Nanoparticle drug delivery

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Nanoparticle drug delivery systems are engineered technologies that use nanoparticles for the targeted delivery and controlled release of therapeutic agents. The modern form of a drug delivery system should minimize side-effects and reduce both dosage and dosage frequency. Recently, nanoparticles have aroused attention due to their potential application for effective drug delivery.^[1]

Nanomaterials exhibit different chemical and physical properties or biological effects compared to larger-scale counterparts that can be beneficial for drug delivery systems. Some important advantages of nanoparticles are their high surface-area-to-volume ratio, chemical and geometric tunability, and their ability to interact with biomolecules to facilitate uptake across the cell membrane. The large surface area also has a large affinity for drugs and small molecules, like ligands or antibodies, for targeting and controlled release purposes.

Nanoparticles refer to a large family of materials both organic and inorganic. Each material has uniquely tunable properties and thus can be selectively designed for specific applications. Despite the many advantages of nanoparticles, there are also many challenges, including but not exclusive to: nanotoxicity, biodistribution and accumulation, and the clearance of nanoparticles by human body.

The National Institute of Biomedical Imaging and Bioengineering has issued the following prospects for future research in nanoparticle drug delivery systems:

1. crossing the blood-brain barrier (BBB) in brain diseases and disorders;
2. enhancing targeted intracellular delivery to ensure the treatments reach the correct structures inside cells;
3. combining diagnosis and treatment.^[2]

The development of new drug systems is time-consuming; it takes approximately seven years to complete fundamental research and development before advancing to preclinical animal studies.^[3]

Characterization[]

Nanoparticle drug delivery focuses on maximizing drug efficacy and minimizing cytotoxicity. Fine-tuning nanoparticle properties for effective drug delivery involves addressing the following factors. The surface-area-to-volume ratio of nanoparticles can be altered to allow for more ligand binding to the surface.^[4] Increasing ligand binding efficiency can decrease dosage and minimize nanoparticle toxicity. Minimizing dosage or dosage frequency also lowers the mass of nanoparticle per mass of drug, thus achieving greater efficiency.^[5] Surface functionalization of nanoparticles is another important design aspect and is often accomplished by bioconjugation or passive adsorption of molecules onto the nanoparticle surface. By functionalizing nanoparticle surfaces with ligands that enhance drug binding, suppress immune response, or provide targeting/controlled release capabilities, both a greater efficacy and lower toxicity are achieved. Efficacy is increased as more drug is delivered to the target site, and toxic side effects are lowered by minimizing the total level of drug in the body. The composition of the nanoparticle can be chosen according to the target environment or desired effect. For example, liposome-based nanoparticles can be biologically degraded after delivery,^[6] thus minimizing the risk of accumulation and toxicity after the therapeutic cargo has been released. Metal nanoparticles, such as gold nanoparticles, have optical qualities(also described in nanomaterials) that allow for less invasive imaging techniques.^[7] Furthermore, the photothermal response of nanoparticles to optical stimulation can be directly utilized for tumor therapy.

Platforms[]

Current nanoparticle drug delivery systems can be cataloged based on their platform composition into several groups: polymeric nanoparticles, inorganic nanoparticles, viral nanoparticles, lipid-based nanoparticles, and nanoparticle albumin-bound (nab) technology. Each family has its unique characteristics.

Polymeric nanoparticles[]

Polymeric nanoparticles are synthetic polymers with a size ranging from 10 to 100 nm. Common synthetic polymeric nanoparticles include polyacrylamide,^[8] polyacrylate,^[9] and chitosan.^[10] Drug molecules can be incorporated either during or after polymerization. Depending on the polymerization chemistry, the drug can be covalently bonded, encapsulated in a hydrophobic core, or conjugated electrostatically.^[9][11] Common synthetic strategies for polymeric nanoparticles include microfluidic approaches,^[12] electrodropping,^[13] high pressure homogenization, and emulsion-based interfacial polymerization.^[14] Polymer biodegradability is an important aspect to consider when choosing the appropriate nanoparticle chemistry. Nanocarriers composed of biodegradable polymers undergo hydrolysis in the body, producing biocompatible small molecules such as lactic acid and glycolic acid.^[15] Polymeric nanoparticles can be created via self assembly or other methods such as particle replication in nonwetting templates (PRINT) which allows customization of composition, size, and shape of the nanoparticle using tiny molds.^[16]

Dendrimers[]

Dendrimers are unique hyper-branched synthetic polymers with monodispersed size, well-defined structure, and a highly functionalized terminal surface. They are typically composed of synthetic or natural amino acid, nucleic acids, and carbohydrates. Therapeutics can be loaded with relative ease onto the interior of the dendrimers or the terminal surface of the branches via electrostatic interaction, hydrophobic interactions, hydrogen bonds, chemical linkages, or covalent conjugation.^[17][18][16] Drug-dendrimer conjugation can elongate the half-life of drugs. Currently, dendrimer use in biological systems is limited due to dendrimer toxicity^[19] and limitations in their synthesis methods.^[20] Dendrimers are also confined within a narrow size range (<15 nm) and current synthesis methods are subject to low yield. The surface groups will reach the de Gennes dense packing limit at high generation level, which seals the interior from the bulk solution – this can be useful for encapsulation of hydrophobic, poorly soluble drug molecules. The seal can be tuned by intramolecular interactions between adjacent surface groups, which can be varied by the condition of the solution, such as pH, polarity, and temperature, a property which can be utilized to tailor encapsulation and controlled release properties.^[21]

Platinum nanoparticles

Inorganic Nanoparticles and Nanocrystals[]

Inorganic nanoparticles have emerged as highly valuable functional building blocks for drug delivery systems due to their well-defined and highly tunable properties such as size, shape, and surface functionalization. Inorganic nanoparticles have been largely adopted to biological and medical applications ranging from imaging and diagnoses to drug delivery.^[22] Inorganic nanoparticles are usually composed of inert metals such as gold and titanium that form nanospheres, however, iron oxide nanoparticles have also become an option.

Quantum dots (QDs), or inorganic semiconductor nanocrystals, have also emerged as valuable tools in the field of bionanotechnology because of their unique size-dependent optical properties and versatile surface chemistry. Their diameters (2 - 10 nm) are on the order of the exciton Bohr radius, resulting in quantum confinement effects analogous to the “particle-in-a-box” model. As a result, optical and electronic properties of quantum dots vary with their size: nanocrystals of larger sizes will emit lower energy light upon fluorescence excitation.^[23]

Surface engineering of QDs is crucial for creating nanoparticle–biomolecule hybrids capable of participating in biological processes. Manipulation of nanocrystal core composition, size, and structure changes QD photo-physical properties Designing coating materials which encapsulate the QD core in an organic shell make nanocrystals biocompatible, and QDs can be further decorated with biomolecules to enable more specific interaction with biological targets. The design of inorganic nanocrystal core coupled with biologically compatible organic shell and surface ligands can combine useful properties of both materials, i.e. optical properties of the QDs and biological functions of ligands attached.^[24]

Toxicity[]

While application of inorganic nanoparticles in bionanotechnology shows encouraging advancements from a materials science perspective, the use of such materials in vivo is limited by issues related with toxicity, biodistribution and bioaccumulation. Because metal inorganic nanoparticle systems degrade into their constituent metal atoms, challenges may arise from the interactions of these materials with biosystems, and a considerable amount of the particles may remain in the body after treatment, leading to buildup of metal particles potentially resulting in toxicity.^[25]

Recently, however, some studies have shown that certain nanoparticle environmental toxicity effects aren’t apparent until nanoparticles undergo transformations to release free metal ions. Under aerobic and anaerobic conditions, it was found that copper, silver, and titanium nanoparticles released low or insignificant levels of metal ions. This is evidence that copper, silver, and titanium NP are slow to release metal ions, and may therefore appear at low levels in the environment.^[26] Additionally, nanoshell coatings significantly protect against degradation in the cellular environment and also reduce QDs toxicity by reducing metal ion leakage from the core.^[23]

Organic Nanocrystals[]

Organic nanocrystals consist of pure drugs and surface active agents required for stabilization. They are defined as carrier-free submicron colloidal drug delivery systems with a mean particle size in the nanometer range. The primary importance of the formulation of drugs into nanocrystals is the increase in particle surface area in contact with the dissolution medium, therefore increasing bioavailability. A number of drug products formulated in this way are on the market.^[27]

Solubility[]

One of the issues faced by drug delivery is the solubility of the drug in the body; around 40% of newly detected chemicals found in drug discovery are poorly soluble in water.^[28] This low solubility affects the bioavailability of the drug, meaning the rate at which the drug reaches the circulatory system and thus the target site. Low bioavailability is most commonly seen in oral administration, which is the preferred choice for drug administration due to its convenience, low costs, and good patient practice.^[28] A measure to improve poor bioavailability is to inject the drugs in a solvent mixture with a solubilizing agent.^[29] However, results show this solution is ineffective, with the solubilizing agent demonstrating side-effects and/or toxicity. Nanocrystals used for drug delivery can increase saturation solubility and dispersion velocity. Generally, saturation solubility is thought to be a function of temperature, but it is also based on other factors, such as crystalline structure and particle size, in regards to nanocrystals. The Ostwald-Freundlich equation below shows this relationship:

${\displaystyle log({\frac {C_{s}}{C_{\alpha }}})={\frac {2\sigma V}{2.303RT\rho r}}}$

Where C_s is the saturation solubility of the nanocrystal, C