ReviewNanoparticles in cellular drug delivery
Graphical abstract
Nanoparticles exploit biological pathways to achieve payload delivery of small molecules to cellular and intracellular targets. Synthetic strategies, including surface, porosity, stealthing, and size modifications, can be utilized to refine the pharmacokinetic properties of nanoparticles and allow for efficient delivery.
Introduction
Nanotechnology is a rapidly expanding field, encompassing the development of man-made materials in the 5–200 nanometer size range. This dimension vastly exceeds that of standard organic molecules, but its lower range approaches that of many proteins and biological macromolecules (Fig. 1).
The first practical applications of nanotechnology can be traced to advances in communications, engineering, physics, chemistry, biology, robotics, and medicine. Nanotechnology has been utilized in medicine for therapeutic drug delivery and the development of treatments for a variety of diseases and disorders. The rise of nanomaterials correlates with further advances in these disciplines.
Nanoparticles appeal to scientists across many disciplines due the opportunity to engineer many properties that might otherwise be incompatible on a single device. Relevant attachments include biologically active molecules, targeting sequences, fluorescent or other imaging devices, biocompatible coatings, and others. Furthermore, the engineering of the particle backbone structure and the size and shape of the nanoparticle core provides yet another dimension of physical control that can be exerted toward the specific tailoring of function. This review focuses on applications in the cellular and intracellular delivery of therapeutic agents. We explore various types of nanoparticles (Fig. 2), ranging from ceramics to liposomes, as well as current methodologies to develop inorganic nanoparticles. A brief discussion of the pharmacokinetic parameters and specific targeting strategies of these nanoparticles follows, presenting suggestions for the mechanisms of cellular and intracellular uptake. Because of the remarkable drug delivery challenges in the central nervous system’s blood-brain barrier, illustrative examples of nanoparticles in the treatment of neurological cancer, neurovascular disorders, and neurodegenerative diseases are provided.
Medical therapies have become more tailored to specific diseases and patients in recent years. Most pharmaceutical agents have primary targets within cells and tissues; ideally, these agents may be preferentially delivered to these sites of action within the cell. Selective subcellular delivery is likely to have greater therapeutic benefits. Cytosolic delivery, for instance, is desirable for drugs that undergo extensive exportation from the cell via efflux transporters such as multi-drug resistance proteins and P-glycoproteins.1 These efflux mechanisms continuously reduce therapeutic intracellular drug concentrations. An intracellular nanoparticle, consequently, may act as a drug depot within the cell. Nanotechnology may be used to achieve therapeutic dosing via targeted therapies, establish sustained-release drug profiles, and provide an intracellular sanctuary to protect therapeutic compounds from efflux or degradation.
Section snippets
Inorganic nanoparticles
Ceramic nanoparticles are typically composed of inorganic compounds such as silica or alumina. However, the nanoparticle core is not limited to just these two materials; rather, metals,2, 3, 4 metal oxides,5, 6, 7, 8, 9, 10, 11, 12 and metal sulfides13, 14, 15 can be used to produce a myriad of nanostructures with varying size, shape, and porosity.
Generally, inorganic nanoparticles may be engineered to evade the reticuloendothelial system by varying size and surface composition. Moreover, they
Gold nanoparticles
The preparation of gold nanoparticles commonly involves the chemical reduction of gold salts in aqueous, organic, or mixed solvent systems. However, the gold surface is extremely reactive, and under these conditions aggregation occurs. To circumvent this issue, gold nanoparticles are regularly reduced in the presence of a stabilizer, which binds to the surface and precludes aggregation via favorable cross-linking and charge properties. Several stabilizers exist for passivation of the gold
Distribution
The natural clearance and excretion mechanisms of the human body provide a framework for the rational design of effective nanoparticles for use in medical therapies. Once a pharmaceutical agent is introduced into the circulatory system, for example by intravenous administration, it is distributed systemically via the vascular and lymphatic systems. The distribution of a drug in a tissue is correlated with the relative amount of cardiac output passing through that tissue. Accordingly, tissues
Nanoparticle uptake by tissues
A succession of several membrane layers provides an obstacle for therapeutic agents attempting to target intracellular structures. During this process, compound is lost due to ineffective partitioning across biological membranes. The extent of partition across a membrane is related directly to the polarity of a molecule; nonpolar or lipophilic molecules easily bypass this obstacle with greater membrane penetration, generally via diffusion. However, the situation is much more complicated, as a
Nanoparticle drug delivery for human therapeutics
Nanoparticles have found widespread use in drug delivery, counting more than a dozen FDA-approved variants with indications ranging from cancer to infection (Table 1).
Conclusions
Nanotechnology will assume an essential place in drug delivery and human therapeutics. A wide variety of nanoparticles exist already, and diverse methods of synthesis have been developed. The pharmacokinetic parameters of these nanoparticles may be altered according to size, shape, and surface functionalization. Careful design of nanoparticle delivery agents will result in successful localization and drug delivery to specific biological targets coupled with the efficient evasion of the
Acknowledgments
We are grateful for support from the National Institutes of Health (GM067082), the National Institute of Allergy and Infectious Diseases (AI33507), and the CMCR program (U19-AI068021). We would also like to acknowledge valuable suggestions of Dr. A. S. Dömling (University of Pittsburgh, Department of Pharmaceutical Sciences) in the preparation of this manuscript.
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