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.Nanoparticles as drug delivery systems, Pharmacological Reports, Volume 64, Issue 5,2012, Pages 1020-1037, ISSN 1734-1140, https://doi.org/10.1016/S1734-1140(12)70901-5.
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: crossing the blood-brain barrier (BBB) in brain diseases and disorders; enhancing targeted intracellular delivery to ensure the treatments reach the correct structures inside cells; combining diagnosis and treatment.Drug Delivery Systems: Getting Drugs to Their Targets in a Controlled Manner .
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.Etheridge, M.L., et al., The big picture on nanomedicine: the state of investigational and approved nanomedicine products. Nanomedicine: Nanotechnology, Biology and Medicine, 2013. 9(1): p. 1-14. doi: 10.1016/j.nano.2012.05.013. Epub 2012 Jun 6.
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. Investigating the Cellular Specificity in Tumors of a Surface-Converting Nanoparticle by Multimodal Imaging Francois Fay, Line Hansen, Stefanie J. C. G. Hectors, Brenda L. Sanchez-Gaytan, Yiming Zhao, Jun Tang, Jazz Munitz, Amr Alaarg, Mounia S. Braza, Anita Gianella, Stuart A. Aaronson, Thomas Reiner, Jørgen Kjems, Robert Langer, Freek J. M. Hoeben, Henk M. Janssen, Claudia Calcagno, Gustav J. Strijkers, Zahi A. Fayad, Carlos Pérez-Medina, and Willem J.M. Mulder Bioconjugate Chemistry 2017 28 (5), 1413-1421 DOI:10.1021/acs.bioconjchem.7b00086. 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.Hainfeld, J.F., et al., Gold nanoparticle hyperthermia reduces radiotherapy dose. Nanomedicine : nanotechnology, biology, and medicine, 2014. 10(8): p. 1609-1617.
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,Biswajit Mukherjee, N.S.D., Ruma Maji, Priyanka Bhowmik, Pranab Jyoti Das and Paramita Paul, Current Status and Future Scope for Nanomaterials in Drug Delivery. Application of Nanotechnology in Drug Delivery. 2013. 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.Jeong, E.H., et al., Gold nanoparticle (AuNP)-based drug delivery and molecular imaging for biomedical applications. Archives of pharmacal research, 2014. 37(1): p. 53-59. 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,Bai, J., et al., One-pot synthesis of polyacrylamide-gold nanocomposite. Materials Chemistry and Physics, 2007. 106(2): p. 412-415. polyacrylate,Turos, E., et al., Antibiotic-conjugated polyacrylate nanoparticles: New opportunities for development of anti-MRSA agents. Bioorganic & Medicinal Chemistry Letters, 2007. 17(1): p. 53-56. and chitosan.Mao, H.-Q., et al., Chitosan-DNA nanoparticles as gene carriers: synthesis, characterization and transfection efficiency. Journal of Controlled Release, 2001. 70(3): p. 399-421. 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.Pinto Reis, C., et al., Nanoencapsulation I. Methods for preparation of drug-loaded polymeric nanoparticles. Nanomedicine: Nanotechnology, Biology and Medicine, 2006. 2(1): p. 8-21. Common synthetic strategies for polymeric nanoparticles include microfluidic approaches,Shim, T.S., S.-H. Kim, and S.-M. Yang, Elaborate Design Strategies Toward Novel Microcarriers for Controlled Encapsulation and Release. Particle & Particle Systems Characterization, 2012. 30(1): p. 9-45. electrodropping,Choi, D.H., et al., Dual Growth Factor Delivery Using Biocompatible Core–Shell Microcapsules for Angiogenesis. Small, 2013. 9(20): p. 3468-3476. high pressure homogenization, and emulsion-based interfacial polymerization.Song, Y., J.-B. Fan, and S. Wang, Recent progress in interfacial polymerization. Materials Chemistry Frontiers, 2017. 1(6): p. 1028-1040. 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.Kumari, A., S.K. Yadav, and S.C. Yadav, Biodegradable polymeric nanoparticles based drug delivery systems. Colloids and Surfaces B: Biointerfaces, 2010. 75(1): p. 1-18. 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.
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.Gillies, E.R. and J.M.J. Fréchet, Dendrimers and dendritic polymers in drug delivery. Drug Discovery Today, 2005. 10(1): p. 35-43.Svenson, S. and D.A. Tomalia, Dendrimers in biomedical applications—reflections on the field. Advanced Drug Delivery Reviews, 2005. 57(15): p. 2106-2129. Drug-dendrimer conjugation can elongate the half-life of drugs. Currently, dendrimer use in biological systems is limited due to dendrimer toxicityJain, K., et al., Dendrimer toxicity: Let's meet the challenge. International Journal of Pharmaceutics, 2010. 394(1): p. 122-142. and limitations in their synthesis methods.Pooja, D., R. Sistla, and H. Kulhari, Chapter 7 - Dendrimer-drug conjugates: Synthesis strategies, stability and application in anticancer drug delivery, in Design of Nanostructures for Theranostics Applications, A.M. Grumezescu, Editor. 2018, William Andrew Publishing. p. 277-303. 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.Boas, U., et al., Synthesis and Properties of New Thiourea-Functionalized Poly(propylene imine) Dendrimers and Their Role as Hosts for Urea Functionalized Guests. The Journal of Organic Chemistry, 2001. 66(6): p. 2136-2145.
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.Giner-Casares, J.J., et al., Inorganic nanoparticles for biomedicine: where materials scientists meet medical research. Materials Today, 2016. 19(1): p. 19-28. 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.Grabowska-Jadach, I., Drozd, M., Kulpińska, D., Komendacka, K., & Pietrzak, M. (2019). Modification of fluorescent nanocrystals with 6-thioguanine: monitoring of drug delivery. Applied Nanoscience, 10 (1), 83–93. doi: 10.1007/s13204-019-01101-6.