Abbreviations: ADR, Adverse drug reaction; BBB, blood-brain barrier; DexAM, cyclodextrin-modified dendritic polyamine; DNA, deoxyribonucleic acid; dpap1, dipeptidyl aminopeptidase 1; DOX, doxorubicin; FDA, Food and Drug Administration; HBC, human breast cancer; hGH, human growth hormone; KRAS, pancreatic cell mutant K-Ras; LF, lethal factor; LFN, lethal factor N-terminal domain; LODER™, Local Drug EluteR; MMP2, activated-matrix metalloproteinase 2; NFs, nanoflowers; NIR, near infrared; NRTIs, nucleoside reverse transcriptase inhibitors; NSCLC, non-small cell lung cancer; PBA, phenylboric acid; PEG, poly(ethylene glycol); PFTH, pathogen-free target host; PLGA, poly (lactic-co-glycolic) acid; SDDS, “smart” drug delivery systems; siRNA, small interfering RNA; SNA, spherical nucleic acid; SV2A, synaptic vesicle glycoprotein 2A; TFRC; TFR, anti-transferrin receptor; UCB, Union Chimique Belge.
It is well understood that the side effects of drugs are secondary undesired reactions of drugs/medications, and quite a number of studies in drug design are ongoing to find a possible way to minimize or eliminate these side effects. A comprehensive study on the mechanism of action of drugs has shown that they exert their effect mostly by functioning as a ligand, binding to a target (mostly proteins) that is subsequently modulated, resulting in a physiological effect. All that the recent research in the prediction of adverse drug reaction (ADR) has tried to achieve is to identify the possible interactions on the basis of structure and complementarities via a variety of approaches. Complementing the quest for a manageable ADR in drug targeting also is the desire to increase efficacy, increase bioavailability, and precision in delivery.
2 Recent trends
This field of research received more awareness in 2008, when it was reported that a drug of the benzodiazepines class could be used in treating chronic pain in mice without the usual side effects associated with pain killers . Similarly, in 2012, a team co-led by researchers at the University of California, San Francisco, School of Pharmacy, Novartis Institute for Biomedical Research (NIBR) and the SeaChange Pharmaceuticals, developed a new set of computer models that successfully predicted negative side effects in 656 marketed drugs on 73 unintended “side-effect” targets, based on the similarity between their chemical structures and molecules known to cause side effects . A program (Altman’s algorithm) now helps us to predict the potential side effects of drugs either alone or in combination with other drugs. This is, however, not the first time attempts are made to solve side-effect problems, but it has been one of the objectives of chemical genomics  and informatics , which use the similarity ensemble approach, and relates proteins based on the set-wise chemical similarity among their ligands . However, then, what decision is the outcome of the predictions of the side effects of a drug leaving us to take concerning that drug? It is indisputable that the prediction of an unknown off-target of drug interactions might prevent disastrous drug toxicities, and serves as a tool for the review of the safety of the drugs. Being able to predict the side effects of a drug, however, does not make a potent substance (drug) impotent. Searching through the history of discovery and usage of drugs reveals that a number of drugs/medications that demonstrate high efficacy in the treatment and management of infections have been taken off the shelf (banned), owing to the fact that the side effects caused by such drugs outweigh their therapeutic benefits. These side effects range from mild to life threatening (fatal). For instance, the fundamental mechanism through which chemotherapeutic drugs used in the treatment of cancer exert their therapeutic activity is by destroying cells; they are, therefore, inherently toxic and have the potential of killing healthy cells that are not the intended targets for their use. Likewise, many drugs pass through the clinical trial stage, but as soon as they hit the market, unknown adverse effects that went through the clinical trial stage undetected begin to appear when they are taken separately or in combination with other drugs (drug-drug interaction). Other specific examples include the appetite suppressant fenfluramine-phentermine (fen-phen), of which the incidents of fatality in numerous patients led to its withdrawal . The mechanism through which fen-phen exerted its side effect is by the activation of the 5-hydroxytryptamine-2B receptor norfenfluramine (a metabolite of fen-phen), resulting in a proliferative valvular heart disease . Terfenadine (an antihistamine) has also been called off the market due to its inhibition of the human ether-a-go-go-related gene potassium channel (KCNH2) resulting in arrhythmias and death . In 2005, 21 medications used in the management of human immunodeficiency virus infection were approved by the US Food and Drug Administration (FDA) (U.S. Department of Health and Human Services, 2014) . All these medications are in the form of either one of nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs, or protease inhibitors administered to the patient either in combined form (highly active antiretroviral therapy) or separately. All these medications have at least a particular side effect. These side effects include hepatotoxicity, hyperglycemia, lipodystrophy, hyperlipidemia, osteonecrosis, osteopenia, osteoporosis, skin rash, lactic acidosis, stroke, vasculitis, gastrointestinal adverse effects, carcinogenicity, cardiovascular toxicity, multiorgan toxicities, neutropenia, and other adverse effects .
The United Nations has preserved a master list of banned drugs since 1979 (frequently updated annually) as an outcome of the United Nations General Assembly resolution 37/137 of December 17, 1982, which had its initial focus on chemical products and pharmaceuticals but afterward was, however, divided into two parts since 1995 and published as separate issues – one on pharmaceuticals and the other on other chemicals . Each country, however, is responsible for the list of drugs they decide to withdraw, as a drug withdrawn from the market in one country may remain on the market of another country. This reveals the absence of agreement on which drug should be banned globally . Countries, however, tend to have different policies on which drugs to withdraw and when to withdraw them. Notable among the conditions for the withdrawal of drugs from the market [9, 10] with examples of such drugs include the following:
Superseded by safer and more effective preparations (e.g. nitrofural, guanofuracin, furazolidone, difurazone dihydroxymethylfuratrizine, and acetylfuratrizine)
Potential for abuse and dependence (e.g. levamfetamine, dexamfetamine, amfetamine, amfepramone, and meprobamate)
Risks outweighing benefits (e.g. amfepramone HCl)
Adverse (side) effects damaging to cells, tissues, organs, generally referred to as “off-targets” (e.g. dantron, diethylaminoethoxyhexestrol, and Neo-Barine)
Lack of efficacy (e.g. benzylpenicillin sodium and Amilprilose)
Lack of substantial evidence of efficacy and safety (e.g. nialamide, mephenesin, and isocarboxazid)
Drug-drug interactions (e.g. mibefradil)
Risk of infection by other disease causing agents (e.g. factor IX and factor VIII)
Diminished sales to the point that product is no longer economically viable (e.g. suprofen)
Inadequate data on pharmacokinetics (e.g. nitrendipine)
One of the major causes of ADRs commonly known as side effects is made evident in the fact that drugs entering the systemic circulation are distributed freely to places where their activity is required, and where their activity is not required known as “off-targets” .
Random sampling of 30 drugs to check the prevalence of common side effects, including nausea, skin rash, diarrhea, fever, headache, constipation, vomiting, insomnia, dizziness, and anorexia, reflected the prevalence of these common side effects as shown in Table 1. Figure 1 represents the degree of occurrence for the various side effects commonly manifested by users of drugs. In about 96% of the drugs where nausea was a side effect, headache and vomiting were also present. This explains that headache and vomiting are often associated with nausea.
Some other causes may be as a result of modulation of the primary target of a drug , and non-specific interactions of reactive metabolites. Receptor sites of drugs are generally inaccessible to our observations or are widely distributed in the body, and therefore direct measurement of drug concentrations at these sites is not practical , and obviously, it has not yet been possible to directly sample drug concentration in some body compartments such as the myocardium. However, this is easily carried out in urine, saliva, blood, plasma and other body fluids. Until now, we do not know the molecular target of some medications. There are also several cases of some researchers facing unplanned difficulties in getting drugs to their intended target . Notable is the case of levetiracetam, a drug manufactured by Union Chimique Belge (UCB) (a Belgian pharmaceutical firm based in Brussels) and approved for use in 1999 by the FDA as a treatment for epilepsy. Reasonable evidence reveal levetiracetam to inhibit the release of neurotransmitters that play a substantial role in producing uncontrolled activity of the central nervous system ; however, levetiracetam suffered pitfalls of side effects that included dizziness, drowsiness, and infections such as the common cold, which led UCB scientists to work on alternatives that bind to synaptic vesicle glycoprotein 2A (SV2A) . As at July 2014, brivaracetam, a drug that resembles levetiracetam in structure with a higher affinity for SV2A, was in phase III clinical trial stage, hoping that it will produce a more rational result in the form of fewer side effects .
Bioavailability is a subsection of absorption of medication; the portion of an administered dosage of an unaltered drug that gets to the systemic circulation for further metabolism. When a medication/drug is administered intravenously, its bioavailability is 100% . However, when a medication is administered via other routes (most especially orally), its bioavailability generally decreases due to incomplete absorption and first-pass metabolism . For polar compounds of which antiretroviral agents are a part of, the major factor restricting their entry lies in the tight junctions that occlude the paracellular pathway across these barriers. In addition, influx and efflux transport systems, or metabolic processes active in both capillary endothelial cells and choroid plexus epithelial cells, can greatly change the bioavailability of a drug in one or several compartments of the central nervous system . Other major factors that may affect drug availability are enzyme induction and inhibition, enzyme polymorphisms, and disease states . The physicochemical factors affecting drug absorption include the pH-partition hypothesis on drug absorption, ionization and pH at absorption site, and lipid solubility . The aim of drug targeting has always been to direct the drug to the target tissue either at cellular level or subcellular level where its activity is required . In a bid to enhance the therapeutic effect of drugs, researchers have long been using antibody-drug conjugation strategies to minimize “off-targets” that result in side effects . However, a 100% success in drug targeting has proven elusive basically due to the fact that most drugs, when administered into the systemic circulation, are freely and at most times evenly distributed throughout the body and, moreover, some of the targeting systems (carriers) are toxic. All the limitations notwithstanding, a 100% success in the desired outcome of drug targeting is very much possible by the collective ability of researchers and therapists to restrategize and alter the pharmacokinetics and pharmacodynamics of drugs to minimize side effects, increase bioavailability, reduce drug dosage, increase drug clearance, and shorten the duration of treatment, the effect of which will definitely return some of the banned drugs to the shelves. Tysabri (natalizumab), a drug that received approval by the FDA in 2004 for treating multiple sclerosis and was withdrawn due to a fatal side effect, got a comeback in 2008 after proving to be effective in managing Crohn’s disease. A similar fate trailed thalidomine . However, many more of these banned drugs could still make a comeback, not because they are applicable to other areas as reported in the case of Tysabri and thalidomine, but because they are applicable for the same use for which they were banned.
Irrespective of such factors as age, weight, disease state, and other factors responsible for variations in the way patients manifest side effects, it is generally very possible to reduce to a minimum or to totally overcome the side effects of drugs/medications.
2.1 Advances in drug targeting and delivery
In actuality, the target of advanced drug delivery systems is to deliver therapeutic agents intact to their specific targets via a medium that can both navigate through and utilize the body’s normal system by means of either a physiological or chemical trigger. Researchers achieve this through micro- and nanotechnology. Polymeric microspheres, polymer micelles, hydrogel-type materials, biodegradable polymers, dendrimers, and electroactive polymers have all be proven in recent times to be useful in achieving the targeting specificity. Beyond the polymer era lays many more advanced methods of making drugs better and safer, and such more advanced and complex methods include forced-pressure injectables, aerosol inhalation devices, transdermal methodologies, and biodegradable polymer networks (designed specifically to transport new gene therapies). Likewise, “smart” drug delivery systems (SDDS) is a system developed to keep drugs at desirable levels in the body aimed at avoiding frequent doses . The ultimate objective SDDS is set to achieve is in the administration of drugs at the right place, time, and dose with specificity in order to cut infidelities in therapy regimen. Such systems include magnetic nanocapsules, microspheres, thermo-triggered squirting, nano-beacon, and various sensors. The remarkable features of the “smart” systems are that they are preprogrammed with self-regulating characteristics, are control timed, are targeted spatially, and monitor drug delivery . SDDS also encompass the use of hydrogels, nanomedicine, and techniques like microencapsulation. One of the major mechanisms of SDDS is that it employs microchips/nanoparticles that could be placed under the skin or into the spinal cord or brain, capable of detecting various chemical signals in the body to deliver drugs. Recently, researchers also proposed an in vitro administration of drugs that will not be applicable to all diseased body components or types of infections but intended for the treatment of infections with “replaceable/replantable target host” . In vitro administration of drugs proposes a sequential six-step laboratory/clinical procedure linking different established clinical/laboratory tools (methods) and channeling them toward treating infections. It begins with the isolation/purification of a pathogen-free target host (PFTH), and thereafter, in vitro expansion/culture of the purified PFTH, in vitro expansion/culture of the purified PFTH, chemical modification of the purified PFTH clone, inhibition/suppression of target host proliferation in the subject (beneficiary), administration of chemically modulated clone to the infected subject, and, finally, monitoring/maintaining the physiological/biochemical processes of the subject under intensive care.
2.2 The implication of nanotechnology in the improvement of drug delivery and reduced side effects
Most of the nanoparticles used as drug delivery vehicles are <100 nm in at least one dimension (particle diameters are usually 1 μm), making their size small, and are taken up by cells more efficiently than larger micromolecules as well as small enough to overcome barriers. They are also made of different biodegradable materials (including natural or synthetic polymers, lipids, or metals). The biodegradable nature enables the nanoparticles that would have been a threat to the biochemical system to be discarded easily. Sometimes, some active constituents of drugs are usually degraded, promoted by the acidic pH of the stomach before they reach their site of action; nanoparticles, however, fosters the stability of these drugs until they get to their target site. Nanoparticles-based drug delivery produces reduced toxicity of drugs, reduced dose, controlled release time, delivery of a higher dose in a short period of time, and modification of pharmacokinetics and biological distribution. Conjugating this drug with nanoparticles solves a bulk of solubility problems. Most times also, the solvent in the delivery of conventional solvent-delivery systems are toxic, in nanotechnology-based drugs; however, the solvent-free nature eliminates the solvent-related toxicities. The problem of drug resistance is also prevented by facilitating movement of drugs across barriers such as the blood-brain barrier (BBB). Part of the advantages of nanoparticles is also that when used in blood, they do not activate neutrophils, and they as well avoid the reticuloendothelial system. These attributes are due to the fact that they are stable and non-toxic, and therefore, non-thrombogenic, non-immunogenic, and non-inflammatory. Natural nanomaterials are usually preferred over synthetic nanomaterials, because they generally have the ability to deliver more than one active constituent using the same carrier, they increase residence time in the body in addition to a sustained release system, and, as a matter of fact, reduce side effects. In summary, the use of nanotechnology-based drugs to enhance/improve drug delivery and minimize the side effects is broadly achieved through improved delivery of weak water-soluble drugs, delivery of drugs by a cell- or tissue-specific method, transcytosis of drugs across tight epithelial and endothelial membrane barriers, delivery of large-macromolecule drugs, co-delivery of two or more therapeutics in combination therapy, visualization of sites of drug delivery with tracking devices, and real-time read on the in vivo efficacy.
2.3 Recent specific advances in drug delivery through nanomedicine
In taking advantage of the high binding affinity phenylboric acid (PBA) has for sialic acids (sialylated glycans), which have more expression on cancer cells, micelles having PBA (PBA-micelles) installed on their surface have been demonstrated in very recent times to be potent in tumor-specific delivery of chemotherapy . This method simply depicts the targeting of nanocarriers to particular tumor cells mediated by ligands. Experimentation that proved the increased potency resulting from the PBA affinity for sialic acid (verified by fluorescence spectroscopy) using melanoma cell line from mouse resulted in a greater uptake, increased intercellular retention time, and increased cytotoxicity (against B16F10 murine melanoma cells in vivo) of oxaliplatin-loaded PBA-micelles, showing a growth retardation of orthotopic and retarded lung metastasis models of melanoma compared to other test variations . Trending recently also is the development of an activated-matrix metalloproteinase 2 (MMP2) nanocarriers as vehicles for the delivery of chemotherapeutics in cancer studies. This stems from the fact that ineffective physicochemical characteristics, poor tumor targeting, ill bioavailability, and side effects are usual and regular limitations often associated with anticancer drugs as evident in clinical outcomes. The composition of the nanopreparation is of an MMP2-sensitive self-assembly poly(ethylene glycol) (PEG) 2000-paclitaxel conjugate, serving as a prodrug and MMP2-sensitive moiety, a cell-penetrating enhancer peptide-PEG1000-phosphoethanolamine (PE), and a nanocarrier building block PEG1000-PE. PEGylated micelle shell (a delivery strategy) is a hydrophilic preparation that is susceptible to cleavage by MMP2 (usually found sufficiently expressed in cancers and responsible for metastasis), ultimately releasing paclitaxel bound to Tat peptide . Experimenting this in carcinoma cells of the human lungs revealed cytotoxic activity that is significantly higher than that of free paclitaxel. However, the toxicity was less in healthy cardiomyocytes. The antitumor activity and tumor accumulation property of the nanopreparation in non-small cell lung cancer (NSCLC) xenografts in mice was more efficacious than its counterparts, the non-targeted micelles, conventional paclitaxel-carrying micelles as well as free paclitaxel . Deoxyribonucleic acid (DNA) nanostructures have also shown ample potential for advanced drug delivery. DNA could be assembled non-canonically in an unconventional way via liquid crystallization or rolling circle replication to generate nanostructures. This process, however, does not take on the rules designated by the Watson-Crick pairing of bases and ultimately lead to structures that are named nanoflowers (NFs). The conventional behaviors of DNA structures such as dissociation at low temperatures, denaturation, and degradation by DNase 1 are significantly resisted by NFs. This exceptional biostability property enables them to function as effective carriers of the active compound. For instance, the cytotoxicity expressed by the chemotherapeutic DOX conjugated with aptamer (a bioimaging agent) NFs in cancer cells significantly exceeds the efficacy of the free DOX (used as control) as evident in flow cytometry studies . It is worthy of note that a high level of caution is important in design and delivery during stem cell research. Being able to achieve a controllable means to direct stem cell differentiation is one of a single most critical breakthrough scientists are working hard at. This is because we will be able to decide the type of cell that is of particular interest for us to produce at every single moment. Progress, however, surfaces as cyclodextrin-modified dendritic polyamine (DexAM) has proven in recent time to be efficient in the delivery of stem cell differentiation factors, small interfering RNA (siRNA), and small molecules. The siRNA has a negative charge, whereas the cyclodextrin portion is packed with a hydrophobic molecule . In an experiment with stem cells, the DexAM delivery retinoic acid and siRNA targeting SRY (sex determining region Y)-box 9 gave forth an outcome of about 71% of the stem cells differentiating into neurons. Meanwhile, a differentiation of about 50% was observed in the cases with DexAM component alone . In mouse xenograft models of human prostate cancer, engineered nanoparticles composed of a biodegradable diblock copolymer [poly(lactide-coglycolide)-b-poly(ethylene glycol)] and a self-synthesized cationic lipid formulated through self-assembly was used in mediating the co-delivery of siRNA [targeting the suppression of vital gene products, REV1 and REV3-like catalytic subunit of DNA polymerase-z (REV3L)] and cisplatin prodrug (a DNA-damaging chemotherapeutic widely used in the treatment of a broad spectrum of malignancies) to the target site. This led to retarded tumor growth and enhanced survival compared with nanoparticles loaded with the prodrug or siRNAs alone, demonstrating the potency of the siRNA-containing NPs to knock down target genes efficiently both in vitro and in vivo toward improving cancer therapy . siRNA (a synthetic RNA designed, targeting a particular mRNA for degradation) has been successfully targeted to pancreatic cell mutant K-Ras (KRAS) G12D using LODER™ (Local Drug EluteR) – the first miniature biodegradable polymeric matrix cancer drug delivery platform to enable insertion of the RNAi (specifically to knock down KRAS expression in vitro as well as in vivo) directly to the core of tumors . As it has always been with similar experiments, the LODER-siRNA combination had a more significant effect than the siRNA alone .
The ferrous iron (FeII) working in synergy with other components has shown to be efficacious in the effective targeting of drugs to diseased tissues of interest . This process is intended to take advantage of the fact that some parasites, such as malaria parasites, produce aberrant levels of mobile ferrous iron (FeII) as a consequence of their catabolism of the host hemoglobin in the infected erythrocyte. Mouse models have been able to prove this principle, which is based on the mechanism that the particular drug to be used in the treatment is conjugated to a linker molecule and a 1,2,4-trioxolane ring (serving as an FeII-sensitive “trigger”) forming a complex, which finally undergoes fragmentation to its initial components in the presence of FeII. A potent inhibitor of the plasmodium dipeptidyl aminopeptidase 1 (dpap1) was attached to a conjugator, targeting it to the red blood cells of mice infected with plasmodium. The conjugate more persistently inhibited dpap1 and decreased parasitemia, showing a relatively increased safety compared to the unconjugated inhibitor used as control . An experiment on staggered lamellae polyprodrug nanostructure has illuminated the possibilities of fostering drug delivery. In a mixture of dioxane and water, creating staggered lamellae characterized by a spiky periphery, the hydrophilic PEG form amphiphilic block polymers that resulted in a self-assembly of about 300 nm in diameter, polymerizing reduction-responsive camptothecin prodrug monomers . These were internalized quicker than the polydrugs that had the flower-, disk- or sphere-like shape. In addition, the drug is easily released under reducing conditions likened to the intracellular microenvironments of tumors. The half-life of the polyprodrug nanostructures proved to persist more than the three other nanostructures . Recently, the oral delivery of nanoparticles has gained attention. Deserving significant attention is the employment of nanoparticles to target the IgG receptor transporter Fc fragment orally. The conjugator used was polylactic acid-PEG as the nanoparticles. Experimentation in mice showed an increased transport across the epithelial colorectal adenocarcinoma monolayer . In a closely related experiment on hypoglycemic response using insulin, the insulin-encapsulated nanoparticles administered orally had a greater half-life than the injection of free insulin. Remarkably, there was zero effect with the oral administration of untargeted insulin . One very sensitive point of immense focus of research over the years has also been the BBB. The delivery of antibodies across the BBB has received much progress via the transferrin receptor-binding Fab fragment. The transferrin receptor is monovalent (a single transferrin receptor) connected to the C-terminal of the heavy chain of the b-amyloid (Ab)-specific monoclonal antibody (mAb) . Very considerable improvements have been achieved in some nervous diseases such as Alzheimer’s disease in which there was a decreased Ab plaque by 55-fold in comparison to the parent antibody. There was improved parenchymal exposure as well as Ab binding in the brain by 50-fold in amyloid precursor protein-driven amyloidosis, using mice as models . The advantage of monovalent binding is that it facilitates transcellular transport, contrary to the lysosome sorting commonly characteristic of bivalent binding. There has also been, in recent times, a little focus channeled to programming a biological system device and using a remote trigger to activate a process when required. This, in rat studies, however, has shown progress as observed in the use of nanoparticle-encapsulated delivery devices for sustained, repeated drug delivery, using near-infrared (NIR) light as a trigger to induce release of drugs . The composition entails a drug encapsulated by a matrix of ethylcellulose made of heat-sensitive gold nanoparticles. Porous membrane for the release of drug is created as a result of exposure to continuous-wave NIR light while suspended in normal saline. Subcutaneous implantation in models of diabetic rats loaded with insulin in the device produced decreased blood glucose levels that correlated to activation with periodic laser pulse intensity following exposure, and produced higher effects (sustained on-state drug release for a minimum of 3 h) compared to the saline-loaded controls with untriggered devices . Evidence has also been reported on the improvement in the surface expression of anti-transferrin receptor (TFRC; TFR) resulting from a lesser degradation of TFRC by the lysosome induced by low-affinity antibody compared to high-affinity antibody . The essence of this is to facilitate a better uptake of BBB penetrants. The bispecific antibodies that act against transferrin receptor and β-secretase in the study traverse the BBB to effectively reduce brain amyloid β levels. Optimization of the TFRC affinity remarkably improved the brain exposure and likewise BACE1 inhibition . The use of cyclodextrin as an encapsulating agent for hydrophobic drugs could likewise be used in their delivery into liposomes. This preencapsulation thrives on the fact that cyclodextrin, in addition to its hydrophilic exterior, has a hydrophobic core that proffers a strong advantage over hydrophobic and non-ionized drugs that cannot cross the hydrophilic membrane barrier into the liposome . Comparing the efficacy of the drug-loaded liposomes with the empty liposomes or free drug using mouse colon cancer xenograft models showed decreased tumor growth without adverse effects. It is worth a very critical noting here that many cancer drugs had previously failed clinical testing as well as are facing ban as a result of toxicity issues . The preencapsulation is, however, offering ample hope in the field of drug delivery as well as reducing the side effects of drugs. Tissue damage associated with vascular inflammation can also be avoided by employing neutrophil-targeting nanoparticles. Nanoparticles of bovine serum albumin loaded with piceatannol (spleen tyrosine kinase inhibitor, which blocks “outside-in” β2 integrin signaling in leukocytes) were preferentially absorbed by polymorphonuclear neutrophils attached adherently around the site of inflammation in an experiment with mice. They lowered neutrophil infiltration and inflammation compared with free piceatannol . A cell-penetrating paired liposome system for intracellular ATP-induced chemotherapy release could be showing evidences for the possibility of treating cancers as shown in a xenograft model of human breast cancer (HBC) in mouse. The experimental design basically entails a test on three variations; free doxorubicin (DOX), DOX-containing liposome, and fusogenic liposome containing ATP-responsive DNA scaffold loaded with DOX . The liposome containing ATP-responsive DNA scaffold loaded with DOX, however, decreased tumor growth when compared to the other two variations both in vitro and in vivo . Similarly, mouse xenograft models of triple-negative breast cancer and NSCLC have proven folate to be useful in coating liposomes to enable a swifter targeting of cancer cells by loading the hydrophobic layer of the liposomes with Tarceva erlotinib and DOX in the hydrophilic region . It is interesting to note that the dual-drug liposomal nanoparticles produced tumor regression, whereas single-drug nanoparticles resulted in continued tumor growth . Trafficking in cells is a matter of concern, as knowledge of what is happening in the cell will help improve the design of therapy. In laboratory-cultured mouse endothelial cells (C166), spherical nucleic acid (SNA) conjugated to nanoparticles, ultimately consisting of a quantum dot core and a fluorescent fluorophore-labeled oligonucleotide designed to independently keep track of intracellular activities, have offered improvement possibilities . SNA nanoparticle conjugates are a class of bionanomaterials consisting of a dense shell of highly oriented oligonucleotides chemically attached typically to a gold nanoparticle core. The trafficking activities of the designed nanoparticles commenced in the early endosomes through the late endosomes, not entering the Golgi bodies or lysosomes. Remarkably, there was degradation and clearance of DNA from the cell, whereas the core was retained . Experiments in an HBC mouse xenograft model has shown pulsatile ultrasound to be useful in triggering the delivery of drugs (e.g. mitoxantrone), peptides, oligonucleotides, and other small bioactive molecules by releasing the drug, on demand (could be turned on and off depending on the need), from injectable cross-linked alginate-based polymer hydrogels, implanted near tumor sites . The result showed well-regulated intermittent release that reduced tumor sizes. By integrating proteomics and imaging analyses of caveolae, mouse and in vitro studies propose that targeting chemotherapeutics to Annexin A1 potently facilitates their active transport to tumor sites. In the tumor tissues of human and rat endothelial caveolae, Annexin A1 had expression, whereas expression was absent in healthy tissues . In mice models expressing prostate, mammary, and lung tumors, intravenous injection of a labeled antibody specifically targeted to Annexin A1 resulted in their transport to the caveolae, including a facilitated uptake by tumor cells showing a rapid and enhanced pumping across the endothelium, as shown through trafficking using fluorophores . This produced >100-fold increased tumor accumulation in comparison with an equivalent injection of antibodies that served as control. Similarly to the above, also trending is the delivery of drugs based on refillable alginate hydrogel depots modified with oligodeoxynucleotides that can be refilled through a direct long-term administration of drugs into the bloodstream. The drug DOX was modified by oligodeoxynucleotides, resulting in a more potent inhibition of the tumor when compared with the efficacy of unmodified DOX . Cancer therapy has also been attempted in very recent times using the anthrax toxin protective antigen to enable the cytosolic delivery of the N-terminal domain (LFN) of the anthrax toxin lethal factor (LF) to mimic antibodies, aimed at inhibiting intracellular oncoprotein . As shown in human chronic myeloid leukemia cell line studies, small antibody mimic conjugated to LFN inhibited intracellular BCR-ABL (its protein target) kinase activity inducing apoptosis, and this is in contrast to a cell-penetrating peptide that was not able to facilitate the cytosolic delivery of these antibody mimics . Bupivacaine (MarcaineTM) is widely known to be a generic anesthetic used in the management of pain by freezing tissue in a specific area, with notable side effects that include low blood pressure, muscle twitching, changes in vision, and irregular heart rates. However, the possibility of improvement as to the reduced adverse effect as well as increased efficacy has been shown possible by employing the use of a “smart” hydrogel delivery system made of chitosan-coated poly(lactic-co-glycolic acid) (PLGA) microparticles, embedded within pluronic F-127 (thermoresponsive gel) . When administered in vitro, the hydrogel-embedded microparticles released bupivacaine in a controlled manner over a period of 7 days and the chitosan-coated microparticles showed no cytotoxic activity against bone marrow mesenchymal stem cells, while causing a less proinflammatory cytokine release from macrophages when compared to the uncoated PLGA microparticles . Ex vivo and in vivo studies have suggested that liposomes chemically stabilized (with the lipid glycerylcaldityl tetraether) have been suggested to be useable in the delivery of drugs (human growth hormone – hGH) through the intestinal mucosal barrier to enhance oral bioavailability. The permeation enhancers used include phenylpiperazine, octadecanethiol, sodium caprate, d-α-tocopheryl polyethylene glycol 400 succinate, or cetylpyridinium chloride . Experimentations in rat small intestinal cross-sections showed the liposomes to possess strong interactions with the mucosal surface of the duodenum and jejunum, resulting in 3.37% plasma bioavailability as against the 0.01% observed for the regular orally administered free model drug hGH . Receptor-mediated endocytosis has also been employed in the delivery of intracellular protein (in this case recombinant human tumor suppressor protein p53 and its tumor-selective supervariant) therapeutics to target sites. Non-covalent protein nanocapsules incorporating copper-free “click chemistry” moieties, redox-sensitive cross-linker, and PEG units were rationally designed . The nanocapsules are then conjugated to anti-Her2 antibody single-chain variable fragment and luteinizing hormone releasing hormone peptide, producing accumulation within tumor cells that have the tendency to overexpress the receptors, leading to the reactivation of p53-mediated apoptosis in cancer cells . In human breast cancer mouse model xenografts, conjugating drugs to silica nanoparticles with optimized sizes (to enable tumor penetration and retention) and targeting it to tumor sites could be useful in the delivery of chemotherapeutics to cancer cells . The complex is composed of a hard silica core, with the outer layer conjugated to irinotecan (chemotherapeutic) and a polyethylene glycol coat synthesized in three distinct sizes, in the diameters of 20 nm, 50 nm and 200 nm, with the 50 nm nanoparticles exhibiting greater uptake, retention, as well as decreased tumor growth and metastasis . There was less toxicity observed compared with the unconjugated irinotecan. B-lactam has gained wide recognition of its potency as an antibiotic against Gram-negative bacteria. However, there has always been a check for a better and enhanced delivery. In pathogenic Escherichia coli (E. coli CFT073, E. coli UTI89, E. coli O157:H7, and E. coli O78:H11) cultures, this hope has been offered by siderophore enterobactin conjugated to the b-lactam (ampicillin) (Ent-Amp/Amx) via a stable PEG linker, offering a 1000-fold higher antibacterial activity compared to free ampicillin . Another interesting evidence here is that Ent-Amp and Ent-Amx selectively kill E. coli CFT073 co-cultured with other bacterial species, with low toxicity against human T84 intestinal cells .
2.4 Recommendations on next steps
Research is continuous and progressive, therefore necessitating the recommendations on next steps to take, and such steps include testing the nanocarriers (delivery vehicle) in additional tumor models apart from mice, process optimization and preclinical pharmacokinetic testing of NFs, developing an optimized version of delivery systems across biological barriers and evaluating them for the delivery of therapeutics, evaluating the delivery of different siRNA and drug payload combinations with nanoparticles, optimizing the efficiency of the siRNA molecules and nanoparticle carrier to increase half-life and target specificity, testing the antitumor effects of the four types of self-assembled nanostructures in mouse xenograft models, phase II/III clinical trial in G12D mutant pancreatic cancer, generating modula monovalent transferrin receptor-binding antibodies specific to primate and human receptors, developing formulations that can be triggered by lower laser powers to improve safety, further elucidating the mechanism of lipopeptide nanoparticles (LPN) uptake by hepatocytes, testing the liposome delivery system on larger animals and adapting it for the delivery of other drugs, evaluating liposomal nanoparticles for delivery of additional combinations of cancer drugs and testing them in disease models, designing SNA nanoparticle conjugates with biodegradable cores to minimize cellular toxicity, identifying optimized dose and release timing for clinical testing, investigating the potential of ANXA1-targeted delivery of cancer therapeutics, evaluating the approach for refilling drug delivery devices designed to promote blood vessel growth and improve wound healing for use in conjunction with stents and vascular grafts, developing a cleavable linker to allow bioactive cargo to be released from carrier upon entry into the cytosol and testing the system in animal cancer models, manufacture of hydrogel delivery system and evaluation in large-animal models of pain, and developing the approach for other pathogenic bacteria. Taking these further could take medicine to the final target.
There is the need to constantly review issues surrounding our use of medications. Lots of methods and advances are still available to us in making drugs safer as well as making banned drugs return to the shelf. As we keep discovering new methods alongside achieving a much clearer view of the mechanism of action of drugs, we can make drugs safer with minimal harm even as we utilize them in the treatment of diseases. Nanomedicine, however, has substantially offered us a huge step into overcoming the barriers emphasized in this review.
We wish to acknowledge Prof. B.C. Nwanguma for providing a part of the literature materials for this work, and Prof. O.F.C. Nwodo who offered critical advice on the modalities for effective research during the course of the review.
Conflict of interest: The authors declare that they have no competing interests.
Eugen L, Michael JK, Steven W, Dmitri M, Jacques H, Jeremy LJ, Paul L, Eckhard W, Allison KD, Serge C, Brian K, Shoichet LU. Large-scale prediction and testing of drug activity on side-effect targets. Nature 2012, 486, 361–367. Google Scholar
Lee S, Lee KH, Song M, Lee D. Building the process-drug-side effect network to discover the relationship between biological processes and side effects. BMC Bioinformatics 2011, 12 (Suppl 2), S2. Google Scholar
Tatonetti NP. Detecting drug interactions from adverse-event reports: interaction between paroxetine and pravastatin increases blood glucose levels. Clin. Pharmacol. Ther. 2011, 90, 133–142. Google Scholar
Keiser MJ. Predicting new molecular targets for known drugs. Nature 2009, 462, 175–181. Google Scholar
Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL. Evidence for possible involvement of 5-HT2B receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 2000, 102, 2836–2841. Google Scholar
Roy M, Dumaine R, Brown AM. HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine. Circulation 1996, 94, 817–823. Google Scholar
U.S. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents (available at http://aidsinfo.nih.gov/guidelines). Retrieved on October 31, 2014.
Aronson JK. MEYLER’s side effects of drugs. In The International Encyclopedia of Adverse Drug Reaction and Interactions, 15th ed., Elsevier: Amsterdam, 2006. Google Scholar
Benson N, Albert IW. Withdrawing drugs in the U.S. versus other countries. INNOVATIONS in Pharmacy 2012, 3, article 87. Available at http://z.umn.edu/INNOVATIONS.
Wong D, Wang M, Cheng Y, Fitzgerald GA. Cardiovascular hazard and non-steroidal anti-inflammatory drugs. Curr. Opin. Pharmacol. 2005, 5, 204–210. Google Scholar
Joseph TD, William JS, William EW, Robert AB, Jane MP. Concepts in Clinical Pharmacokinetics, 6th ed., American Society of Health-System Pharmacists: Bethesda, MD, 2014, ISBN: 978-1-58528-3873. Google Scholar
Megan C. Drug development: illuminated targets. Nature 2014, 511, S12–S13. Google Scholar
Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, Fuks B. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc. Natl. Acad. Sci. 2004, 101, 9861–9866. Google Scholar
Mula, M. Drug development: illuminated targets. Expert Rev. Neurother. 2014, 14, 361–365. Google Scholar
Van Paesschen W, Hirsch E, Johnson M, Falter U, von Rosenstiel P. Efficacy and tolerability of adjunctive brivaracetam in adults with uncontrolled partial-onset seizures: a phase IIb, randomized, controlled trial. Epilepsia 2013, 54, 89–97. Google Scholar
Griffin JP. The Textbook of Pharmaceutical Medicine, 6th ed., BMJ Books: Hoboken, NJ, 2009. ISBN 978-1-14051-8035-1. Google Scholar
Mukonzo JK, Nanzigu S, Rekić D, Waako P, Röshammar D, Ashton M, Ogwal-Okeng J, Gustafsson LL, Aklillu E. HIV/AIDS patients display lower relative bioavailability of efavirenz than healthy subjects. Clin. Pharmacokinet. 2011, 50, 531–540. Google Scholar
Strazielle N, Ghersi-Egea JF. Factors affecting delivery of antiviral drugs to the brain. Rev. Med. Virol. 2005, 15, 105–133. Google Scholar
Romil S. Practical Hepatic Pathology: A Diagnostic Approach, 1st ed., Elsevier: USA, 2011. Google Scholar
Wolters K, Thomas LL, David AW. Foye’s Medicinal Chemistry, 7th ed., Lippincott Williams and Wilkins: USA, 2012. Google Scholar
Yvonne P, Thomas R. Pharmaceutics – Drug Delivery and Targeting. Fastrack, Pharmaceutical Press: London, 2010. ISBN 9780853697626. Google Scholar
Agath RJ, Helga R, Suzanna C, Sunil B, Douglas DL, Sylvia W, Yvonne C, Michelle S, Siao PT, Mark SD, Yanmei L, Meng YG, Carl N, Jihong Y, Chien CL, Eileen D, Jeffrey G, Viswanatham K, Amy K, Kevin M, Kelly F, Rayna V, Sarajane R, Susan DS, Wai LW, Henry BL, Richard V, Mark XS, Richard HS, Paul P, William M. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat. Biotech. 2008, 26, 925–932. Google Scholar
Bjorn G. Despite potential side effects, two drugs make a comeback. Nat. Med. 2008, 14, 226. Google Scholar
Venkata NK, Swathi SK, Thirumal M. Recent advances in smart drug delivery systems. Int. J. Novel Drug Deliv. Technol. 2011, 1, 3. Google Scholar
Odiba AS, Wannang N, Joshua EP, Iroha OK, Ukegbu CY, Onosakponome KI, Chukwunonyelum I, Anunobi OO. Curing HIV-1 infection via in vitro ultra-sensitive modification of HIV-1 uninfected CD4+ cells using antiviral agents. Adv. Life Sci. Technol. 2014, 24, 15–20. Google Scholar
Stephanie D, Horacio C, Takehiko I, Yutaka M, Shutaro K, Takashi Y, Akira, Yuji M, Nobuhiro N, Kazunori K. Phenylboronic acid-installed polymeric micelles for targeting sialylated epitopes in solid tumors. J. Am. Chem. Soc. 2013, 135, 15501–15507. Google Scholar
Lin Z, Tao W, Federico P, Anton T, Vladimir PT. Enhanced anticancer activity of nanopreparation containing an MMP2-sensitive PEG-drug conjugate and cell-penetrating moiety. J. Am. Chem. Soc. 2013, 110, 17047–17052. Google Scholar
Guizhi Z, Rong H, Zilong Z, Zhuo C, Xiaobing Z, Weihong T. Noncanonical self-assembly of multifunctional DNA nanoflowers for biomedical applications. J. Am. Chem. Soc. 2013, 135, 16438–16445. Google Scholar
Shreyas S, Aniruddh S, Pijus KS, Ki-Bum L. Single vehicular delivery of siRNA and small molecules to control stem cell differentiation. J. Am. Chem. Soc. 2013, 135, 15682–15685. Google Scholar
Xiaoyang X, Kun X, Xue-Qing Z, Eric MP, Ga YP, Danica SC, Jinjun S, Jun W, Philip WK, Stephen JL, Robert L, Graham CW, Omid CF. Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug. Proc. Natl. Acad. Sci. 2013, 110, 18638–18643. Google Scholar
Elina ZK, Racheli G, Itzhak HR, Elad H, Zivia B, Ariel O, Adva S, Talia G, Abraham JD, Eylon Y, Hilla G, Ludmila R, Alina S, Rami E, Abed K, Ayala H, Maor L, Yael K, Eran G, Alan D, Yael H, Sagit A, Rinat A, Edgar D, Ingrid TC, Erica MWL, Juan V, Hao L, Laura EE, Adam RR, Matthew B. Mutant KRAS is a druggable target for pancreatic cancer. Proc. Natl. Acad. Sci. 2013, 110, 20723–20728. Google Scholar
Edgar D, Ingrid TC, Erica M, Lauterwasser W, Juan V, Hao L, Laura EE, Adam RR, Matthew B. Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo. Proc. Natl. Acad. Sci. 2013, 110, 18244–18249. Google Scholar
Xianglong H, Jinming H, Jie T, Zhishen G, Guoying Z, Kaifu L, Shiyong L. Polyprodrug amphiphiles: hierarchical assemblies for shape-regulated cellular internalization, trafficking, and drug delivery. J. Am. Chem. Soc. 2013, 135, 17617–17629. Google Scholar
Eric MP, Frank A, Timothy TK, Etgar LN, Rohit K, Richard SB, Robert L Omid CF, Omid CF. Transepithelial transport of Fc-targeted nanoparticles by the neonatal Fc receptor for oral delivery. Sci. Transl. Med. 2013, 5, 213ra167. Google Scholar
Jens N, Bernd B, Ludovic C, Eduard U, Hadassah S, Peter M, Petra R, Jan OS, Wilma L, Alain CT, Hansruedi L, Anirvan G, Per-Ola F. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron 2014, 81, 49–60. Google Scholar
Brian PT, Manuel A, Sahadev AS, Brian M, Obiajulu SO, Boaz M, Cristina FS, Leyre G, Jia Z, Angela Z, Jesus S, Robert L, Daniel SK. Near-infrared-actuated devices for remotely controlled drug delivery. Proc. Natl. Acad. Sci. 2014, 111, 1349–1354. Google Scholar
Nga BL, Joy YY, Daniela B, Justin E, Andrew BC, Yin Z, Wilman L, Yanmei L, Mark SD, Robby MW, Inhee C, Ryan JW. Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants. J. Exp. Med. 2014, 211, 233–244. Google Scholar
Surojit S, Anja CF, Kenneth WK, Shibin Z, Bert V. Remote loading of preencapsulated drugs into stealth liposomes. Proc. Natl. Acad. Sci. 2014, 111, 2283–2288. Google Scholar
Zhenjia W, Jing L, Jaehyung C, Asrar BM. Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils. Nat. Nanotechnol. 2014, 9, 204–210. Google Scholar
Ran M, Tianyue J, Zhen G. Enhanced anticancer efficacy by ATP-mediated liposomal drug delivery. Angew. Chem. Int. Ed. 2014, 53, 5815–5820. Google Scholar
Stephen WM, Michael JL, Zhou JD, Erik CD, Elise S, Kevin ES, Nisarg JS, Michael BY, Paula TH. A nanoparticle-based combination chemotherapy delivery system for enhanced tumor killing by dynamic rewiring of signaling pathways. Sci. Signal. 2014, 7, ra44. Google Scholar
Xiaochen AW, Chung Hang JC, Chuan Z, Liangliang H, Chad AM. Intracellular fate of spherical nucleic acid nanoparticle conjugates. J. Am. Chem. Soc. 2014, 136, 7726–7733. Google Scholar
Nathaniel H, Cathal JK, Xuanhe Z, Jaeyun K, Christine AC, Zhigang S, David JM. Ultrasound-triggered disruption and self-healing of reversibly cross-linked hydrogels for drug delivery and enhanced chemotherapy. Proc. Natl. Acad. Sci. 2014, 111, 9762–9767. Google Scholar
Phil O, Jacqueline ET, Per B, Halina W, Yan Li, Jan ES. In vivo proteomic imaging analysis of caveolae reveals pumping system to penetrate solid tumors. Nat. Med. 2014, 20, 1062–1068. Google Scholar
Yevgeny B, Eduardo AS, Cathal JK, Sarah AL, Alex M, Kathleen DM, Michael A, David JM. Refilling drug delivery depots through the blood. Proc. Natl. Acad. Sci. 2014, 111, 12722–12727. Google Scholar
Xiaoli L, Amy ER, Bradley LP. Delivery of antibody mimics into mammalian cells via anthrax toxin protective antigen. ChemBioChem. 2014, 15, 2458–2466. Google Scholar
Francesca T, Silvia M, Bruna C, Iman KY, Marta AB, Jeffrey LVE, Massimo A, Ennio T. Potential avoidance of adverse analgesic effects using a biologically. J. Pharm. Sci. 2014, 103, 3724–3732. Google Scholar
Parmentier J, Hofhaus G, Thomas S, Cuesta LC, Gropp F, Schröder R, Hartmann K, Fricker G. Improved oral bioavailability of human growth hormone by a combination of liposomes containing bio-enhancers and tetraether lipids and omeprazole. J. Pharm. Sci. 2014, 103, 3985–3993. Google Scholar
Muxun Z, Yarong L, Renee SH, Nova W, Wanyi T, Kye J, Pin W, Zhen G, Yi Tang. Clickable protein nanocapsules for targeted delivery of recombinant p53 protein. J. Am. Chem. Soc. 2014, 136, 15319–15325. Google Scholar
Li T, Xujuan Y, Qian Y, Kaimin C, Hua W, Isthier C, Catherine Y, Qin Z, Mincheol K, James AH, Iwona TD, Lawrence WD. Investigating the optimal size of anticancer nanomedicine. Proc. Natl. Acad. Sci. 2014, 111, 15344–15349. Google Scholar
Tengfei Z, Elizabeth MN. Enterobactin-mediated delivery of β-lactam antibiotics enhances antibacterial activity against pathogenic Escherichia coli. J. Am. Chem. Soc. 2014, 136, 9677–9691. Google Scholar
About the article
Arome Odiba is a biochemist [MSc in Biochemistry (Biomedicine Proteomics and Biotechnology), PhD in Human Genetic and Molecular Biology]. He is a research assistant at the University of Nigeria.
Chimere Ukegbu is a biochemist [MSc in Biochemistry (Pharmacology), PhD in Pharmacology]. He is a research assistant at the Department of Biochemistry, University of Nigeria.
Oluchukwu Anunobi is a biochemist [MSc in Biochemistry (Industrial Biochemistry and Biotechnology)] at the University of Nigeria. She is interested in cancer research.
Ike Chukwunonyelum is a biochemist [MSc in Biochemistry (Pharmacology)] and interested in the use of alternative medicine to cure microbial infections.
Juliet Esemonu is a biochemist [MSc in Biochemistry (Industrial Biochemistry and Biotechnology)] at the University of Nigeria and interested in nano-research as well as cancer research.
Published Online: 2016-01-21
Published in Print: 2016-04-01