Is there a niche for zinc oxide nanoparticles in future drug discovery?

KEYWORDS:

• Antibacterial
• anticancer
• zinc oxide
• cosmetic
• imaging
• nanoparticle
• toxicity

1. Synthesis, physicochemical, pharmacokinetic, and toxic properties

Zinc oxide (ZnO) exists in the nature as a mineral in the crust of the Earth and is the second most abundant mineral in the human body after iron. It has been recognized as GRAS (Generally Recognized as Safe) by FDA since ZnO nanoparticles >100 nm are considered biocompatible. ZnO is less toxic than other metal oxide nanoparticles such as Titanium dioxide (TiO₂₎, is inexpensive, and does not react with most pharmaceutical active ingredients, contributing to its advantageous potential as drug delivery material [1]. ZnO is luminescent, a semiconductor with a wide bandgap of excitation energy, and an alternative to Cadmium (Cd)-based imaging and therefore used to visualize tissues or cells besides its applications to electronics and optics. In fact, ZnO nanoparticles coated with Silicon dioxide (SiO₂) have been used as theranostic for imaging of cancer cells and delivery of anticancer molecule curcumin to these cells [2].

Several synthetic methods to obtain ZnO nanoparticles have been reported that result in different particle characteristics, including microwave decomposition, simple wet chemistry, deposition simple precipitation, hydrothermal synthesis, solvothermal method, and microwave hydrothermal method. However, it is noteworthy that most recent papers focus on the ‘green synthesis’ of ZnO nanoparticles using a plant source to facilitate the reaction [1,3].

Pharmacokinetic properties of ZnO nanoparticles of different size have been studied using different administration routes such as oral gavage, inhalation, intraperitoneal administration, intrathecal instillation, and dermal application. However, the biodistribution and in vivo fate can be altered using nanotechnology and administering ZnO in nanoparticulate form. Oral absorption is directly proportional to dose while particle size does not seem to have a significant effect contrary to surface charge, resulting in higher absorption for negatively charged nanoparticles. Tissue distribution is characterized by accumulation in liver, kidneys, and lungs for oral administration and liver, spleen, kidneys, lung, and heart for intraperitoneal administration independent of particle size. Major excretion route ‘s known to be through feces; however smaller particles are excreted via urine. Larger ZnO nanoparticles are excreted through feces independent of surface charge so clearance process begins sooner for smaller ZnO nanoparticles. Skin penetration is reported to be limited to the upper 1–2 layers of the stratum corneum after 48 h and is relativity lower when compared to titanium dioxide used in sunscreens like ZnO. Pulmonary clearance is biphasic with initial rapid clearance and slower terminal half-life for inhaled ZnO particles although 97% of ZnO is cleared on Day 7. Interestingly, zinc levels in thoracic lymph nodes and bone marrow are higher in coated (SiO₂) ZnO nanoparticles and skeletal muscle, skin, and blood levels are higher in uncoated ZnO nanoparticles [4,5].

Reported toxicities associated with the liver, lung, nervous system, and immune system are dose and exposure dependent. Accumulation risk is high in long-term high dose intake. Antibacterial activity of ZnO nanoparticles requires higher doses than that causing toxicity; therefore, disinfection with ZnO may be a risk for human use.

2. Pharmacological effects and therapeutic potential

ZnO nanoparticles associated with several biological effects could be the basis of therapeutic outcome. Among those reported in literature, antimicrobial activity is one of the most studied. The mechanism for the antimicrobial activity is based on reactive oxygen species (ROS) generation at the particle surface, release of zinc ion, and membrane dysfunction. Both antimicrobial and antibacterial activities are based on the generation of ROS on the surface of ZnO. Gram negative and positive spores resistant to high temperatures and high pressure can be killed with ZnO nanoparticles depending on both concentration and extent (exposure time). This activity is believed to result from generation of hydrogen peroxide and binding of particles to the surface of the bacteria with static forces. Particle size variation and surface area/volume ratio affect the antibacterial activity [1].

Anticancer activity of the ZnO nanoparticles is attributed to the selective antiproliferative effect. Although the mechanism of this selective anticancer activity is unclear, hypotheses include generation of ROS-inducing apoptotic pathways by releasing apoptotic factors from the mitochondrial intermembrane space leading to formation of apoptosomes that activate enzymes leading the cell to death. ZnO is prone to rapid dissolution at acidic media, i.e., lysosomes after uptake in particulate form. Wiesmann et al. [6] explained the anticancer potential of ZnO nanoparticles first by their positive charge under physiological conditions, facilitating interaction with negatively charged tumor cell due to Warburg effect. ZnO nanoparticle release Zn2⁺ ion in the body affecting intracellular zinc homeostasis, and this release is easier in acidic environment of the tumor. The impact of ZnO on cytoskeleton and cellular membranes and cellular uptake is based on redox equilibrium and interaction of Zn with DNA and RNA.

Several studies are published on the antifungal, anti-inflammatory, and wound-healing properties resulting from the strong antimicrobial activity and epithelialization stimulating effect. A very interesting biological effect of ZnO nanoparticles is their role in the synthesis, storage, and secretion of insulin leading to an antidiabetic activity causing biochemical normalization of blood glucose levels and serum insulin levels in animal model [1]. A major efficacy of ZnO nanoparticles is reported in skin diseases based on antiseptic and antibacterial activity as well as typical use in sunscreen formulations with the broadest spectrum of UVA and UVB and completely photostable.

3. Applications as drug delivery system

Although the intrinsic pharmacological and biological effects of ZnO nanoparticles are well known, studies reporting ZnO nanoparticles as drug delivery systems are more recent and fewer. Most of these studies are based on the pH-dependent release properties of ZnO nanoparticles usually after coating with a polysaccharide or polymer. Some examples include oval, luminescent ZnO nanoparticles coated with PEG and β-cyclodextrin encapsulating curcumin with antibacterial and cytotoxic effects [7], self-assembling core-shell ZnO-methacrylate nanocapsules for the pH triggered release of isotretinoin [8], ZnO chelating with dopamine and coating top graphene oxide for pH responsive delivery of doxorubicin along with antibacterial activity [9], albumin grafted polycaprolactone coated ZnO nanoparticles loaded with cloxacillin for inhalation [10], red fluorescent ZnO nanoparticles grafted with polyglycerol and arginylglycyl aspartic acid RGD peptide for targeted doxorubicin delivery pH-dependent release properties to achieve selective cytotoxicity [11], highly selective and sensitive CaZnO stealth nanoparticles for the detection of SARS CoV-2 spike antigen [12], ZnO/polyvinylidene nanocomposite fiber as bone graft for osteoblast formation and antibacterial property [13], cross-linked ZnO-chitosan hydrogel bead loaded with model drug ibuprofen and cross-linked carboxymethyl cellulose/ZnO pH-sensitive hydrogel bead to deliver model drug propranolol [14], phenyl boronic acid modified pH responsive ZnO nanoparticles for the targeting of overexpressed sialic acid receptors on the surface of non-small cell lung tumors for quercetin delivery in tumor-induced mice [15], layer-by-layer coated Poly(L-lysine)/ZnO/mesoporous silica nanoparticles with charge reversal property in vivo carrying doxorubicin in which ZnO blocks the pores of the mesoporous silica nanoparticle and is dissolved once inside the cancer cell [16], and superparamagnetic iron nanoparticles coated with aminated starch/ZnO tagged with folic acid for curcumin delivery to HepG2 and MCF7 cancer cells [17].

Drug delivery systems using ZnO as base material or coating tend to focus aim toward targeting and stimuli-sensitive release properties.

4. Expert opinion

Metallic drug delivery systems have not yet reached the patient bedside due to constraints about their narrow therapeutic index, possibility to accumulate in excretion organs, and lack of biodegradability which limits the repeated administration and chronic use for these inorganic materials. Introducing the nanotechnology element into the already questionable biological fate of metallic nanoparticles add up to the drawbacks of developing drug delivery systems based on metals.

However, ZnO provides a promising basis in drug delivery in the form of nanoparticle base material or coating. Importantly, the intrinsic antimicrobial, antibacterial, antifungal, and anticancer effects can cause synergism and potentiate the therapeutic effect of the ZnO-based drug delivery systems. The antidiabetic activity of ZnO nanoparticles is worth for further evaluation in combination with antidiabetic drugs used in clinics. Regarding formulation and manufacturing aspects in drug delivery, ZnO nanoparticles are easy to modify with diverse coatings (SiO₂, Polyethylene glycol (PEG), β-cyclodextrin (β-CD), phenylboronic acid, etc.) to enhance bioimaging and luminescence properties, evading of the immune system and reticuloendothelial system RES uptake and increasing the targeting ability to cancer cells with a relatively lower cost compared to other polymeric or polysaccharide nanomaterials.

It should be noted that ZnO is also a flexible coating agent to modify the release and intracellular uptake of other polymeric or inorganic nanoparticles. Currently, the most promising asset for ZnO nanoparticles in drug discovery and drug delivery would be the pH-dependent or pH-triggered bioactivity that could prove to be very beneficial in tumor targeting, oral drug delivery, and dermal drug delivery for skin diseases. Luminescent property of ZnO contributes to the drug delivery capability by rendering theranostic and imaging properties to drug delivery systems based on Zn²⁺. It is of my opinion that research based on nanoparticulate applications of ZnO could provide new developments in the drug delivery, especially for the diagnosis, imaging, and therapy of cancers.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.