Effective drug delivery ensures release of the active drug substance at the right location within the body at the right time in the right quantity. As both small molecule and biologic drug substances become increasingly complex with challenging properties, such as low solubility and permeability and limited ability to pass through cell membranes and/or biologic barriers, drug delivery systems that enhance bioavailability and enable targeted and sustained delivery despite diverse genetic, physiological, and environmental factors1 have become crucial to the success of many novel medications. The unique physical, chemical, and biologic properties of nanoscale carriers make them ideal vehicles for achieving optimal drug delivery, even for challenging drug substances.
Many Drug Delivery Challenges
Effective drug delivery ensures release of the active drug substance at the right location within the body at the right time in the right quantity. As both small molecule and biologic drug substances become increasingly complex with challenging properties, such as low solubility and permeability and limited ability to pass through cell membranes and/or biologic barriers, drug delivery systems that enhance bioavailability and enable targeted and sustained delivery despite diverse genetic, physiological, and environmental factors1 have become crucial to the success of many novel medications.
Advantages of Nanoscale Solutions
Nanoscale systems are attracting significant attention due to their ability to overcome many of the delivery challenges facing drug developers today. The high surface area/volume ratio of nanoscale materials imparts unique physical, chemical, and biologic properties, which can be further modified through surface functionalization to support highly efficient cell/tissue targeting.1–5
Many nanoscale drug delivery systems are also designed to protect the drug substance from degradation, enabling sustained release and more consistent dosing. Avoiding first-pass metabolism allows reduced drug loads while achieving greater efficacy with fewer side effects.6 In addition, nanoscale drug delivery systems support the shift from daily to long-acting injectable formulations administered subcutaneously.6-8 Nanoparticles also can more readily enter cells and pass through biologic barriers, leading to more efficient drug substance uptake.
In many cases, it is possible to deliver two or more active pharmaceutical ingredients (APIs) simultaneously, improving the effectiveness of combination therapies.9 The diversity of nanomaterials available for drug delivery applications is an addition advantage, as it is possible to design specific delivery systems that address the requirements of the drug substance, indication, and route of administration.
For these reasons, nanoscale delivery systems have been used in the formulation of drug products for the treatment of many types of diseases, targeting cancer, infectious diseases, autoimmune, inflammatory, and neurologic conditions, generic disorders, and more.4
Wide Range of Technologies
Drug products leveraging nanotechnology as defined by the U.S. Food and Drug Administration (FDA) have at least one internal or surface structure or an external dimension falling in the 1–100 nm range, or are engineered to have physical, chemical, or biological properties attributable to their sizes, even if they reach up to 1 μm (1000 nm).10
Nanoscale delivery systems can be generated through particle-size reduction or through bottom-up generation via solubilization.6 They include nanoparticles, nanocrystals, nanocapsules, nanoemulsions, and nanomicelles, among other structures, and may comprise both inorganic and organic materials. Inorganics include metal nanoparticles, mesoporous silica structures, carbon nanotubes, and quantum dots, while organics include lipidic systems; natural and synthetic polymers; proteins; oligonucleotides; oligo/polysaccharides, such as cyclodextrins; and biomimetic materials, such as exosomes/extracellular vesicles and phagosomes.2–4,11
Drug delivery using nanotechnology can be achieved using two mechanisms: passive and active targeting.2,3,12 Passive targeting is achieved through enhanced permeability and retention (EPR) into targeted cells, which leverages the inherent properties of nanoscale materials. Active targeting is realized through functionalization of the surfaces of nanoscale drug carriers to enable selective binding to specific cells/tissues. Ligands used for modification include antibodies; aptamers; peptides; small molecules; natural compounds, such as folate, hyaluronic acid, and transferrin; and biomimetic materials, such as cell membranes.
Choice of nanocarrier system is dictated by the nature of the API, the desired release profile, the targeted cells/tissues, route of administration, and other factors. Ideal nanoscale drug delivery vehicles are biocompatible, stable, provide sufficient protection to the API, enable targeted drug delivery, and can be produced using manufacturing processes that are scalable and cost-effective.3
Inorganic Options
The most widely used inorganic nanoscale systems used in pharmaceutical applications are based on metal nanoparticles, most notably gold, silver, and iron oxide, the latter of which exhibit magnetic properties. Functionalized iron oxide nanoparticles are used as contrast agents for magnetic resonance imaging to track the movement of certain cells.4 Magnetic nanoparticles (MNPs) are also used for the diagnosis of various gastrointestinal conditions.1 Gold nanoparticles with functionalized surfaces have also been used for diagnostic purposes and are under investigation as theragnostic — products with both therapeutic and diagnostic capabilities, thus allowing monitoring of therapeutic effects in real time.13
Noble metal nanoparticle drug delivery systems show promise for targeted delivery of APIs to tumors as well. In some cases, once delivered to the target cells, nanoparticles are modified not only to target certain cells, but exhibit cancer killing capabilities activated by light to achieve high potency with high specificity.4
Meanwhile, magnetic nanoparticles comprising iron oxide cores surrounded by functional and biocompatible materials that enable high drug loading have been engineered to target specific sites in the body, such as areas of inflammation or tumors.1 Manipulation with a magnetic field ensures delivery to the target sites in the body. Some drug delivery systems using magnetic nanoparticles are designed to facilitate hyperthermia treatment, in which the application of a magnetic field generates intense heat, causing cell death in the cells targeted by the nanoparticles without damaging healthy tissue.
Magnetic nanoparticles (MNPs) are being explored for the delivery of cancer treatments and, due to their ability to cross the blood–brain barrier, neurological disorders.1 Examples include ECO/siDANCR nanoparticles that deliver siRNA for the treatment of triple-negative breast cancer and magnetic microhydrogels that achieve more effective neuron activation than superparamagnetic iron oxide nanoparticles (SPIONs). Various other approaches, including magnetic nanovesicles and magnetothermal nanoparticle technology, are being explored for the treatment of Parkinson’s and Alzheimer’s diseases. MNPs also show potential for the treatment of gastrointestinal cancers and inflammation and cardiovascular disorders.
Mesoporous silica nanoparticles have shown promise for drug delivery, but more information is needed before these systems can advance to clinical trials.3 Questions remain about their biocompatibility owing to potential negative interactions of silanol groups with red blood cells, as well other important attributes.
Lipid-Based Systems
Nanoscale lipidic drug delivery systems are the most widely used type of nanocarriers. They include liposomes, solid lipid nanoparticles, self-nanoemulsifying drug delivery systems (SNEDDS), and lipid-based nanocapsules.13 In fact, DoxilTM (doxorubicin liposomal injection) for the treatment of various cancers was the first nanoscale drug formulation to receive FDA approval (1995). Lipidic systems are attractive due to their biocompatibility and drug-loading capacity.5
Liposomes are the most common form of lipid-based nanoscale delivery systems.3 These spherical vesicles comprising lipid bilayers encapsulate water-soluble (hydrophilic) compounds within an aqueous internal compartment. Lipid-based oil-in-water nanoemulsions are of growing interest, however, because they encapsulate hydrophobic compounds, which comprise a growing percentage of small molecule drugs in development.
Solid lipid nanoparticles (SLNs or LNPs), are also of increasing importance following demonstration of their effectiveness in protecting and facilitating the delivery of mRNA vaccines. They are well-suited to encapsulate lipophilic APIs due to their stiff core, which provides increased stability compared with liposomes.5
The properties of lipidic systems can be controlled through selection of lipids with different properties and modified via functionalization to increase stability, extend half-lives, and enable enhanced targeting capabilites.13 In particular, surface PEGylation has been used to increase circulation times for liposomal drugs.14 Modification in support of stimuli-responsive behavior (to acidic pH, heat, reactive oxygen species, and other factors) has also been investigated. Liposomes that absorb near-infrared light (e.g., lipid bilayer–coated polydopamine-templated CaCO3 hollow nanoparticles) have been explored for photothermal treatment in combination with traditional cancer therapies with reduced side effects, while liposomes engineered as nanoradiosensitizers have been shown to enhance the effect of radiotherapy. Nanoscale liposomal therapies that cause immunogenic cell death have been shown to also improve the effectiveness of traditional cancer treatments.
Stabilized Lipidoid Nanoparticle (SNaP LNP®) technology from Ethris is a new nanoscale drug delivery system that allows efficient transport of mRNA via inhalation to the respiratory tract, as well as via intramuscular injection for vaccination.15 The proprietary lipidoid formulation has a unique composition and stabilization mix that allows excellent mRNA stability at temperatures ranging from –20 °C to room temperature. Formulations using the Snap LNP® technology can be lyophilized for improved storage properties or spray dried to produce dry powder forms.
Polymeric Designs
Polymer-based nanoscale drug delivery systems can take the form on nanoparticles, nanocapsules, micelles, dendrimers, nanogels, and others. They can be composed on natural polymers, such as albumin and various proteins, or synthetic polymers suitable for pharmaceutical use, such as poly(lactide-co-glycolide) polymers (LG polymers), and poly(ethylene glycol) (PEG)/LG polymer diblock copolymers. They are often used in immunotherapy applications and designed for targeted and sustained release of the drug substance.16
Examples include Abraxane®, an albumin-bound nanoparticle containing paclitaxel and polymer micelle-based nanosystems Genexol®, Nanoxel®, and Apealea®, which contain paclitaxel or docetaxel and provide greater solubility and greater targeting to tumors with reduced toxicity compared with the free drugs.5
Adjusting the polymer composition and molecular weight and the ligands used for functionalization allows for significant tuning of polymeric nanoscale drug delivery systems.16 Other advantages of polymeric systems include high drug loading levels and production using well-established, controlled, and scalable processes.16 Polymeric micelles, for instance, can also be used to encapsulate both hydrophobic and hydrophilic compounds depending on the composition of the polymer used.3
Polymeric core-shell nanocapsules for drug delivery encapsulate drug substances in a core-shell polymeric matrix and are attractive for dermatological applications owing to their ability to enhance the bioavailability of poorly soluble drugs when delivered topically.3 Dendrimers are highly branched polymeric structures that encapsulate drug substances in cavities formed between the branches, or dendrons. They provide controlled release, but the use of cationic end groups presents some toxicity concerns that must be addressed.
Hydrogel nanoparticles comprising biocompatible hydrophilic cross-linked networks that absorb large quantities of aqueous solutions can be used to deliver drug substances.3 The chemical and physical crosslinks in the network can be designed to suit specific drug substances and target cells. While production of these nanoparticles is relatively simple, there is often significant batch-to-batch variation with respect to size, polydispersity, and stability, which can be an issue for drug delivery.
Polymeric nanoparticles derived from proteins, such as fibroins and albumin, are attractive as drug delivery systems because they are biocompatible and biodegradable, easily manufactured, have high stability, and can carry many types of drug substances, including DNA/RNA, small molecules, and biologics, such as peptide hormones.13,17 In addition to Abraxane, approved products include OncasparTM, a PEGylated version of the enzyme asparaginase, for the treatment of acute lymphoblastic leukemia in adults and children, and OntakTM, based on a recombinant diphtheria fusion toxin, for the treatment of human CD25+ cutaneous T cell lymphoma.
Biomimetic Alternatives
One of the challenges faced by many drug delivery technologies is avoiding recognition by the immune system as a foreign agent. Biomimetic drug delivery systems overcome this difficulty by leveraging biological materials that exist within the human body. Nanoscale biomimetic solutions combine this approach with nanotechnology.
Exosomes, a type of extracellular vesicle (EV), are perhaps the most widely pursed approach.16 Exosomes are nanoparticles produced by cells to transport cellular material and enable intercellular communication. They are produced by most mammalian cells and have specific properties associated with their parent cell types. As native particles, they are immune silent and able to pass through biological barriers. These properties make them ideal as drug delivery systems.
Technologies have been developed to produce exosomes that can be loaded internally (in the lumen), bound to biologic molecules on their surfaces (e.g., antibodies, peptides), and/or conjugated/linked to small molecules. Advances in cell line engineering and exosome purification at large scale are providing access to enough to support clinical studies and ultimately commercial manufacture.
Self-assembled peptide particles and virus-like particles are other examples of biomimetic nanostructures being investigated as drug delivery vehicles.16 Biomimetic nanoscale drug delivery systems generated through the coating of nanoparticles or other nanocarriers with cellular materials, such as cancer or immune cell membranes.12
DNA-Based Constructs
One of the newest types of nanostructures being developed as nanoscale drug delivery systems are DNA frameworks produced using DNA origami.2 Like biomimetic nanocarriers, DNA-based systems are immune-silent. They can also be constructed to support precise targeting, efficient cellular uptake, and programmable release of many types of drug substances, from genetic material to antivirals/antibiotics.
One company developing such systems is CPTx, which uses single-stranded DNA (ssDNA) and proprietary software to generate DNA nanostructures with specific shapes, sizes, and site-specific functionalization.16 Made from high-purity ssDNA (available in research to commercial scales) using programmable DNA nanofabrication, the DNA nanocarriers overcome immunogenicity and targeting concerns while also enabling delivery of multiple therapeutic payloads. For gene delivery, CPTx’s DNA nanocarriers also support non-integrated gene expression. CPTx has, according to the company, established viable manufacturing processes, developed fit-for-purpose analytical methods, and continues to make advances supporting improved performance in many applications.
Ongoing Innovation to Overcome Existing Limitations
Nanoscale drug delivery, while offering many benefits, also presents some hurdles to drug developers seeking to leverage realize the maximum advantages these technologies may provide.2,5,6,13 Some solutions, for instance, can present safety/toxicity concerns if not properly designed. Others are rapidly cleared from the bloodstream, leading to reduced efficacy. For some nanoscale carriers, readily scalable, consistent, cost-effective manufacturing processes have yet to be establishes. Achieving truly highly selective cell/tissue targeting remains a constant challenge for many nanoscale delivery systems. Careful formulation and the use of highly pure, high-quality excipients are thus crucial to ensure success.
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