Addressing Drug Delivery Challenges with Nano- and Micro-sized Carriers

A therapeutic candidate can demonstrate strong biological activity and still underperform in vivo if its properties present drug delivery challenges.^1,2 Several factors can limit whether an API reaches its intended target at a sufficient concentration and for the necessary duration, including:

• Poor solubility and formulation stability, particularly for hydrophobic APIs
• Premature degradation of proteins, nucleic acids, and other sensitive payloads
• Biological barriers, including mucosal surfaces and cell membranes
• Non-specific distribution that exposes healthy tissues to a therapeutic
• Rapid clearance through renal filtration, phagocytosis, or enzymatic degradation

Particle-based drug delivery provides additional tools for addressing these challenges. By complementing the properties of the therapeutic with the properties that support effective delivery, particle carriers introduce an additional set of design parameters that can be tailored around the needs of the API and its intended application. Particle size, morphology, composition, and surface chemistry can be adjusted to influence properties such as solubility, stability, biodistribution, cellular uptake, and release kinetics.

In this article, we explore these common drug delivery challenges and the particle design strategies that can be used to address them.

Improving the Delivery of Poorly Soluble Therapeutics

Hydrophobicity can support important therapeutic properties, including interactions with hydrophobic binding sites and transport across cell membranes.^2,3 However, poor aqueous solubility can present a significant drug delivery challenge, limiting the amount of API available for absorption and contributing to low or variable bioavailability.⁴

Particle-based drug delivery provides an alternative to modifying the therapeutic itself to improve its formulation behavior. Encapsulating a hydrophobic API within a compatible carrier can improve its dispersibility in aqueous environments while retaining the molecular properties responsible for its therapeutic activity. The formulation can then be designed around the desired route of administration, dose, stability requirements, and release profile.

Learn more about encapsulating hydrophobic molecules in polymeric particles

Protecting Sensitive APIs from Premature Degradation

Premature degradation is a common drug delivery challenge for sensitive APIs. Proteins and peptides can be degraded by proteases or lose activity through denaturation and aggregation, while unprotected nucleic acids can be rapidly degraded by nucleases.^5,6 Small-molecule APIs may undergo hydrolysis, oxidation, photolysis, or other chemical degradation pathways depending on their molecular structure and surrounding environment. In each case, degradation reduces the amount of intact, active API available to reach the intended biological target.

Encapsulation within a particle carrier can help protect sensitive APIs from the surrounding biological environment during transport. The carrier can then be designed to release the therapeutic at the intended site or over a controlled period, providing greater control over when and where the API becomes available. Mesoporous silica nanoparticles (MSNs), for example, can encapsulate therapeutic payloads within their porous structure, and pore-capping strategies can further retain and protect the payload until release is triggered.

Explore our mesoporous silica nanoparticle portfolio and use our MSN Selection Guide to identify the particle properties that best fit your application. See how these design principles translate into therapeutic delivery in our MSN drug delivery case study.

Navigating Biological Barriers

Reaching the intended target often requires a therapeutic to navigate multiple biological barriers, from transport across tissue interfaces to cellular uptake and intracellular trafficking. These barriers can limit how much of the administered API ultimately reaches its site of action.

Particle carriers can be designed to interact with biological transport and uptake pathways that the free API may not readily access, providing additional strategies for navigating this drug delivery challenge. For example, targeting ligands can be incorporated onto the particle surface to engage specific cell-surface receptors and promote receptor-mediated uptake. Once inside the cell, carriers can influence intracellular trafficking or facilitate endosomal escape.⁷

Controlling Therapeutic Distribution

When therapeutics are administered systemically, the API can distribute throughout the body rather than exclusively to its intended target. This non-specific distribution can expose healthy tissues to the therapeutic, increasing the risk of off-target effects and toxicity.⁸

Particle carriers can help limit off-target exposure by encapsulating the API and providing greater control over its distribution in the body. Particle size and surface properties can influence interactions with different tissues, while surface functionalization provides an additional opportunity to promote more specific biological targeting. Antibodies, antibody fragments, aptamers, proteins, peptides, and other oligonucleotides can be conjugated to appropriately functionalized particle surfaces to recognize specific receptors or other molecular targets.⁹ Particle design therefore provides an additional layer of control over where a therapeutic accumulates without requiring modification of the API itself.

Extending Therapeutic Exposure

Many traditional therapeutics are cleared from circulation before sufficient exposure at the target is achieved. Small molecules and biologics may undergo renal filtration, hepatic clearance, or uptake by phagocytic cells depending on properties such as molecular size, geometry, and charge.¹⁰ Rapid clearance can limit therapeutic exposure and require more frequent or higher dosing to maintain an effective concentration.

Particle carriers provide additional ways to extend therapeutic exposure. Particle properties can be tailored to influence circulation and clearance, while controlled-release strategies can extend how long an API remains available after administration. For example, biodegradable particles such as PLGA can be designed to release encapsulated APIs over periods ranging from weeks to months. Together, these strategies can extend therapeutic exposure and potentially reduce dosing frequency.^11,12

Explore how polymer composition and particle design can be tailored around release requirements in our white paper.

Designing the Carrier Around the Drug Delivery Challenge

The value of particle-based drug delivery is not tied to any single particle property or material. Instead, it comes from the ability to engineer the carrier around the specific drug delivery challenges limiting a therapeutic. Depending on the program, that may mean improving formulation of a poorly soluble API, protecting a sensitive payload, changing its distribution, facilitating transport across a biological barrier, or controlling when the API is released.

Particle composition, size, morphology, and surface chemistry provide interconnected design parameters for addressing these requirements. The appropriate combination depends on the API, route of administration, biological target, and performance goals of the program.

In an upcoming article, we'll look more closely at commonly used particle platforms for drug delivery and how their different properties can help guide platform selection.

Related Resources

• Nanomedicine CDMO Services
• Microparticles for Dermatology & Aesthetic Applications
• Enhancing Therapeutic Delivery with Mesoporous Silica 

References