Targeted drug delivery

Passive targeting is achieved by incorporating the therapeutic agent into a macromolecule or nanoparticle that passively reaches the target organ. In passive targeting, the drug's success is directly related to circulation time.[6] This is achieved by cloaking the nanoparticle with some sort of coating. Several substances can achieve this, with one of them being polyethylene glycol (PEG). By adding PEG to the surface of the nanoparticle, it is rendered hydrophilic, thus allowing water molecules to bind to the oxygen molecules on PEG via hydrogen bonding. The result of this bond is a film of hydration around the nanoparticle which makes the substance antiphagocytic. The particles obtain this property due to the hydrophobic interactions that are natural to the reticuloendothelial system (RES), thus the drug-loaded nanoparticle is able to stay in circulation for a longer period of time.[7] To work in conjunction with this mechanism of passive targeting, nanoparticles that are between 10 and 100 nanometers in size have been found to circulate systemically for longer periods of time.[8]

Active targeting of drug-loaded nanoparticles enhances the effects of passive targeting to make the nanoparticle more specific to a target site. There are several ways that active targeting can be accomplished. One way to actively target solely diseased tissue in the body is to know the nature of a receptor on the cell for which the drug will be targeted to.[9] Researchers can then utilize cell-specific ligands that will allow the nanoparticle to bind specifically to the cell that has the complementary receptor. This form of active targeting was found to be successful when utilizing transferrin as the cell-specific ligand.[9] The transferrin was conjugated to the nanoparticle to target tumor cells that possess transferrin-receptor mediated endocytosis mechanisms on their membrane. This means of targeting was found to increase uptake, as opposed to non-conjugated nanoparticles. Another cell-specific ligand is the RGD motif which binds to the integrin αvβ3.[10] This integrin is upregulated in tumor and activated endothelial cells.[11] Conjugation of RGD to chemotherapeutic-loaded nanoparticles has been shown to increase cancer cell uptake in vitro and therapeutic efficacy in vivo.[10]

Active targeting can also be achieved by utilizing magnetoliposomes, which usually serves as a contrast agent in magnetic resonance imaging.[9] Thus, by grafting these liposomes with a desired drug to deliver to a region of the body, magnetic positioning could aid with this process.

Furthermore, a nanoparticle could possess the capability to be activated by a trigger that is specific to the target site, such as utilizing materials that are pH responsive.[9] Most of the body has a consistent, neutral pH. However, some areas of the body are naturally more acidic than others, and, thus, nanoparticles can take advantage of this ability by releasing the drug when it encounters a specific pH.[9] Another specific triggering mechanism is based on the redox potential. One of the side effects of tumors is hypoxia, which alters the redox potential in the vicinity of the tumor. By modifying the redox potential that triggers the payload release the vesicles can be selective to different types of tumors.[12]

By utilizing both passive and active targeting, a drug-loaded nanoparticle has a heightened advantage over a conventional drug. It is able to circulate throughout the body for an extended period of time until it is successfully attracted to its target through the use of cell-specific ligands, magnetic positioning, or pH responsive materials. Because of these advantages, side effects from conventional drugs will be largely reduced as a result of the drug-loaded nanoparticles affecting only diseased tissue.[13] However, an emerging field known as nanotoxicology has concerns that the nanoparticles themselves could pose a threat to both the environment and human health with side effects of their own.[14] Active targeting can also be achieved through peptide based drug targeting system.[15]

Cell Surface Peptides provide one way to introduce drug delivery into a target cell.[16] This method is accomplished by the peptide binding to a target cells surface receptors, in a way that bypasses immune defenses that would otherwise compromise a slower delivery, without causing harm to the host. In particular, peptides, such as intercellular adhesion molecule-1, have shown a great deal of binding ability in a target cell. This method has shown a degree of efficacy in treating both autoimmune diseases as well as forms of cancer as a result of this binding affinity.[17] Peptide mediated delivery is also of promise due to the low cost of creating the peptides as well as the simplicity of their structure.

Liposomes are composite structures made of phospholipids and may contain small amounts of other molecules. Though liposomes can vary in size from low micrometer range to tens of micrometers, unilamellar liposomes, as pictured here, are typically in the lower size range, with various targeting ligands attached to their surface, allowing for their surface-attachment and accumulation in pathological areas for treatment of disease.[18]

The most common vehicle currently used for targeted drug delivery is the liposome.[19] Liposomes are non-toxic, non-hemolytic, and non-immunogenic even upon repeated injections; they are biocompatible and biodegradable and can be designed to avoid clearance mechanisms (reticuloendothelial system (RES), renal clearance, chemical or enzymatic inactivation, etc.)[20][21] Lipid-based, ligand-coated nanocarriers can store their payload in the hydrophobic shell or the hydrophilic interior depending on the nature of the drug/contrast agent being carried.[5]

The only problem to using liposomes in vivo is their immediate uptake and clearance by the RES system and their relatively low stability in vitro. To combat this, polyethylene glycol (PEG) can be added to the surface of the liposomes. Increasing the mole percent of PEG on the surface of the liposomes by 4-10% significantly increased circulation time in vivo from 200 to 1000 minutes.[5]

PEGylation of the liposomal nanocarrier elongates the half-life of the construct while maintaining the passive targeting mechanism that is commonly conferred to lipid-based nanocarriers.[22] When used as a delivery system, the ability to induce instability in the construct is commonly exploited allowing the selective release of the encapsulated therapeutic agent in close proximity to the target tissue/cell in vivo. This nanocarrier system is commonly used in anti-cancer treatments as the acidity of the tumour mass caused by an over-reliance on glycolysis triggers drug release.[22][23][24]

Additional endogenous trigger pathways have been explored through the exploitation of inner and outer tumor environments, such as reactive oxygen species, glutathione, enzymes, hypoxia, and adenosine-5’- triphosphate (ATP), all of which are generally highly present in and around tumors.[25] External triggers are also used, such as light, low frequency ultrasound (LFUS), electrical fields, and magnetic fields.[26] In specific, LFUS has demonstrated high efficacy in the controlled trigger of various drugs in mice, such as cisplatin and calcein.[27][28]

Another type of drug delivery vehicle used is polymeric micelles. They are prepared from certain amphiphilic co-polymers consisting of both hydrophilic and hydrophobic monomer units.[2] They can be used to carry drugs that have poor solubility. This method offers little in the terms of size control or function malleability. Techniques that utilize reactive polymers along with a hydrophobic additive to produce a larger micelle that create a range of sizes have been developed.[29]

Dendrimers are also polymer-based delivery vehicles. They have a core that branches out in regular intervals to form a small, spherical, and very dense nanocarrier.[30]

Biodegradable particles have the ability to target diseased tissue as well as deliver their payload as a controlled-release therapy.[31] Biodegradable particles bearing ligands to P-selectin, endothelial selectin (E-selectin) and ICAM-1 have been found to adhere to inflamed endothelium.[32] Therefore, the use of biodegradable particles can also be used for cardiac tissue.

The success of DNA nanotechnology in constructing artificially designed nanostructures out of nucleic acids such as DNA, combined with the demonstration of systems for DNA computing, has led to speculation that artificial nucleic acid nanodevices can be used to target drug delivery based upon directly sensing its environment. These methods make use of DNA solely as a structural material and a chemical, and do not make use of its biological role as the carrier of genetic information. Nucleic acid logic circuits that could potentially be used as the core of a system that releases a drug only in response to a stimulus such as a specific mRNA have been demonstrated.[33] In addition, a DNA "box" with a controllable lid has been synthesized using the DNA origami method. This structure could encapsulate a drug in its closed state, and open to release it only in response to a desired stimulus.[34]