Nanodrugs have emerged from the collaboration between nanotechnology and biomedical studies. The development of nanodrugs aims to achieve specific drug targeting and delivery, improved safety and biocompatibility, and improved pharmacokinetic behavior.
The promising properties of nanodrugs have led to considerable improvements in the treatment of pulmonary, central nervous system and cardiovascular diseases, vascular thrombosis; gene therapy, nanonephrology, and cancer treatment.
With the famous words of Richard Feynman “There’s Plenty of Room at the Bottom. An invitation to enter a new field of physics”, the doors towards nanotechnology have opened and started to influence every field of science. Medicinal science was no exception to this; in fact, it was one of the first to jump the bandwagon. The idea of incorporating nanotechnology to the medicinal world was first presented by K. Eric Drexler, Chris Peterson and Gayle Pergamit in their book “Unbounding the Future. The Nanotechnology Revolution” published in 1991, in which the term “nanomedicine” was supposedly used for the first time. Nanodrugs constitute an important subsection of nanomedicine applications. Even though the early studies of nanodrugs focused on improving the molecular properties of already available therapeutic and diagnostic agents, recent researches focus on developing and application of new therapeutic and diagnostic methods. The main purpose in the development of nanodrugs is specific drug targeting and delivery, improved safety and biocompatibility, faster development of new medicine with a wide safety margin; and improved pharmacokinetic behavior. Thus, nanodrug systems provide a lower frequency of administration by providing maximized therapeutic effects and minimized systemic side effects, possibly leading to better clinical results. When deciphering the world of nanodrugs it is important to get an understanding of the pharmacokinetic characteristics, production methods of nanodrugs, nanodrug delivery systems, and the release control systems of nanodrugs. The prominent nanodrug delivery systems are lipid nanosystems including liposomes, emulsions, and solid lipid nanoparticles; inorganic nanomaterials including quantum dots, iron oxide, gold, hafnium nanoparticles, carbon nanotubes, anti-bacterial graphene and graphene oxide; and polymer nanosystems including dendrimers, nanoparticles, nanosponges, micelles, nanogels, and fibers. The promising properties of nanodrugs are employed in various therapeutic applications such as the treatment of pulmonary, central nervous system and cardiovascular diseases, vascular thrombosis; gene therapy, nanonephrology, and cancer treatment.
The Pharmacokinetic Characteristics of Nanodrugs
Nanodrugs offer several pharmacokinetic advantages such as specific drug delivery, high metabolic stability, high membrane permeability, improved bioavailability, and long duration of action. Altering the biopharmaceutical, pharmacokinetic, and physicochemical properties of nanodrugs can lead to desirable drug properties and aid various challenges in therapeutic applications. The physicochemical properties such as size, surface charge, and hydrophobicity affect the pharmacokinetic characteristic of nanodrugs greatly. For example, mucosal or transdermal absorption depends on the size, surface charge, and hydrophobicity of the drugs. The size of the particles is a key factor; smaller nanodrugs (particles) are characterized by higher transcellular uptake than larger particles. The particle size limits for the absorption by intestinal cells are 300 nm while nanoparticles smaller than 500 nm can penetrate the bloodstream. Two different targeting mechanisms govern the pharmacokinetic characteristics of nanodrugs; passive and active targeting.
Passive targeting is mainly based on the enhanced permeability and retention (EPR) effect which is caused by the enhanced permeability of capillaries due to damages on the diseased spot. These damages are caused by tumor, inflammation, hypertension, and so on weakening the discharge capacity of the lymph blood vessel. Hence, the molecular assembly is easier through the blood vessels in the damaged spot. Nanodrug systems increase the EPR effect by enhancing the stability of the drug and lengthening the in vivo circulation duration. Passive targeting is applied in cancer treatment studies and results in the reduction of peripheral side effects as well as an improvement in the treatment of solid tumors.
Active targeting is achieved through the binding of selective or responsive ligands on the nanodrugs. This type of targeting delivers drugs to specific organizations or release drugs under certain physical conditions. Three different mechanisms provide targeted delivery to the nanodrugs first of which is the environment sensitive delivery. Thermo-sensitive or pH-sensitive polymers are used for the release of nanodrugs under specific temperatures or acidity at different body tissues or organs. Environment sensitive delivery is usually achieved by utilizing micelles as carrier nanomaterials. When the carrier material is exposed to the external stimuli, it depolymerizes to the monomers, and nanodrugs are released out of the vector. The second mechanism utilizes special targeting ligands such as antibodies, lectins, sugars, hormones, and so on. The ligands are anchored to the surface of the carrier material and this carrier-ligand composite can be specifically identified by the epicyte receptors. This mechanism results in the accurate transmission of nanodrugs to the target spot. Studies on ligand targeted active delivery show that drug efficiency increases greatly. The third approach utilizes the inclusion of functional materials into the micelles along with the drugs without affecting the performance of micelles. Nanoparticles encapsulated in the micelles aids the release of the drug under external excitation conditions such as IR light or magnetic field by impacting the performance of the drug. Pharmacokinetic characteristics of nanodrugs are also strongly dependant on the nanodrug delivery systems since protecting the integrity of drugs is important.
Nanodrug Delivery Systems
Nanodrug delivery systems play an extremely important role in the successful implementation of nanotechnology based therapeutic applications. Combining nanodrug delivery systems with the nanodrug targeting methods provide enhanced therapeutic effects. Three different nanosystems are utilized in the nanodrug delivery; lipid nanosystems, inorganic nanomaterials, and polymeric nanosystems. Each of these systems has their advantage/disadvantages, promising applications in therapeutics, and requires further development for widespread clinical applications.
Lipid nanosystems include emulsions, liposomes, and solid-lipid nanoparticles. Emulsions create the basis of self-emulsifying drug delivery systems (SEDDSs) which consist of mixtures of oil, surfactant, co-solvent, and solubilized drug. Emulsion-based drugs have been utilized in order to enhance the oral bioavailability of highly lipophilic drugs. These nanosystems quickly form oil-in-water emulsions increasing the diffusion rate of the drugs. The size of the oil droplets formed by self-emulsification is generally below 250 μm. A potential disadvantage of emulsion systems is the rapid increase of systemic exposure resulting in toxicity.
Liposomes consist of aqueous microcapsules enveloped by phospholipids or cholesterol containing multilayer structures. Liposomes as carriers are further categorized according to their size as small unilamellar vesicles with 25-50 nm diameters, large unilamellar vesicles, and multilamellar vesicles with diameters ranging from 100 to 150 nm. The alluring feature of liposomes is their resemblance to the cell membrane with the hydrophobic outer shell and inner hydrophilic section which contributes to their biocompatibility greatly. The aqueous inner section of liposomes stores hydrophilic agents and the lipid part of hydrophobic agents. Liposomes are frequently utilized as pharmaceutical carriers due to their ability to load high amounts of hydrophilic and hydrophobic therapeutic agents, the ability to shield drug molecules from the external conditions, ability to acquire targeting properties through surface functionalization, and high systemic circulation with the use of inert polymers in their structure. However, conventional liposomes face several challenges such as nonspecific uptake, opsonization, and rapid clearance. Incorporating hydrophilic polymers such as PEG onto the surface of liposomes can aid the elimination of these drawbacks for a much more effective result. Today, there are various different FDA approved liposomal drugs used in oncology.
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The unstable nature and uncontrolled release of liposomes have led to the development of solid lipid nanoparticles. These are colloidal nanoparticles of triglycerides, diglycerides, monoglycerides, solid fats, or waxes. To achieve better stability these nanoparticles are treated with surfactants. Solid lipid nanoparticles show better physical stability, modulate the release of drugs, have lower manufacturing costs, and simpler production methodology. As opposed to liposomes, they offer various routes of applications such as intervenous, oral, by inhalation, transdermal, nasal, or intervesical. Different application options provide ease of delivery for the peptides and proteins. For example, the oral delivery of insulin has been considered a challenge due to the gastrointestinal barriers however; the use of solid lipid nanoparticles approach shows promising results for the solution to this problem. On the other hand, solid lipid nanoparticles have lower drug loading capacity, show drug repulsion after recrystallization, and relatively high water content. Even though solid lipid nanoparticles are promising, clinical studies have yet to be conducted in this area.
Inorganic engineered nanoparticles have also attracted a lot of attention in nanodrug development applications. Quantum dots, iron oxide, gold, hafnium nanoparticles, carbon nanotubes, anti-bacterial graphene, and graphene oxide are frequently used in these systems. The particle size of these particles is either reduced by the “top-down” approach to 10-100 nm or the produced at these diameters through controlled precipitation, namely the “bottom-up” approach. The high surface area of nanoparticles increases the diffusion rate while the small size facilitates the penetration through capillaries and increases the nanodrug uptake in the targeted tissue. Gold nanoparticles are particularly used in hyperthermic therapies due to their ability to convert photon energy to heat. Carbon nanotubes have great drug loading capacities due to their cylindric structure and high surface area. Nanoparticles increase maximum drug concentration and bioavailability up to dozens of folds compared to the conventional micrometer sized particles. Toxicity induced by membrane damage and induction of oxidative stress needs to be taken into consideration when developing nanoparticles based nanodrugs. Surface functionalization through biocompatible polymers is often employed for the reduction of cytotoxicity of these materials, especially for carbon-based nanoparticles. For example, chitosan modified single-walled carbon nanotubes targeted by folic acid with doxorubicin is found to be more effective and less toxic than free drugs. Furthermore, the antibacterial property of CNTs, graphene fullerenes, and graphene oxide is found to be useful in nanodrug applications. Potential cytotoxicity of CNTs and graphene based materials can be reduced through encapsulation by proteins without interfering with the antibacterial property of these structures. Recently, a lower dose diclofenac nanoparticles capsule was developed for the treatment of mild to moderate acute pain in adults. There are many other examples of engineered nanoparticles in nanodrug applications of including cancer treatment applications.
Polymeric nanodrugs are promising pharmaceutical materials for the new era of medicine. Polymers used in polymeric Nanodrugs are divided into two categories as natural polymers like proteins, peptides, glycans, starches or cellulose and synthetic polymers like polylactic acid (PLA), or polycaprolactone (PLC). Synthetic polymers used in nanodrugs are biocompatible and biodegradable polyesters. Polymer nanosystems include dendrimers, nanoparticles, nanosponges, micelles, nanogels, and fibers. Polymeric Nanodrugs provide protection against degradation, higher stability, various available ways of application, controlled drug release, and prolonged drug action. Due to the biocompatible nature of polymers, they are biodegradable, show low toxicity, and immunogenicity. Natural polymer nanoparticles such as apoferritin and albumin are used in clinical trials for cancer treatment as promising nanodrugs. The results show a higher overall response rate and decreased immunogenicity. Nanosponges are hyper-crosslinked colloidal nanostructures with high porosity in which drugs can be encapsulated. The spherical shape and diameter below 500 nm allow nanosponges to be used in various application forms such as topical, aerosol, and tablets. Dendrimers are another polymeric carrier material for nanodrugs. They consist of highly branched macromolecules with a specific size and shape. The size of the dendrimers ranges from 1-100 nm. The core of dendrimers is hydrophobic while the outer part is hydrophilic. Drugs can either be encapsulated inside the hydrophobic core or attached to the hydrophilic surface of dendrimers. Properties of dendrimers are strongly dependant on their surface functional groups. Dendrimers offer biocompatibility, easy elimination from the body, and significantly expressed EPR effect. However, dendrimers show cytotoxicity to normal cells due to the physiological stability and the cationic groups in their structure. Thus, surface functionalization plays an important role in the development of dendrimer nanodrug systems. Dendrimers have been suggested as a tool in the solubilization of poorly soluble drugs, and poly(amidoamine) dendrimers and other polymeric dendrimers have been applied to flurbiprofen, methotrexate, and piroxicam for solubilization and targeted delivery. Micelles have become a popular polymeric structure in recent years. They are spherical nanostructures with a size of 10-50 nm, a hydrophobic tail, and a hydrophilic head. Micelles are usually used as carriers of hydrophobic nanodrugs and can be applied directly into the circulation like liposomes or via inhalation or transdermally. These nanostructures offer the protection of internal drugs from degradation, solubility enhancement, and targeted delivery. The core-shell structure of micelles successfully mimics the natural transport systems hence, improve the absorption and distribution of nanodrugs while avoiding opsonization and phagocytic clearance by RES uptake. The micellar nanoparticles can be applied to liquid eye drops, to attenuate the rapid elimination of the drugs from the precorneal area, offering a longer duration of action. The safety profile of micelles in cancer treatment also showed better toxicity levels than the free-drug applications. Nanofibers attract attention as nanodrugs because of their high surface-to-volume ratio and microporosity. They are used in nanodrug delivery systems for various therapeutics including anti-cancer agents. The wide variety of polymer options that can be used in the nanofiber matrix allow the loading and subsequent release of both hydrophobic and hydrophilic agents. Amphiphilic polymers such as PEG in the nanofiber matrix aid the solubility of hydrophobic drugs in the aqueous environment. The studies on polymeric nanosystems show that these materials have great potential in nanodrug applications even though they require further development and clinical testing to be utilized widely.
Even though nanodrugs rely mostly on the nano delivery systems, the low drug loading capacity of carriers which is usually below 20% and possible side effects induced by the carrier structures motivated scientists to develop carrier-free nanodrugs. Carrier-free nanodrugs refer to those nano-sized self-delivery drugs that fabricated by several active agents without or with minimum use of inert materials. Carrier-free multi-agent drugs offer an all-in-one nanosystem for therapy, suppression of the multidrug resistance which is a big challenge for cancer treatment, low toxicity, and side effects due to the absence of a carrier, good targeting ability, excellent drug loading capacity, and pharmacokinetics. Carrier-free nanodrugs are especially considered for cancer treatment studies.
Release Control of Nanodrugs
Another advantage of nanodrug systems is the controllability of drug release to the nanodrug delivery systems. The release of drug from the nanoparticles occurs at a constant speed in a scheduled period of time. The controlled release of drugs is achieved through leaching, infiltration, proliferation or dissolution, and the effect of specific tissue or organ. Furthermore, the premature release of drugs by degradation is inhibited by the protective nature of nanocarriers extending the effective time of drugs. The controlled release of nanodrugs can also reduce the peak phenomenon of blood concentration, reduce side effects, and improve efficacy. Diffusion control, chemical control, and solvent control are some of the methods for controlled drug release. Diffusion control is the most common mechanism of controlled drug release, especially in the case of nondegradable polymer carriers. The drug content in the nano-carrier complex is released at a certain rate through diffusion. In the case of biodegradable polymers, the diffusion control still plays an important role in the drug release if the degradation rate is considerably smaller than the diffusion rate. The factors affecting the diffusion controlled drug release are the geometric design of the system, condition, and quality of the ambient medium, the character and the structure of the host materials, the solubility, and the loading amount of the nanodrug. Chemical controlled release system controls the rate of drug release through hydrolysis, zymohydrolysis, and other chemical reactions. There are two different categories of chemical controlled systems according to the role of drug and carrier structure; degradable system and side-chain system. In the degradable systems, there is no chemical bonding between drugs and the carrier polymer instead drug is dispersed and encapsulated in the biodegradable polymer network. The rate of drug release is controlled by the rate of polymer degradation and erosion. The carrier material is non-toxic and can be discharged in vitro or absorbed by the tissue through the regulation of polymer degradation. The rate of degradation which is strongly related to the polymer molecular weight, crystallinity, the hydrophilic, or hydrophobic nature governs the release of nanodrugs. The degradation or dissolution of carrier material can be controlled through chemical or physical interference such as reshaping, modification, and additives to the polymer structure. In the side-chain system, the carrier material can be either degradable or nondegradable. Through the chemical bonds that can be hydrolyzed or enzymolized drugs can be attached to the primary chain or side chain of the polymer. The rate of drug release is controlled through hydrolysis or enzymolysis. Solvent-control systems involve infiltration or swelling mechanisms. The soluble drug encapsulated in the carrier polymer is released after the nanodrug carrier system enters the appropriate media. The external solvent rushes into the carrier system forming a stable saturated solution increasing the osmotic pressure of the system which then leads to the release of drugs to the outside of the nanodrug carrier structure. Swelling is a much more common mechanism of solvent-control systems. Solvent penetration causes the swelling of the carrier system and equality of polymer glass transition temperature to the environment leading to the release of the drug content. The drug release rate depends on various factors such as the nature of the polymer, temperature, and pH of the environment, hydrophilicity, and hydrophobicity. More often than not, the controlled release of nanodrugs is managed through a combination of these three mechanisms creating a complex but effective process. The controlled drug release prolongs the effective treatment type and efficacy.
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The Specific Application Areas of Nanodrugs
Several different therapeutic areas have dipped their toe in the exciting world of nanodrugs. The attractive properties of nanodrugs such as targeted delivery and controlled drug release have been utilized in the treatment of pulmonary, central nervous system and cardiovascular diseases, vascular thrombosis; gene therapy, nanonephrology, and cancer treatment. The vast majority of clinical trials are studying cancer patients (~72%), and the other biomedical applications are in infectious diseases (~6%), imaging (~2%), and dental composites (~0.2%).
Nanodrugs in the Treatment of Pulmonary Diseases
Inhalation of aerosols is considered a major invention in pulmonary disorders. However, there are certain downsides such as difficulty in dosing, loss of drug compounds during inhalation, enzymatic degradation in the lungs, and high manufacturing costs. These limitations affect the use of aerosols. The stabilizing effect and protection against drug release in bronchi make nanodrug delivery systems an attractive choice for pulmonary therapy applications.
Nanodrugs for the Treatment of Central Nervous System Diseases
The blood-brain barrier which is a highly selective semipermeable membrane barrier that only allows transportation of molecules with a high o/w partition coefficient considerably affects the molecular uptake of drugs. Even though the mechanisms are still unclear, nanoparticles can pass the blood-brain barrier and enter the central nervous system. Hence, nanodrugs can be used for efficient drug delivery for the treatment of central nervous system diseases. It is important to note that nanodrugs in this field are still in the clinical trial and require further development for widespread use.
Nanodrugs for the Treatment of Vascular Thrombosis
The conventional therapies of the vascular thrombosis show limitations such as rapid drug washout, the short plasma half-life of the drugs, and severe side effects. Effective nanodrug delivery systems with optimum drug loading are promising solutions to these side effects since encapsulation enhances drug hail-life and circulation stability. Due to their biocompatibility and biodegradability, polymeric nanoparticles and liposomal nanocarriers are mainly preferred as nanodrug delivery systems for the treatment of vascular thrombosis.
Nanodrugs for Gene Therapy
Nanodrug delivery systems with a diameter of 100 nm or less are proven to be effective carriers for transgene vectors. Bionanoparticles and Nanosized viral vectors show beneficial results due to increased stability and selectivity. However, studies for gene therapy are still in clinical trials and haven’t been approved by the FDA due to disadvantages like immunogenicity, oncogenicity, and potential viral recombination problems.
Nanophrenology deals with protein structures at atomic levels for nano-imaging and nanomedicinal treatment of various kidney diseases. Nanoparticles are widely utilized in this area of nanomedicine for renal targeting and renal imaging, the treatment of renovascular hypertension and acute renal failure, renal transplantation, and ischemic-reperfusion injury, as well as the neoplasm of the kidney. There are several different approved nanodrugs in this area marketed as products by different companies such as Sanofi Aventis, AMAG Pharmaceuticals, and Hoffman-La Roche).
Nanodrugs for the Treatment of Cardiovascular Disease
Cardiovascular diseases are one of the most common fetal conditions in the world accounting the one-third of deaths worldwide. Consequently, there are a lot of studies focused on developing novel effective treatments for cardiovascular diseases including nanodrugs. Some of the nano delivery systems employed for the treatment of cardiovascular diseases are liposomes, biodegradable nanoparticles, carbon-carbon nanoparticle, and albumin nanoparticle complexes, and core-shell nanoparticles of polyethylene glycol-based block copolymers.
Nanodrugs for Cancer Treatment
Cancer is without a doubt one of the most worrying conditions due to the lack of efficient treatment methods, serious side effects of conventional treatments, and the problem of early diagnosis. Hence, a lot of studies are conducted around the world for better solutions and more effective approaches. The limitations of conventional cancer therapies such as surgery, radiation, and chemotherapy are the lack of aqueous solubility of the drugs, multidrug resistance, and the lack of selectivity towards cancer cells. Nanodrugs are promising alternatives to aid these limitations of conventional cancer therapies. Multidrug resistance, one of the biggest challenges of chemotherapy, can be reduced by using y using solid lipid nanoparticles, mesoporous silica nanoparticles, nanoparticulated chemosensitizer, nanoparticulated poloxamer, polymeric nanoparticles, and magnetic nanoparticles. The hydrophobic nature of chemotherapeutic drugs can be managed by albumin-based and chitosan-based nanoparticles, nanocrystals, liposomal systems, polymeric micelles. Furthermore, the lack of selectivity can be remedied by the targeting of nanodrugs which would significantly reduce undesired tissue damage and serious side effects. However, direct targeting of diseased tissue still hasn’t been achieved. Currently, there are various FDA approved and marketed nanodrugs in the pharmaceutical industry.
The Safety of Nanodrugs
Biocompatibility is described as the acceptable reaction of live tissue to the foreign materials injected into the body. It refers to the compatibility between the host and the material including histocompatibility and blood compatibility. Furthermore, biocompatibility is a two-sided coin requiring biosafety and bio functionality simultaneously. In the end, nanodrugs are foreign substances to the human body and naturally expected to cause some sort of repulsive phenomenon or response in the body. However, this response is expected to be acceptable by the host inducing no harmful effects if the nanodrugs are applied successfully. For this reason, nanotoxicology is emerging as an important subdiscipline to assess the biocompatibility of nanodrugs. The fact that there are no sufficient methods to investigate the safety of nanoparticles makes it challenging to understand the toxicology of nanodrugs. Building a better understanding of nanotoxicology and its mechanisms would provide great help to the development of new nanodrugs and the appropriate clinical applications.
Final Outlook on Nanodrugs
The colliding worlds of pharmaceutical studies and nanotechnology have led to the emergence of nanodrugs. With the development of nanodrug systems, the drawbacks of conventional drugs such as lack of targeted delivery, undesired concentration in the blood, short circulation of drug molecules, and considerable side-effects are aimed to be remedied. To achieve this improvement, the pharmacokinetic characteristics of nanodrugs, the nanodrug delivery systems, and the release control systems of nanodrugs must be understood properly. The valuable pharmacokinetic characteristics of nanodrugs are specific drug delivery, high metabolic stability, high membrane permeability, improved bioavailability, and long duration of action. The particle size of nanodrugs has a great impact on the pharmacokinetic characteristics of nanodrugs since tissue permeability is greatly dependant on this parameter. Two different mechanisms govern the targeted delivery of nanodrugs which are passive and active targeting. Nanodrug delivery systems are another important component of the implementation of nanotechnology based therapeutic applications. The main delivery systems are lipid nanosystems including liposomes, emulsions, and solid lipid nanoparticles; inorganic nanomaterials including quantum dots, iron oxide, gold, hafnium nanoparticles, carbon nanotubes, anti-bacterial graphene and graphene oxide; and polymer nanosystems including dendrimers, nanoparticles, nanosponges, micelles, nanogels, and fibers. Each of these nanocarrier systems has its advantage and disadvantages compatible with different drug and tissue properties. In addition to the nanodrug carrier-based systems, carrier-free nanodrugs have also been developed to try and eliminate the undesired effects of carrier materials such as the accumulation of degradation products and low drug loading capacities. Combining nanodrug delivery systems with the nanodrug targeting methods provide enhanced therapeutic effects. The controlled-release of nanodrug is an attractive property governed by three different mechanisms; diffusion control, chemical control, and solvent control. These control mechanisms are often utilized in combination with each other to achieve optimum drug release conditions.
Nanodrugs developed by fine-tuning the chemical and physical properties of drug and carrier components have been employed in the various therapeutic applications. The prominent therapeutic applications of the nanodrugs are the treatment of pulmonary, central nervous system and cardiovascular diseases, vascular thrombosis; gene therapy, nanonephrology, and cancer treatment. The safety of nanodrugs is an important matter to take into consideration. Nanodrugs must show acceptable biocompatibility, provide biosafety and bio functionality simultaneously. Nanotoxicity is a newly emerged subfield just to provide tangible progress on the safety of nanodrugs. Further understanding of nanotoxicity of nanodrugs could allow the development of new nanodrugs and the appropriate clinical applications. All in all, nanodrugs are novel therapeutic agents that have great potential for the effective, fast, and safe treatment of several different diseases.
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