The solubility revolution: nanotechnology in drug delivery
Nanotechnology is revolutionising drug delivery by tackling the solubility and bioavailability challenges that lead to many drugs failing clinical trials. Some of the most promising nano drug delivery systems currently being studied are metal-organic frameworks (MOFs), carbon nanotubes (CNTs), mesoporous silica nanoparticles (MSNs), nanoemulsions, and solid lipid nanoparticles. We have consulted industry experts, reviewed scientific literature, and analysed clinical trial data in order to bring you this informative snapshot of the key issues and trends in nano drug delivery techniques.
Nanotechnology is revolutionising drug delivery by tackling the key challenges in solubility and bioavailability that significantly impact drug efficacy. More than one-third of approved drugs and almost 90% of active pharmaceutical ingredients (APIs) in the discovery pipeline face bioavailability hurdles due to low solubility affecting drug delivery. In fact, poor bioavailability is likely a key factor in the 90% failure rate of drugs in clinical trials.
Advances in nanotechnology have stimulated the development of several promising drug delivery systems, as demonstrated by numerous preclinical studies and clinical trials. These include metal-organic frameworks (MOFs), carbon nanotubes (CNTs), mesoporous silica nanoparticles (MSNs), nanoemulsions, and solid lipid nanoparticles.
Given the potential of nano delivery systems to rejuvenate underperforming marketed drugs and pre-clinical candidates that have previously been jettisoned due to poor water solubility, we have consulted industry experts, reviewed scientific literature, and analysed clinical trial data to produce this snapshot of promising and versatile nano drug delivery techniques.
Low solubility in drugs is caused by two main factors. Firstly, high crystalline lattice energy results from strong intermolecular forces within the drug structure, including hydrogen bonds, van der Waals forces, and ionic interactions - creating a tightly packed, highly organised structure with poor dissolution properties. Secondly, drug discovery screening techniques based on receptor binding affinity often produce lipophilic candidates with poor water solubility.
Nanotechnology drug delivery techniques effectively address both challenges. By increasing surface area and encapsulating drugs, these platforms enhance dissolution and bioavailability, protect drugs from degradation, offer controlled and sustained release, and enable targeted delivery to specific tissues, thus minimising side effects. Nanocarriers can also protect drugs from enzymatic and hydrolytic degradation in the GI tract, prolong the drug's presence in the gut through adhesion to mucus, and significantly enhance drug absorption.
Figure 1
Mesoporous silica nanoparticles (MSNs) are characterised by their porous structure and large surface area. They have a well-ordered arrangement of pores with diameters typically between two and 50 nanometres. The structure of MSNs includes a silica framework that forms the walls of the pores, creating a high surface area that can be functionalised for various applications.
Carbon nanotubes (CNTs) are cylindrical structures formed from graphene sheets. There are single-walled (SWCNTs) and multi-walled (MWCNTs) types. Their high surface area and ability to be chemically modified make them ideal for drug delivery.
Metal-organic frameworks (MOFs) are crystalline materials made from metal ions and organic ligands. Their porous structure, high surface area, and tuneable chemistry make them suitable for drug delivery.
Adapted from Kumari L et al.(2023), Advancement in Solubilization Approaches: A Step towards Bioavailability Enhancement of Poorly Soluble Drugs. Life, 13
Image created with Biorender.com
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MOF delivery platforms integrate drugs with metal ions or complexes via covalent bonds to form two- or three-dimensional, porous, crystalline "honeycomb-like" structures, with excellent solubility properties. The customisable nature of these structures allows for variation in pore size, surface area, and functional groups to accommodate a wide range of APIs. For example, the flavonoid quercetin has potential as an anti-cancer and anti-hypertensive drug but suffers from poor water solubility. Wang et al overcame this limitation by loading it into polymer coated MOFs, resulting in a greater than 100-fold increase in solubility when compared with the pure drug. Similarly, to enhance the solubility of the anti-hypertension drug azilsartan, He et al, designed a polymer coated MOF system that achieved a 340-fold increase in drug solubility and 10-fold improvement in bioavailability when comparison with the pure drug.
CNTs are another promising prospect for drug delivery, due to their unique physiochemical properties. These include a high surface area, high drug loading capacity, and the ability to penetrate cell membranes. Their capacity to be chemically modified to enhance solubility, drug loading, and targeting is also a significant advantage. For example, scientists at the New Jersey Institute of Technology successfully loaded the hydrophobic antimicrobial drugs griseofulvin and sulfamethoxazole into CNTs, dramatically enhancing solubility for both compounds. Additionally, CNTs can be conjugated with molecules like the epidermal growth factor (EGF) to target cancer cells that overexpress EGF receptors. Although the US Food and Drug Administration (FDA) has yet to approve a CNT-delivered drug, several promising candidates are in preclinical development, including the chemotherapies cisplatin, doxorubicin, and paclitaxel.
MSN nanoparticles meanwhile offer researchers a high surface area and large pore volume, enabling significant drug loading and controlled release. Their porous structure aids the dissolution of poorly soluble drugs, and allows for sustained delivery, thereby improving therapeutic efficacy. MSNs are non-toxic, chemically stable and their surfaces can be functionalised with targeting molecules, which enhances the specificity and efficiency of drug delivery. This functionalisation enables the precise targeting of diseased cells, minimising side effects and offering the potential to improve therapeutic outcomes. MSNs have shown promise in delivering a wide range of therapeutic agents, including anticancer drugs and antibiotics. For instance, a breakthrough study carried out at the University of Antwerp achieved greatly improved bioavailability of the oral, poorly soluble anti-cholesterol drug fenofibrate, compared to an approved micronised formulation, by using MSNs.
In summary, by addressing key challenges in drug solubility, bioavailability, targeting and toxicity, nano drug delivery systems have made significant strides in recent years, and offer us the potential to transform medicine. This is demonstrated by the variety of platforms in advanced preclinical work and clinical trials, although challenges remain. In a recent article in the journal Life, Dr Anshul Gupte, Senior Director of Scientific and Technical Affairs at Catalent, noted: “These difficulties include the transition of nanocarriers from the laboratory to the pharmaceutical market, influenced by factors such as fabrication costs, reproducibility of formulation properties at production scale, and benefits to the human population due to the divergent pharmacokinetics profile.” Despite these hurdles, Dr Gupte noted more optimistically that: "innovative drug delivery technologies continue to advance and provide undeniable benefits. As a result, nanotechnology offers formulation scientists an opportunity to expand their research and development to address problems associated with poorly soluble drugs, thereby increasing therapeutic efficacy.”
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