Nanoparticles as a Targeted Drug Delivery System

Each injection of Novavax vaccine includes many spike nanoparticles (i.e., Matrix-M adjuvant), along with a compound extracted from the soapbark tree. The compound attracts immune cells to the site of the injection and causes them to respond more strongly to the nanoparticles.

Matrix-M is composed of 40 nanometer particles based on saponin extracted from the Quillaja saponaria Molina bark together with cholesterol and phospholipid.

In this article, we will cover the details of nanoparticles used in the targeted drug delivery system. The clinical use of drug delivery systems is significant.^[22] with a global market of over $150 US billion in 2013.

Controlled Drug Delivery Systems

Conventional drug administration often requires high dosages or repeated administration to stimulate a therapeutic effect, which can lower overall efficacy and patient compliance, and result in severe side effects and even toxicity.^[16-18]

For example, intravenously administered Interleukin-12 (IL-12) resulted in systematic toxicities, including deaths in a clinical trial.^[19] Oral administration, which is the most common approach for delivering pharmaceuticals, is frequently limited by poor targeting and short circulation times (<12 hours).^[20] Peptide and protein drugs often have short serum half-lives of only minutes to hours.^[21]

To address these issues, controlled nanodrug delivery can be used to:^[22-23]

• Improve efficacy
• Reduce toxicity
• Enhance distribution
• Improve patient compliance

Advantages of Nanosizing Drugs

Advantages of nanosizing drugs include:

• Increase surface area
• Enhances solubility
• Increase rate of dissolution
• Increase oral bioavailability
• More rapid onset of therapeutic action
• Decreased dose
• Decreased patient-to-patient variability
• Target specificity
• In cancer chemotherapy, cytostatic drugs damage both malignant and normal cells alike. But, nanodrug delivery selectively targets malignant tumor only
• Limited side effects

Nanoparticles as a Targeted Drug Delivery System

Nanoparticles (NPs) have been investigated as potential drug delivery system in recent years.^[24] Drugs, growth factors or other biomolecules can be conjugated to nanoparticles to aid targeted delivery.^[25] This nanoparticle-assisted delivery allows for spatial and temporal controls of the loaded drugs to achieve the most desirable biological outcome.

In summary, benefits of using nanoparticles as a targeted drug delivery include:

• Easy to control how the drugs are available to cells and tissues over time and in space
• A very extended release can be achieved by combining hydrophobic interactions and degradation-controlled mechanisms, as exemplified by a PEO–PPO–PEO hydrogel (Pluronic F127) encapsulating drug-laden PLGA nanoparticles.^[29]
• Small size → Easy penetration through capillaries → Drug accumulation at target site
• The small size not only makes them needle-injectable, but also leads to a large surface area for bioconjugation, facile natural clearance and can enhance penetration through tissue barriers.
• Nanoparticles of size 10–100 nm are suitable for systemic drug administration, because they can leave small blood vessels through fenestrations in the endothelial lining, allowing for extravasation into tissues
• Along with the size and size distribution, deformability, shape and surface chemistry are other factors to consider in designing drug delivery systems.^[26,27]
• It has been revealed that cellular internalization is faster for nanogels of positive zeta potential or with high aspect ratios (for example, those with a rod-like shape).^[28]
• Use of biodegradable material for preparation → Sustained drug release application
• Exhibit higher intracellular uptake
• Nanoparticles are thought to aggregate on phospholipid bilayers^[33] and pass through cell membranes in organisms.^[34,35] However, it is unlikely the particles would enter the cell nucleus, Golgi complex, endoplasmic reticulum or other internal cellular components due to the particle size and intercellular agglomeration.^[36]
• DNA delivery using nanogels can improve cellular uptake and prolong circulation time, as compared to non-encapsulated DNA.^[6]
• Can penetrate the submucosal layers while the microcarriers are predominantly localized on the epithelial lining
• Can be administered into systemic circulation without the problems of particle aggregation or blockage of fine blood capillaries
• Binding to cell surface, insertion in cell surface & binding to cell nucleii is possible due to conjugation of nanoparticle with targeting protein

Figure 1.  Bio-distribution of drugs—from cellular targeting, uptake to drug releasing 

Types of NP

Nanoparticles can exist as a powder or in a solid matrix. Semi-solid and soft nanoparticles have also been produced. A prototype nanoparticle of semi-solid nature is the liposome. Various types of liposome nanoparticles are currently used clinically as delivery systems for anticancer drugs and vaccines.

Different types of nanoparticles include:

• Polymeric nanoparticle
• Solid lipid nanoparticle
• Nanosuspension
• Polymeric Micelles
• Ceramic nanoparticles
• Liposomes
• Dendrimers
• Magnetic nanoparticles
• Nanoshells coated with gold
• Nanowires
• Nanopores
• Quantum dots
• Ferrofluids

Methods of NP Preparation

There are several methods for creating nanoparticles. For example, nanogels can be produced with emulsion and nanomolding techniques.^[30]

Amphiphilic intramolecular cross-linking^[37]

• Heat cross-linking
• Chemical cross-linking

Polymerization based methods

• Polymerization of monomers in situ
• Emulsion (micellar) polymerization
• Dispersion polymerization
• Interfacial condensation polymerization
• Interfacial complexation.

Polymer precipitation methods

• Solvent extraction/Evaporation
• Solvent displacement (Nanoprecipitation)
• Salting out

Polymers for NP

Polymeric nanoparticles consist of a biodegradable polymer that is biocompatible and nontoxic.^[15] Features such as biocompatibility are also required for potential application in tissue engineering, drug and gene delivery, and new vaccination strategies. The below is a list of commonly used biodegradable polymers in the fabrication of polymeric nanoparticles:

Proteins

• Gelatin
• Albumin
• Lectins
• Legumin
• Vicilin

Polysaccharides

• Alginate
• Dextran
• Chitosan
• Agarose
• Pullulan

Synthetic Polymers

Repolymerized

• Poly(e-caprolactone)
• Polylactic acid
• Poly(lactide-co- glycolide)
• Polystyrene

Polymerized in process

• Poly(isobutylcynoacrylate)
• Poly(butylcynoacrylate)
• Poly(hexylcynoacrylate)
• Polymethylmethacrylate

Figure 2. Drug entrapment modes of nanoparticles, nanospheres and nanocapsules

Figure 3.  Thermosensitive nanoparticles used for selective release of the content after specific localization^[38] 

Use of NP Formulations in Drug Delivery

The aims for nanoparticle entrapment of drugs are either enhanced delivery to, or uptake by, target cells and/or a reduction in the toxicity of the free drug to non-target organs. Both situations will result in an increase of therapeutic index, the margin between the doses resulting in a therapeutic efficacy (eg, tumor cell death) and toxicity to other organ systems. For these aims, creation of long-lived and target-specific nanoparticles is needed.

The entrapment of chemotherapeutics in nanosized formulations like liposomes has been already subject of study for considerable time.^[31,32]

The scenario of a drug is delivered to its target cells is illustrated below:

• The targeted nanoparticle finds the specific cellular target.
• The nanoparticle binds to the surface of the cell
• If the target is internalized (i.e. folate receptors) the nanoparticle is carried to the intracellular environment
• If the target is not internalized (i.e. annexin A2) the delivery system has been engineered to release the nanoparticle at the surface of the cell allowing for endocytosis to occur.

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