1. Introduction
The evolution of nanoscale sciences and nanotechnology over the past two decades is responsible for the availability and growing prominence of the field of nanomedicine. Nanomedicine is a broad term to describe the use of devices or materials on the nanoscale (sizes in nm) to assess, diagnose, treat, or preserve health [ 1 ]. Applying nanomedicine could include modifying how drugs are delivered in the body as a means for optimization, using imaging for various purposes, and drug tracking within the body [ 1 , 2 ].
With the inception of nanomedicine, the community discovered the intrinsic ability of this science to circumvent some of the most fundamental shortcomings of traditional medicine, including off-target drug side effects, non-specific cell-targeting, and drug instability. Stemming from these advancements are the rapidly emerging novel formulations called nanopharmaceuticals and nanonutraceuticals [ 2 ]. Nanomedicine is at the forefront of anticancer medicine, owing to the potential to limit the aforementioned shortcomings of traditional medicine. Resistance to chemotherapy has been a major challenge in treatment, due to insufficient targeting and the presence of efflux pumps (p-glycoproteins (P-gp)) in the tumor that pumps out the chemotherapeutic agents. Nanoparticles (NPs) carry medications and have the ability to overcome resistance through specific targeting of tumor cells [ 3 ]. It is important to investigate the history and current knowledge of nanopharmaceuticals and nanonutraceuticals as a means to better understand the anticancer properties that these formulations hold and their potential in moving forward.
This review covers the current repertoire of nanopharmaceuticals and nanonutraceuticals that have been approved for cancer treatment or that exhibit extensively documented anticancer properties. We also give a brief summary of common nanoformulation techniques, their application potentials and limitations, as well as some novel developments in nanoscale formulations that show promise for future growth of nanopharmaceuticals and nanonutraceuticals.
2. Nanoformulations
The following nanoformulations are currently being widely studied in the medical community. Each one has specific advantages and disadvantages that make them unique. They all have applicability for use in cancer treatment or diagnosis. Some nano structures are better suited for certain types of drug delivery or tumor detection over others. Additionally, each of these existing drug delivery systems have paved the way for novel nanoformulations that have come to the forefront of studies in recent years.
Various nanoplatforms are being used, from liposomes over the past two decades to metallic NPs (iron and gold) in diagnosis to polymeric and solid NPs in targeted therapeutics, as highlighted below.
2.1. Liposomes
Conventional liposomes are spherical amphiphilic phospholipid vesicles, approximately 25 nm–2500 nm in size that can protect hydrophobic or hydrophilic materials from aqueous or non-aqueous environments, respectively, by forming a closed bilayer around the material [ 4 ]. This particular feature is beneficial for the delivery of both hydrophobic and hydrophilic chemotherapy to targeted sites. For mechanisms of delivery and composition, there are five classes of liposomes that can be utilized to optimize a product’s likelihood of achieving intended effects. These classes are pH-sensitive, cationic, conventional, long-circulating, and immuno-liposomes [ 2 , 5 , 6 ]. pH-sensitive liposomes stabilize when the external pH is altered, usually from a slightly alkaline or neutral pH to an acidic pH, which makes them stable at the physiological pH of 7.4 [ 7 ]. However, the pH-sensitive liposomes dissociate and release their content within the tumor, infected, or inflamed areas, which exhibit acidic properties [ 7 ]. Cationic liposomes are made using positively charged lipids and can interact with negatively-charged compounds in the body like DNA [ 8 ]. They can be used for the delivery of vaccines against cancer by loading synthetically long peptides into the liposomes to be delivered to dendritic cells, hence enhancing immune response [ 8 ]. Conventional liposomes were the first generation of liposomes and consist of a lipid bilayer. The bilayer can be neutral, cationic, or anionic phospholipids as well as cholesterol, which encompasses the aqueous volume [ 9 ]. The major disadvantage of conventional liposomes is their fast elimination from the blood. Long-circulating liposomes are generated by coupling of biocompatible polymers like polyethylene glycol (PEG) to the liposomal surface that protects the liposome from being cleared rapidly from the body [ 9 ]. Immuno-liposomes are created by attaching antibodies to the surface of the liposome. Such alteration in the liposomal structure allows for specific tissue targeting by binding to receptors specific to tumor cells [ 10 ].
Liposomal formulation is limited by its instability, poor solubility, high cost of production, and potential leakage of contained drug [ 4 ], though with recent advancements these issues are improving dramatically [ 11 ]. Liposomes have proven to be an efficacious and safe drug delivery system that is both biocompatible and biodegradable and does not have a risk of immunogenicity or toxicity [ 12 ]. They serve as a scaffold for carrying drugs and imaging agents, thereby increasing the circulation half-life and achieve targeting specificity. Doxorubicin HCL liposome (Doxil) is an example of a successful liposomal nano-anticancer agent used in the treatment of ovarian cancer, multiple myeloma, and AIDS-related Kaposi’s sarcoma [ 13 , 14 ]. Doxorubicin is a hydrophilic drug that is encapsulated inside the aqueous core of a liposome. The utilization of nanomedicine to deliver doxorubicin not only prolongs the half-life and increases the concentration of doxorubicin in tumor cells, but also leads to significant reduction in adverse events like cardiotoxicity because doxorubicin as Doxil is not bioavailable to cardiac cells [ 13 ].
Liposomes can also be used for imaging and have shown potential as contrast agents for magnetic resonance imaging (MRI) in in vivo studies [ 15 ]. Liposomes can serve as a vessel to deliver MRI paramagnetic contrast agents, such as gadolinium, thus increasing contrast specificity to parts of the body that are of interest and thereby reducing systemic toxicity [ 16 ].
2.2. Polymeric Micelles
Polymeric micelles (PMs) are amphiphilic block copolymers with an average diameter of 10–100 nm that arrange via self-aggregation into nanoscale core-shell structures [ 17 ]. The core consists of a dense hydrophobic region and the shell consists of hydrophilic co-polymers. PMs vary in their stability in blood and in drug release rate, and they may be tweaked by the choice of chemical linkage to their surface, e.g., esters [ 18 ]. The most widely studied copolymers are poly(ester)s, poly(L-amino acid)s, and poly(propylene oxide) [ 19 ]. Having a hydrophilic surface protects them from non-specific uptake, which allows this formulation to be used for systemic delivery of hydrophobic chemotherapeutic agents [ 20 ]. Another attractive quality of PMs owing to their hydrophilic shell and nanoscopic size is that mechanical clearance of the micelles by renal filtration, reticuloendothelial system (RES) uptake, and/or by the spleen is prevented, allowing for prolonged circulation in the blood [ 21 ]. An example of a PM-formulated anticancer drug is Genexol-PM, a PM formulation of paclitaxel [ 22 ]. Paclitaxel is a poorly water-soluble chemotherapeutic agent used in the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and AIDS-related Kaposi’s sarcomas [ 23 ]. In order to solubilize paclitaxel, it is often formulated in Cremophor EL (polyoxyethylated castor oil), which can lead to hypersensitivity reactions and requires pre-medication with diphenhydramine, corticosteroids, and H2 antagonists [ 23 ]. Genexol-PM overcomes the hypersensitivity reaction and has been approved in Korea for the treatment of advanced lung cancer and metastatic breast cancer [ 22 ].
2.3. Dendrimers
Dendrimers are tree-like branched-structure polymers whose shape and size are easily influenced and controlled via polymerization reactions. Branched nanostructures form around a spherical core with the ends of the dendrimers available for conjugation and molecule attachments [ 24 , 25 ]. Utilizing this structure permits drug and gene delivery (i.e., DNA/RNA) specificity as well as size and weight of molecule specificity, with exceptional entrapment efficiency. The high level of architectural control over dendrimers’ structure makes them compelling in various settings, including chemotherapy with reduced cytotoxicity, gene therapy, immune system stimulation, increasing bioavailability, and as contrast agents for MRI [ 25 ]. Like liposomes, dendrimers can increase the solubility and bioavailability of water-insoluble agents by either encapsulating the drug/oligonucleotide in their internal cavities or attaching them though electrostatic or hydrophobic interactions to their surface [ 26 ]. Dendrimers can also serve as vehicles to transport nucleic acid-based chemotherapies, which are hydrophilic molecules that cannot easily penetrate the cell membrane [ 26 ].
2.4. Quantum Dots
Quantum dots (QDs) are semiconducting materials in nanocrystal form, 2–10 nm in size, with an inorganic core and an organic-coated shell [ 27 , 28 ]. QDs can emit fluorescence when stimulated by light. This unique characteristic of QDs makes them a useful technology in imaging and tracking of intracellular processes [ 29 , 30 ]. QDs can accumulate in tumor tissue, allowing for tumor visualization and non-invasive diagnosis [ 30 ]. QDs have shown promising results when studied in vitro for rapid localizations of HER-2 receptors and for targeted chemotherapy and imaging-guided therapy [ 31 ].
2.5. Additional Novel Formulations
Adding to the commonly used formulations discussed above, Table 1 lists additional novel formulations, their size, and a brief summary of their characteristics and application potential.
3. Nanopharmaceuticals
The creation of nanotechnology birthed limitless potential in many fields. Most relevant for this review is the field of nanomedicine. Specifically, in cancer therapy this technology has allowed a choice of formulations with benefits that were previously unavailable. These benefits include targeting tumor cells, initiation of apoptosis, and accumulation of drug in specific tissue for increased exposure to cancer cells. Formulation of existing pharmaceuticals into the nanoscale has decreased toxicity and increased cell specificity. Table 2 summarizes nanopharmaceuticals that have been approved for the indicated applications. The success of these nanopharmaceuticals has proven the legitimacy of this technology and its potential in the field of oncology, a field that has been particularly limited by many obstacles, such as costs of development, regulatory frameworks, applicability of test protocols, and mechanisms to test for safety/efficacy [ 83 ]. As nanomedicine has matured, there has been vast commercialization of related technology, including hardware and software that can be used to create and customize these nanoformulations with reproducible quality and quantity in modest-sized lab settings [ 84 ].
Active nano-targeting for tumor-targeted delivery could be achieved using high-affinity ligand for a unique target that is overexpressed by cancer cells and their associated microenvironment, such as the case with integrin αvβ3, PSMA, or CD44 for delivery of chemotherapy into specific tumors [ 85 , 86 , 87 , 88 , 89 , 90 , 91 ]. Nanotechnology has been studied in vitro and in vivo to potentially restrict the action of the anti-angiogenic agent, diamino tetraiodothyroacetic acid (DAT) to the integrin avβ3 by conjugating DAT to PLGA NPs, forming DAT-conjugated PLGA (NDAT). The results of the study showed that nanotechnology allows for more specific tumor targeting, thereby allowing the use of lower doses of the toxic chemotherapeutic regimens [ 85 ]. Similarly, theranostic nanocarriers (folate-HBPE (CT20p)) were studied in the delivery of therapeutic peptide (CT20p) to allow for a more selective toxicity to prostate cancer cells that express PSMA. The results of the in vivo study indicated that nanocarriers can significantly and selectively facilitate tumor reduction [ 86 ]. Similar promising results were also shown in other studies, for example in the use of docetaxel nano-targeted delivery for the treatment of prostate cancer, use of NDAT for the targeted delivery of paclitaxel, cisplatin, and doxorubicin in tumor xenografts and in the delivery of toremifene in prostate cancer [ 87 , 88 , 89 , 90 , 91 ].
4. Nanonutraceuticals
Nutraceuticals are typically defined as pharmaceutical-grade standardized nutrients derived from food sources that, in addition to providing basic nutrients, also provide extra health benefits [ 92 ]. They mainly differ from non-pharmaceuticals in that they do not provide a pharmacologically active ingredient and instead deliver nutritional supplementation for medicinal purposes [ 93 ]. There has been widespread growth in the use of phytochemicals in nutraceuticals [ 94 ].
Phytochemicals are the naturally occurring chemicals in many plants that exhibit biologically active characteristics, including plant growth or defense. Many of these phytochemicals have been studied for centuries for their wide-ranging effects and medicinal value [ 94 ]. Phytochemicals like flavonoids suppress oxidative stress-induced DNA damage, primarily through their antioxidant properties, and thus they play a role in cancer chemoprevention [ 95 , 96 ]. Another example is the use of indoles found in cabbage that reduce the effects of estrogen and hence reduce the risk of developing breast cancer [ 97 ]. Capsaicin, found in chili pepper, is believed to protect DNA from carcinogens [ 98 ]. Formulating these nutraceuticals on the nanoscale, similarly to nanopharmaceuticals, may allow more pronounced and targeted effects that were previously unachievable.
Nutraceuticals derived from phytochemicals that have been studied for their potential anticancer properties exhibit promising results. Table 3 is a comprehensive list of phytochemicals that have been nano-formulated and studied in the corresponding cancer models. Moving forward, this subgroup of nanomedicine has great potential for growth because the major limiting characteristics of nutraceuticals, such as poor bioavailability and limited absorption in the gastrointestinal tract, can be overcome [ 99 ]. As the trend of seeking natural alternatives for prescription medications continues to grow, the younger, less-explored field of nanonutraceuticals may prove to be the lowest hanging fruit of all.
The physicochemical properties of phytochemicals such as polyphenols, phytosterols, carotenoids, vitamins, and minerals have a number of limitations, such as solubility, stability, and permeability, which could be improved using biodegradable nano assembly systems such as PLGA, chitosan, and natural fatty acids. Nanoformulation of natural bioactive compounds or natural extracts has demonstrated improved bio-accessibility/bioavailability. Different nanonutraceuticals demonstrated improved pharmacokinetic and pharmacodynamic properties that could facilitate their transition into pharmaceuticals and nanopharmaceuticals [ 125 , 174 , 175 , 176 , 177 , 178 ].
5. The Promising Future for Oncology with Nanomedicine
There are innumerable limitations when it comes to oncologic therapy. Most often cited is the lack of targeting and cell specification that leads to exaggerated negative side effects. These side effects are typically detrimental to patients’ health and can have a significant impact on quality of life. Using nanotechnology with enhanced tumor targeting capabilities may significantly save patients from immense pain and suffering and will combat multi-drug resistance and enhance tumor killing [ 179 ].
Nanotechnology has much potential in that it could be used for cancer diagnosis, treatment, and potentially the development of vaccines. Nanotechnology allows for more sensitive diagnosis of cancer by targeting specific cancer biomarkers, such as exosomes, cancer-associated proteins, circulating tumor DNA, and tumor cells [ 180 ]. Nanotechnology has been extensively studied in laboratory settings, however clinical data are often lacking. There are multiple ongoing trials looking at the use of nanotechnology in increasing the sensitivity and specificity of cancer diagnosis. A phase 1 trial is currently evaluating the use of ultrasmall silica particle in brain tumor imaging in humans [ 181 ]. This is the first human trial evaluating silica NPs in brain cancers. Understanding the mechanisms of distribution and excretion of the silica NPs in humans would be beneficial in future targeted oncological therapies. Carbon NPs are being studied as lymph node tracers in colorectal cancers to assess whether carbon NPs can increase lymph node yield after surgery [ 182 ]. Ferumoxytol-iron oxide NPs magnetic resonance is being evaluated as a potential tool to gain insights about the spread of cancers [ 183 ]. Another study evaluated the use of nanosensors in the diagnosis of gastric diseases [ 184 ]. Nanochip technology is also being studied as a potential tool for monitoring treatment response and detection of relapse in patients with diffuse large B-cell lymphomas [ 185 ]. As clinical research continues, we will see nanotechnology flourish in the field of oncology to aid in diagnosis and treatment.
6. Challenges and Promises in the Advancement of Nanoproducts (Nanomedicine)
Challenges facing the delivery of NPs carrying anticancer drugs to solid tumors include tumor microenvironments, matrix barriers such as fibrosis, collagen, and other matrices, tumor heterogeneity with variable vasculature, and the poorly vascularized tumor core. Current research in NP-based tumor drug delivery is focused on “active” targeting of NPs to the target rather than the traditional “passive” targeting through the enhanced permeability and retention (EPR) system.
Nonpharmaceutical formulations have distinct challenges from conventional pharmaceutical products that make their development more challenging. Cost of production of nanopharmaceuticals poses an important challenge. Nanopharmaceuticals are highly complex molecules that require careful selection of shape, vehicles, inorganic materials, and optimization of pharmacokinetic parameters to meet therapeutic needs and proper storage. Large-scale production of nanotherapeutics require high-efficiency equipment, time, and space. The higher the complexity of the desired nonpharmaceutical, the higher the cost of production and cost of acquisition. The cost-effectiveness of developing nanopharmaceuticals/nanonutraceuticals must be taken into consideration [ 186 , 187 ]. To justify their cost of production, a carefully planned and well-designed manufacturing process is going to be essential [ 188 ]. If careful manufacturing planning is not completed, reliability of nanotechnology in cancer diagnosis and treatment may be compromised. For example, there are various factors that affect the NP detection signaling and thus the sensitivity and specificity of cancer detection [ 189 ]. Manufacturing might not be an issue for all approved products that were aimed at passive targeting, but it might represent a challenge for active nano-targeting where there is a need to chemically conjugate the targeting moiety (small molecule, antibody, or aptamer) to the nanoplatform and then load the drugs to be delivered into the tumor and its microenvironment. However, those challenges can also be overcome. An example of such success is the case with BIND-014, a PSMA-targeted ACCURIN containing docetaxel, in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. BIND-014 was clinically active and well-tolerated and the study met its primary endpoint, with 71% of patients achieving relative progression-free survival of at least six months. Unfortunately, the success rate for phase 3 trials was a mere ~14%, with failures stemming from lack of efficacy [ 190 , 191 ].
Physiochemical properties of the NPs such as shape, size, surface charges, surface ligands, absorption, distribution, metabolization, and excretion play a role in potential toxicity in the human body. Moreover, long-term toxicity from prolonged NP exposure (e.g., from nano-based imaging and treatment) cannot be fully and quickly known from in vivo studies [ 188 ].
Another important challenge to consider is FDA regulation of nanopharmaceuticals/nanonutraceuticals. Currently, the FDA approach to reviewing nanopharmaceuticals is the same as products that do not contain nanomaterials. Complexity and diversity of nano formulations is increasing significantly and thus the regulatory structure set forth by the FDA seems inadequate. Challenges involving safety, efficacy, and proper labeling are likely to arise [ 188 , 192 , 193 ].
Despite these challenges, nano-delivery of approved or new novel anticancer mechanisms holds great promise in the improved management of cancer and other disorders [ 194 , 195 , 196 , 197 , 198 ]. Nanoparticle-based drug delivery improves efficacy, solubility of hydrophobic drugs, half-lives of unstable compounds and proteins, and allows controlled and targeted release of drugs at the tumor site and its microenvironment. Ultimately, the integration of various enabling technologies and cross-collaboration with multidisciplinary theoretical and experimental scientists across academia and the pharmaceutical industry will accelerate these developments from the bench to the bedside and eventually to the market. Effective and safe cancer management continues to be a major issue in achieving improved survival and quality of life, because most anticancer drugs are cytotoxic and have a narrow therapeutic index.
7. Moving Forward Toward the Adaption of Nanomedicine toward Precision Medicine
Several nanopharmaceutical products in cancer and non-cancer indications are progressing at various stages of clinical development with great promises to improve the efficacy and safety of existing or new and novel compounds [ 199 ]. Clearly nanomedicine has provided recent success in drug delivery and tumor targetability that will increase the adaption of nanoproducts in cancer and beyond in the upcoming 2020–2030 decade. Nano-targeted delivery of active pharmaceuticals or biopharmaceuticals into the tumor site and its microenvironment should improve efficacy and safety as well as bypass hepatic pharmacogenomic variability in drug metabolism, allowing for better precision medicines in cancer and beyond.
8. Conclusions
The once hypothetical visions of what nanotechnology had to offer nanomedicine, specifically in the subgroups of nanopharmaceuticals and nanonutraceuticals, are now becoming reality. With the extensive investments that have been put into nanomedicine over the past two decades, there have been groundbreaking discoveries that paved the way to the approvals of many nanopharmaceuticals, with many more currently in process. In recent years, billions of dollars have been fronted to create academic institutes dedicated to the study of nanotechnology, and thus scientists are flocking to the field, with many dedicated to the study of nanomedicine. As nanomedicine continues to prove its value and legitimacy, nanoformulations of pharmaceuticals and nutraceuticals should continue to grow prolifically. Oncology, in particular, has many obstacles to overcome, because current treatment options are less than ideal. Thus, the options for oncology therapeutics are just beginning to propagate as the gold rush to nanomedicine matures. It is, however, important to remember that although nanotechnology holds great potential, it may not be the answer to curing all cancers.
Funding
This research received no external funding.
Conflicts of Interest
S.A.M. holds stock in NanoPharmaceuticals LLC, which is developing anticancer drugs. All other authors declare no competing financial interest.
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