INTRODUCTION

Development of new drugs is an arduous process that requires a huge investment of money and time with no guarantee of returns on investments. The average time it takes to bring a new molecular entity or a biologic agent to the market is between 10 and 15 years at an estimated cost between $800 million and $0.2 billion (1,2). In most cases, it is difficult for drug manufacturers to recuperate development and marketing costs. It is reported that 80% of approved drugs fail to yield profitable earnings for the companies that developed them (2,3). The goal of drug development process is to satisfactorily demonstrate therapeutic efficacy as well as achieve a desirable toxicity-to-benefit ratio (2,4,5). Therefore, strategies that apply drug candidates with established toxicity profiles (drug repurposing) can effectively improve success rate of development process. Drug repurposing (repositioning) entails identification of new uses for existing drugs with the advantage of reducing development time and cost (4,6,7). Typically, drug candidates with known safety profiles could be sourced from (a) FDA approved drugs, (b) drugs undergoing clinical development for a different application, or (c) drugs that have been abandoned or failed to demonstrate efficacy during clinical trials (phase II or III).

The success of drug repositioning depends on the need to maximize therapeutic efficacy at new targets while negating/minimizing off-target effects. In order to achieve the goal of drug repurposing, it is important to achieve the desired in vivo drug release profiles that will lead to the desired pharmacokinetics/biodistribution. In this regard, drug delivery systems play a vital role in ensuring the success of drug repositioning. Thus, the focus of this mini-review is to identify and highlight some of the properties of drug delivery systems (especially nanocarriers) that have been employed in drug repurposing.

OVERVIEW OF DRUG REPURPOSING PROCESS

There are many ways to identify new indications and targets for old drugs, as entailed in repurposing process. Drug profiling has made it possible to identify new targets for existing drugs, in addition to exploring multiple known targets (8). Early-stage identification largely includes elucidating pathways using screening methods to identify receptors and targets, which may involve application of in silico screening, in vitro assays, and in vivo experiments (9). A major success for the in silico screening approach occurred during screening for drugs that would modify cancer-related gene expression. A hit for phenothiazine-like compounds, widely known for their potent anti-psychotic effects, was uncovered and they are now being investigated as therapies for cancer treatment (10,11,12). The second method, in vitro screening, has also yielded important data for repurposing of drugs. Identification of the COX-2 pathway as a major player in many tumors led to the investigational use of COX-2 inhibitors in cancer research. One example is the testing of celecoxib, an anti-inflammatory agent that is generally prescribed for arthritic conditions, for use in colorectal cancer, showing promising results (13). The final early-stage method, using in vivo studies, has also demonstrated success in finding therapies, especially for rare diseases, such as fragile X syndrome. A rare genetic condition characterized by developmental disabilities with no known cure is now showing improved outcomes with the use of the repurposed drug minocycline, an antibiotic (14). This clinical trial came about after minocycline demonstrated an ability to rescue dendritic function in vivo in mice with dendritic abnormalities (15,16).

Despite the successes of early-stage identification of candidate drugs for repurposing, many are identified at the later stages (i.e., clinical trials or post-market data) by recognizing side effects and toxicities, as well as through observation of off-target effects. A notable case example of an approved drug that has been repurposed based on side effects is clonidine, indicated for use as an anti-hypertensive, which is now also approved for use in the management of attention-deficit hyperactivity disorder (ADHD) because of the mild sedating side effects (17). The application of toxicity data has also played an important role in drug repositioning. Two well-known instances of this include the chemotherapy drug, methotrexate, and the anti-malarial drug, chloroquine. Both gained approval for use in autoimmune disorders at lower doses, to cause the desired level of immunosuppression for patients with these conditions (18,19). Additionally, coincident observations made by researchers have led to the repositioning of drugs, as well. A prominent example of utilizing off-target effects for repositioning includes “statin” drugs that were originally approved for hyperlipidemia, which are now sought after for their pleiotropic effects, namely in anti-inflammatory pathways and bone regeneration (20).

STRATEGIES TO ACHIEVE SUCCESSFUL DRUG REPURPOSING

Once a drug candidate has been identified, to accomplish successful drug repurposing, it is imperative to examine the best way to achieve and maximize the drug interaction with the new target. A suitable strategy is to adopt a route of administration that is different from the original mode of application of the drug. Modification of the route of administration has been applied for several drugs to improve bioavailability or modify the concentration of drugs at the new site of action, while avoiding the original target effects (21,22,23,24,25,26). For instance, beta-blockers, originally indicated for heart rate control, were repositioned for use as eye drops to locally treat glaucoma without systemic effects (27). Additionally, minoxidil, the anti-hypertensive, was reformulated as a topical foam for hair loss to avoid systemic absorption (28).

An alternative repurposing strategy may involve modification of the drug, which can be accomplished through the structure-activity relationship of functional groups to improve new target selectivity or application of prodrugs. For instance, the investigational activities of low anti-coagulant heparin CX-01 showed great promise as a potential therapeutic agent in acute myeloid leukemia (29,30). Drug modification may also involve conjugation of ligands for active targeting, as applied in the use of the anti-plasmodial agent, ferrocene-quinoline, being complexed with gold to ensure targeting of HIV (31).

We are of the opinion that delivery system utilization is crucial in repurposing drugs with exceptional promise in honing the benefits of changing the route of drug administration, drug targeting, and/or drug modification to ensure proper delivery to the new target. Delivery systems offer a unique potential for repurposing applications by allowing researchers to overcome obstacles of solubility, ADME, and targeting, thus significantly expanding the range of deliverable drugs and potential novel indications. Additionally, these systems may allow the delivery of multiple drugs in a single carrier, which further increases the inherent value in repurposing applications. This flexibility arises from the broad range of materials, and physical and chemical modifications available that can allow unique, adaptable, and/or responsive release profiles.

APPLICATION OF NANOCARRIER SYSTEMS IN DRUG REPURPOSING

Nanocarrier systems such as nanoparticles, liposomes, and micelles have gained much popularity in drug repurposing (21,22,23,24,25,26,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47). The attractiveness of these nanocarrier systems can be attributed to factors, such as size, composition, structure, flexibility in multidrug loading flexibility, and the high surface area-to-volume ratio with amenability to targeted drug delivery (25,36,37,43,47) (Table I).

Table I Representative List of the Application of Nanocarrier Systems in Drug Repurposing. These Examples Were Selected to Highlight Different Roles That Nanocarrier Systems Play in Drug Repurposing
Full size table

Nanoparticles are prominent examples of nanocarrier systems. They have become increasingly common in drug repositioning and can be utilized for a wide range of indications. For instance, repurposing of anti-inflammatory drugs (such as ibuprofen, ketoprofen, and celecoxib) as therapeutic agents for cancer (gastric, brain, breast, and colon cancers) relied on use of nanoparticulate delivery systems to achieve tumor-targeted delivery (32,33,34,35,36). Metformin, an anti-diabetic drug, has also been repositioned as part of dual therapy with doxorubicin through the use of nanoparticles as an anti-inflammatory and anti-cancer agent (36). Another indication for which nanoparticles have significantly improved drug repositioning is bone regeneration. In this regard, nanocarriers can maximize the effects of repurposed drugs on bone cells through local delivery strategies, bone retention, and/or bone targeting. A notable example is the focus on anti-hyperlipidemic drugs of the statin class whose potential effects on bone fracture healing cannot be successfully realized without suitable delivery systems (38,39).

Liposomes are also becoming popular in drug repurposing, especially for their ability to entrap both hydrophobic and hydrophilic drugs. One such example is a novel treatment for pulmonary arterial hypertension using fasudil, indicated for subarachnoid hemorrhage treatment, alongside superoxide dismutase (SOD), for the formulation of an inhaled medication (25). This example highlights the use of delivery systems to provide a platform that protects therapeutic agents, like SOD, from premature degradation. Other instances of the favorability of liposomes in drug repurposing are mostly in cancer treatment. Examples include, celecoxib being formulated with a liposomal carrier for stable and prolonged release as an anti-tumor agent (40), and artemisinin, approved for malaria treatment, being loaded into nanoliposomes for testing in a hepatocarcinoma xenograft model (41). Furthermore, indications such as epilepsy have benefitted from repurposing drugs with the use of liposomal systems to enhance blood-brain barrier (BBB) delivery, by using curcumin, a popular anti-inflammatory herbal supplement, for treating seizures in mice (42).

Finally, micelles have also significantly improved the delivery of repositioned drugs with the capability to load multiple drugs. One such example is the micellar formulation of the anti-diabetic, metformin, in combination with the anti-cancer drug, paclitaxel, for the treatment of breast cancer metastases (43). Therapeutic management of breast cancer metastasis has also benefitted from the use of repurposed atorvastatin, loaded into pH-responsive micelles (44). This example additionally showcases the adaptability of micellar systems in achieving optimal drug profiles as needed for therapeutic effectiveness. Moreover, the pleiotropic effects of the statins have also lent themselves to the treatment of edema, represented in a study of atorvastatin-loaded copolymeric micelles and used as a systemic anti-inflammatory treatment (45).

OUR PERSPECTIVES/CONCLUSION

Drug repurposing has now been widely accepted as an attractive strategy to combat the shortage of drugs, low approval rates for new drugs, and high drug prices. This is because repurposing provides the opportunity to save time and money, and can significantly benefit rare and orphan diseases, which are frequently neglected in drug development due to low returns on investments for manufacturers. Herein, we highlighted that drug delivery systems (namely nanocarriers) are critical tools in addressing the challenges plaguing the drug repurposing process. These nanocarriers are especially important in accomplishing (i) modification of the release profiles of repurposed drugs, (ii) configuration of the repurposed drug for a different route of administration, (iii) targeting and/or increasing retention of drug at new sites of action to negate off-target effects, and (iv) reformulation of the repurposed drug alone or in combination with other drugs to increase therapeutic efficacy and/or patient adherence to treatment.