains fabrication problems, such as difficult processability and limited organic solvent and irreproducible drug release kinetics. New star-shaped block copolymers, of which the typical molecular architecture is presented, results from their distinct solution properties, thermal properties and morphology. Their unique physical properties are due to the three-dimensional, hyperbranched molecular architecture and influence microsphere fabrication, drug release and degradation profiles. We recently synthesized thermosensitive biodegradable hydrogel consisting of polyethylene oxide and poly(L-lactic acid). Aqueous solution of these copolymers with proper combination of molecular weights exhibit temperature-dependent reversible sol-gel transition. Desired molecular arrangements provide unique behavior that sol (at low temperature) form gel (at body temperature). The use of these two biodegradable polymers have great advantages for sustained injectable drug delivery systems. The formulation is simple, which is totally free of organic solvent. In sol or aqueous solution state of this polymer solubilized hydrophobic drugs prior to form gel matrix.     

Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention.

In recent years scientific and technological advancements have been made in the research and development of rate-controlled oral drug delivery systems by overcoming physiological adversities, such as short gastric residence times (GRT) and unpredictable gastric emptying times (GET). Several approaches are currently utilized in the prolongation of the GRT, including floating drug delivery systems (FDDS), also known as hydrodynamically balanced systems (HBS), swelling and expanding systems, polymeric bioadhesive systems, modified-shape systems, high-density systems, and other delayed gastric emptying devices. In this review, the current technological developments of FDDS including patented delivery systems and marketed products, and their advantages and future potential for oral controlled drug delivery are discussed.     

Tissue selective drug delivery utilizing carrier-mediated transport systems.

This paper describes some successful examples of a tissue selective drug delivery by utilizing specialized transporter(s) expressed in the targeted tissue cells. These are as follows: (1) oral delivery via H(+)/oligopeptide transporter, rat or human Pept1, in the intestine for beta-lactam antibiotics and a newly synthesized dipeptide, L-dopa-L-phenylalanine; (2) tumor cell specific delivery via the newly discovered H(+)/oligopeptide transporter(s) expressed in human fibrosarcoma cell line HT-1080 for model oligopeptides, glycylsarcosine and carnosine; (3) oral and hepatic delivery via an H(+)/monocarboxylate transporter in the intestine and an organic anion transporter in the liver for HMG-CoA reductase inhibitor, pravastatin; and (4) lung selective delivery via some type of transporter and avoidance of transfer into the brain via P-glycoprotein at the blood-brain barrier for a new quinolone antibacterial, HSR-903.     

Branched biodegradable polyesters for parenteral drug delivery systems.

Continuous, 'infusion-like' drug release profiles from biodegradable parenteral delivery systems are difficult to achieve for proteins and other hydrophilic macromolecular drugs with commonly used linear polyesters from lactic acid (PLA) and its random copolymers with glycolic acid (PLG). Drug release rates can be modified either by increasing the hydrophilicity of polyesters or by manipulating the polymer architecture to adjust polymer degradation rates and thus drug release. Therefore, we investigated different branching concepts for biodegradable polyesters of PLA and PLG. For one four- and eight-arm poly(ethylene oxide)s (PEO) were grafted with shorter polyester chains leading to star-branched structures. Secondly we obtained comb-like polyesters using both charged and uncharged dextrans or poly(vinyl alcohol)s (PVA) as hydrophilic backbones. The star-shaped and brush-like grafted polymers were intensively characterized by methods, such as NMR, IR, SEC-SLS, DSC and viscosity measurements. Tailor-made properties make these novel biodegradable polyesters promising candidates for parenteral protein delivery systems. While the star-branched polyesters have shown some interesting properties with respect to their degradation behavior, retaining the PEO blocks longer than ABA triblock copolymers, their release properties need further optimization. Brush-like branched polyesters on the other hand seem to possess both degradation and release properties meriting further investigations for parenteral protein delivery systems.     

Intratracheal catheters as drug delivery systems

Medication delivery into the lungs can be used to provide a high therapeutic index for agents targeted to specific lung diseases. In addition, the lung can be used as a portal of entry for other agents targeted to systemic diseases. Delivery of medications into the lung can be accomplished by either instillation or aerosolization. Instillation approaches are limited by the fluid volume that can be given safely, and instilled liquids distribute according to gravity. In contrast, aerosolization approaches can deliver larger volumes over longer periods and aerosols distribute according to ventilation. In the mechanically ventilated patient, externally generated aerosols have very poor lung delivery because the endotracheal tube functions as a barrier to aerosol passage. Novel aerosol generating systems at the ends of small-diameter catheters that can be placed into the trachea (or beyond) are being developed to address this. In vitro testing has shown these systems to be capable of producing appropriately sized particles, with high rates of lung deposition. These catheters could be coupled with tracheal gas insufflation systems, not only to deliver therapeutic aerosols but also to create water aerosols to supply necessary humidification during tracheal gas insufflation.     

Dendritic systems for drug delivery applications

Dendrimers are synthetic, highly branched and nanometer-sized macromolecules that offer potential application to various fields. They have uniform size and molecular weight, wide internal cavity and modifiable surface functionality that made them very attractive for biological and drug delivery applications. Commercially available PAMAM (polyamidoamine) dendrimers are most frequently used for construction of delivery system by modification of surface amino groups. One of the examples is anticancer drug-PAMAM conjugate with folic acid (FA) for targeting. DNA linked FA-PAMAM and FITC-PAMAM conjugates have been recently developed. Polyester dendrimers are expected to be biodegradable and less toxic to cells. An example is shown. Lastly, construction of a delivery system using caged compounds for photochemical release of drug is described.     

Developments in liposomal drug delivery systems

Liposomes are the leading drug delivery systems for the systemic (iv.) administration of drugs. There are now liposomal formulations of conventional drugs that have received clinical approval and many others in clinical trials that bring benefits of reduced toxicity and enhanced efficacy for the treatment of cancer and other life-threatening diseases. The mechanisms giving rise to the therapeutic advantages of liposomes, such as the ability of long-circulating liposomes to preferentially accumulate at disease sites including tumours, sites of infection and sites of inflammation are increasingly well understood. Further, liposome-based formulations of genetic drugs such as antisense oligonucleotides and plasmids for gene therapy that have clear potential for systemic utility are increasingly available. This paper reviews the liposomal drug delivery field, summarises the success of liposomes for the delivery of small molecules and indicates how this success is being built on to design effective carriers for genetic drugs.     

Buccal/gingival drug delivery systems

As a continuation of our previous work on oral mucosal adhesive tablets for the administration of insulin and for treatment of aphtous stomatitis, we have investigated a similar type of dosage form using hydroxypropyl cellulose, Carbopol and lidocaine of a model drug for the treatment of toothache by applying the system to the human gingiva. It may be expected that this dosage form affords a prolonged anesthetic action.Next, we have formulated an adhesive gingival plaster which contains 50 μg of prostaglandin F_2α (PGF_2α) for the facilitation of tooth movement. A study using monkeys showed that daily application of the plasters accelerates the orthodontic process, and thereby reduces the time required for the tooth movement. Additionally, in order to investigate the tissue distribution of the active ingredient, plasters containing ¹⁴C-labeled PGF_2α were applied to the cheek pouches of hamsters. Autoradiographic, histologic examination of the surrounding tissue reveals that the labeled component had distributed in connective tissues and muscularis, and remained in situ for 8 hours after patch application. No irritation of the mucosal surfaces in any studies performed so far was observed.     

New developments in drug delivery systems

The rate-controlled drug delivery systems outlined above have been steadily introduced into the biomedical community since the middle of the 1970s. It is the author's belief that many more of the conventional drug delivery systems which we have been using for many decades will be gradually replaced, in coming years, by these high-tech-based rate-controlled drug delivery systems.