Drug Delivery Applications of Nanoparticles

• Introduction to drug delivery enabling properties of nanoparticles
• Nanoparticle selection guidelines
• Examples of drug delivery applications

Introduction to Drug Delivery Enabling Properties of Nanoparticles

Drug delivery is a notoriously difficult task, with numerous variables affecting the efficacy of a given active ingredient. The integration of tailored nanoparticles into drug delivery applications has been used to address limitations of conventional drug delivery, particularly challenges associated with targeting and timed release.

Designing a nanoparticle-enabled drug delivery system includes many intersecting considerations, including method of delivery, the target location of the drug payload, uptake kinetics, and circulation time. A key lever in this design process is the functionalization of the nanoparticle surface. The introduction of functional surface chemistry groups enables attachment of a milieu of targeting ligands that will help to guide the nanoparticle to its desired location within the body, such as organ-specific cell membrane proteins, circulating biomarkers, or other disease-specific proteins. Appropriately designed surface chemistries also enable the nanoparticle to withstand its environment prior to delivery. These designs vary dependent on the requirements of the delivery method, with different considerations for oral, topical, intravenous, or inhalation delivery routes.

A nanomedicine may be needed to deliver a therapeutic, to inhibit or promote enzymatic activity, to upregulate or down-regulate a particular pathway, induce apoptosis, or deliver genetic material. The nanomedicine needs to not only deliver the payload to the correct location but needs to maintain the appropriate concentration (the “therapeutic window) for sufficient time to be efficacious. To accomplish this, the nanomedicine needs to circulate in the body long enough to release its targeted drug payload and maintain a therapeutic concentration before the body’s immune system clears the nanoparticle. Nanoparticle quality by design (QbD) considerations for this end application include: Will the nanomedicine need to be administered once or multiple times? What are the desired drug release kinetics? Do the nanoparticles accumulate in the body or what is the clearance pathway? The ability to tailor the nanoparticle composition, size, shape, and surface functionalization allows the nanomedicine’s release, circulation and clearance profiles to be tailored to address these questions.

Along with customization options for nanoparticle based delivery systems, this format offers an additional benefit in the ability to encapsulate cytotoxic drug payloads at high loadings while masking their presence prior to targeted delivery. This format builds on recently approved antibody drug conjugates (ADCs) used as new chemotherapeutic agents, for example, in which a monoclonal antibody (mAb) is covalently attached to a drug molecule to improve the delivery of cytotoxic materials to tumors compared to traditional administration routes. Since few molecules of the drug can be attached to each antibody, however, ADCs suffer from relatively low drug loading. By using porous or hollow nanoparticles that are engineered to encapsulate the drug while targeting specific locations in the body, the highly concentrated payload and reduction in non-specific delivery may improve therapeutic efficacy and patient outcomes.

References

• Mitchell, Michael J., et al. “Engineering precision nanoparticles for Drug Delivery.” Nature Reviews Drug Discovery, vol. 20, no. 2, 2020, pp. 101–124. doi.org/10.1038/s41573-020-0090-8.

Related Material

• White Paper: Applications of Nanoparticles in Targeted Drug Delivery and Photothermal Therapy

Nanoparticle Selection Guidelines

The selection of nanoparticle type and surface chemistry for drug delivery applications depends on a variety of factors, such as delivery route, chemical properties and toxicity of the drug to be loaded, the desired drug concentration in the nanomedicine, and desired lifetime within the body.

Nanoparticle Material and Morphology

Silica Nanoparticles: Solid or porous silica (amorphous SiO₂) nanoparticles can be reproducibly prepared across a range of sizes, with high uniformity, and modified via standard silane chemistry to introduce a wide variety of surface functionalization possibilities. Although silica is an inorganic material, it is a common compound in biological creatures and can be biodegraded then ultimately renally excreted. Due to this combination of biocompatibility and biodegradability, silica nanomaterials are the delivery vehicle of choice for a diverse range of active pharmaceutical ingredients (APIs). Solid silica particles have nanopores that can incorporate low molecular weight species, or the surface may be functionalized to be highly positively charged to electrostatically adsorb genetic material, for example to deliver silencing RNA to specific cells.

The delivery of larger drug molecules or higher loadings of payloads can be accomplished using mesoporous silica nanoparticles (MSNs), which have attracted significant attention over the last two decades primarily due to their versatility of cargo loading capability and surface functionalization. This family of biocompatible inorganic nanoparticles is able to accommodate a wide variety of APIs, from small hydrophobic drugs to large biomolecules, by simply varying the size of its pores and selective surface modification, which can often be independently tailored to introduce different functionality either inside or outside its porous matrix. High loading capability up to 30% by weight for small molecules in mesoporous silica has been demonstrated, and it is not uncommon to reach 10% by weight for messenger RNA (mRNA) in large pore particles.

Download our MSN Loading Protocol

Other types of nanoparticles may be incorporated into the core of solid and mesoporous silica nanoparticles, creating composite particles with multiple functionalities or to introduce particles that may act as tracers. For example, silica shells with tunable thickness and surface chemistry may be deposited around Au cores, and such particles may be used in pharmacokinetic, pharmacodynamic, and biodistribution studies, where the concentration and location of such particles may be determined by elemental analysis of Au, which does not occur naturally within the body.

Application	Key Design Parameter*	Advantage	Visual Representation
✓ Drug Delivery ✓ Catalysis ✓ Chemical Removal	Hexagonal pore geometry	Controlled molecular adsorption & release	MCM-41**
	Negative (silica) or positive (aminated) surface functionality options	Ability to perform specific chemical transformations
	100 nm particles with 3 nm pores	Accommodates most small molecules & drugs
	Large pore radial geometry	Accommodates larger APIs

*Certain design parameters require a custom design – contact us to learn more
**Radial and cubic pore geometries also available as custom materials

Metal Nanoparticles: Gold is the most widely used metal for nanoparticle drug delivery and therapeutic applications, due to the inert chemical properties of the material and general biocompatibility. Current interest in gold nanoparticles in nanomedicine typically exploit the unique optical properties of gold, specifically the localized surface plasmon resonance (LSPR) that can be tuned from visible to near infrared (NIR) wavelengths by changing the particle size and morphology. As a material with advanced capabilities in both the therapeutics and diagnostics realms, gold-based nanoparticles can be readily utilized as theranostics agents, combining these two application areas, and have been utilized in diverse applications ranging from two-photon luminescence to photodynamic and photothermal therapeutics, to identification of cells via Surface Enhanced Raman Spectroscopy (SERS).

PLGA Nanoparticles: Over the past few decades, nanoparticles fabricated from poly(lactic-co-glycolic acid) (PLGA) have been attractive vehicles for drug delivery due to FDA approval of the polymer for therapeutic uses and the biocompatibility and biodegradability of the material. This class of copolymer can be made with different ratios of lactic acid and glycolic acid to adjust material properties and the degradation rate in the body, and the terminal end groups of the polymer can also be chosen to create PLGA terminated with carboxylic acids, esters, and amines, providing a great deal of versatility in nanoparticle design and functionalization. Depending on the application needs, the synthesis route for the PLGA particles may be tuned to yield uniform particles in sizes between 100 nm to 1 µm. The combination of these characteristics allows us to encapsulate a wide range of APIs including hydrophobic and hydrophilic small molecules, proteins, and RNA, with typical loadings up to 10 wt% of API.

Read more about our PLGA fabrication and manufacturing capabilities

Nanoparticle Surface Modification

Implementing nanoparticles for drug delivery applications requires the selection of not only the appropriate particle size, shape, and material type but also the appropriate surface chemistry and targeting ligands. At nanoComposix, we can modify the surface of many nanoparticles with specific functional groups, biocompatible polymers, and biomolecules (proteins, antibodies, oligonucleotides). The table below summarizes some of the most common surface modifications employed by nanoComposix for drug delivery applications.

Modification	Description
	Polyethylene glycol (PEG) ligands offer a high degree of biocompatibility, can improve stability in high salt environments, and reduce non-specific interactions. PEG ligands can be covalently bound to the metal surface to produce stable coatings. In addition, certain bi-functional PEGs can be employed to introduce other surface functionalization.
	Antibodies (Ab), including fragments and VHH single domain antibodies can be conjugated onto a variety of nanoparticles using standard EDC/NHS chemistry or via a host of bioorthogonal click chemistry methods, depending on the particle type.
	Proteins are able to be conjugated onto a nanoparticle surface using the same type of conjugation chemistry used for Ab. If more than one protein per nanoparticle needs to be conjugated onto a nanoparticle, this can be accomplished using bioorthogonal click chemistry.
	Sometimes only a short fragment is needed to direct the nanomedicine to the correct target, and can be accomplished by conjugating specific peptide sequences to the nanoparticle surface.
	Oligonucleotides (oligos) can be covalently attached or encapsulated.
	Various fluorophores can be covalently attached or may be encapsulated within the nanoparticle.