While most microstructure materials have similar properties as the corresponding bulk materials, the properties of materials with nanometer dimensions are significantiy different from those of bulk materials (Cao et al., 2013). The nanometer size of the nanomaterials renders them: (1) large fraction of surface atoms; (2) high surface energy; (3) spatial confinement; and (4) reduced imperfections, which normally do not exist in the corresponding bulk material.

At the nanometer scale, properties become size-dependent, which include: (1) chemical properties – reactivity, catalysis; (2) thermal properties – melting temperature; (3) mechanical properties – adhesion, capillary forces; (4) optical properties – absorption and scattering of light; (5) electrical properties – tunneling current; and (6) magnetic properties – superparamagnetic effect.

As the particle size gets smaller for nanometer particles, the ratio of the surface atomic number to the total number of atoms increases sharply (Jacobs et al., 1997). The surface-to-volume ratio (and consequently the fraction of the surface atoms with respect to the bulk ones) also increases (Issa et al., 2013). The large surface-to-volume ratio of the NPs is the key factor to the novel physical, chemical and mechanical properties compared to those of the corresponding bulk state. The surface area to volume ratio in NPs has a significant effect on the particle properties. As particle size decreases, a greater portion of the atoms are found at the surface compared to those inside, which results in NPs having a much greater surface area per unit volume compared with larger particles. It leads to NPs being more chemically reactive meaning that a given mass of material in nanoparticulate form will be much more reactive than the same mass of material made up of larger particles (Buzea et al., 2007).

One of the most direct effects of reducing the size of materials to the nanometer range is the appearance of quantum effects due to the confinement of the movement of electrons. This leads to discrete energy levels depending on the size of the structure. When the size of a particle is smaller than the de Broglie wavelength, electrons and holes are spatially confined and electric dipoles are formed, and discrete electronic energy levels would be formed in all materials. Once particles get so small, the quasi-continuous assumption for the Fermi-Dirac probability distribution is no longer valid and the energy levels must be considered discrete for the electrons because different mechanisms take precedence, resulting in a different phenomenon such that the oxidation, reduction and catalytic properties change (Ekimov et al., 1993). Early in 1996, Volokitin et al. (1996) had already confirmed that quantum size strongly influences the thermodynamic properties of metallic NPs. Following this line, artificial structures with properties different from those of the corresponding bulk materials can be created.

Owing to a large number of active atoms on the surface, NPs have specific surface adsorption, dispersion, aggregation, rheological properties and viscosity of colloidal suspension properties (Spampinato et al., 2015). Normally, the NPs are chemically more active than those of the corresponding bulk material are (Luo et al., 2006). As Li and Zhu (2006) reported the high chemical reactivity of silver (Ag) NPs with hydrochloric acid and characterized by X-ray powder diffraction gives direct evidence of the reaction, which has been proven impossible for the bulkAg.

NPs are small in size but large in surface area, which is excellent support for active catalytic activity (Zhang and Fu, 2013). Normally, NP catalytic activities are quite different from the traditional catalysts. Metal NPs dispersed on an oxide support often show a much higher catalytic activity than the single-component NPs (Lee et al., 2010b). Poreless nanometer catalysts can avoid the use of conventional means when the reactants to the pore diffusion, which are not attached to the inert carrier, can go directly into the liquid phase of the reaction system (Trovarelli, 1997).

The optical properties of metal NPs have been of interest in physical chemistry for a long time. NPs often possess unexpected optical properties, as they are small enough to confine their electrons and produce quantum effects. For example, gold NPs appear deep red to black in solution (Mandal, 2012). Depending on the size of the smallest feature, the interaction of light with structured materials can be very different. The coupling between several metallic NPs can induce a field enhancement in the surrounding media, which can increase phenomena such as scattering, absorption, luminescence or Raman scattering (Berginc, 2011).

NPs also have higher hardness, higher plasticity, higher specific heat and thermal expansion, higher conductivity, higher diffusivity, lower sintering temperature and sintering shrinkage than large ones (Zhang et al., 2013a). Other properties unique among NPs include surface plasmon resonance in some metal particles and superparamagnetism in magnetic materials (Chen et al., 2015d; Estelrich et al., 2015; Hussein-Al-Ali et al., 2014; Skopalik et al., 2014), which makes them desirable as a magnetic-targeting tool for medical applications.

In this paper, we use the words “potential applications” meaning at present most of the research evidence for nanomaterials used in nanomedicine is from cell culture or animal experiments. As Marchal et al. (2015) pointed out: “The hope raised by promising preclinical studies has often resulted in disappointment when nanomedicines have been applied in patients.”

Disease diagnosis is a very important part of clinical medicine, and accurate and high precision of diagnosis is an important requirement for effective treatment. NPs can be smaller than red blood cells. After the NPs have been injected into the bloodstream, it can free flow in the blood vessels and be transported to various parts of the body. In this way, NPs can be used as a means of monitoring and diagnosis of diseases. Studies indicate that nanotechnology has brought a rapid development of diagnostic technology in medical fields, which can be mainly classified into the following aspects.

With the mutual infiltration of nanoscience and modern technology, nanomaterials are widely investigated in the medical field for drug delivery (Xing and Zhang, 2004). Drug delivery focuses on maximizing bioavailability both at specific places in the body and over a period of time, which can potentially be achieved through molecular targeting by nanoengineered carriers (Drbohlavova et al., 2013). Compared with traditional drugs,drugs carried by nanocarriers have the following characteristics.

Instead of macro-level conventional instruments, nanomedical instruments can be designed at micro-levels for disease diagnosis or treatment. Dramatically, nanotechnology may bring us new instruments to examine tissue in unprecedented detail. Sensors smaller than a cell may give us an insight and exquisitely precise look at ongoing functions of the human body (Merkle, 1996).

Gene therapy by means of nanotechnology can be simply defined as nanogene medicine. Exogenous genes and their construction are mostly DNA molecules of nanometer size. Technology using nanocarriers to deliver these exogenous genes into the receptor cells belongs to nanogene medicine (Wu et al., 2016). Biodegradable and biocompatible polymeric nanocarriers due to unique properties such as excellent biocompatibility, prolonged gene circulation time, prevented gene degradation, passive targeting by using the enhanced permeability and retention effect, and possibly modulating polymer structure to obtain desirable therapeutic efficacy, are considered as the most promising gene delivery vehicles (Mokhtarzadeh et al., 2016). For example, lipid NPs, called liposome protamine/DNA lipoplex (LPD), are used for ocular gene delivery (Wang et al., 2015b). Recently, there have been promising results achieved with LPD NPs to deliver functional genes and microRNA to treat retinal diseases (Rajala et al., 2014; Takahashi et al., 2015). Some advantages of these peptide-modified LPD NPs might be: (1) liposome NPs are able to deliver large molecular cargo; (2) optimization of peptide-modified LPD NPs allows multiple mutant genes to be simultaneously co-delivered to one vector; and (3) peptide-modified LPD NP formulations are more biocompatible and safe (Wang et al., 2015b). Polyak et al. (2016) tried using systemic delivery of siRNA by another novel nanocarrier, aminated poly(α) glutamate, for the treatment of solid tumors in an ovarian adenocarcinoma-bearing mice model. They found that it is an efficacious and safe anticancer siRNA delivery vehicle following systemic administration. An anticancer siRNA, siPlk1-polyplex, delivered by this nanocarrier, inhibited tumor growth by 73% and 87% compared with siCtrl-polyplex or saline-treated mice, respectively, leading to prolonged overall survival.

In summary, although certain progress has been achieved in nanogene medicine, it is still in the early developmental stage.

As stated above, gene therapy has emerged as an alternative for the treatment of diseases (Mastorakos et al., 2015). One of the advantages of nanotechnology is the feasibility to construct therapeutic particles that carry multiple therapeutics with a defined structure and stoichiometry. Accordingly, the field of RNA nanotechnology is emerging (Chen et al., 2015a; Guo, 2010; Roh, 2012; Shukla et al., 2011). However, controlled assembly of stable RNA NPs with multiple functionalities, which retain their original role, is challenging due to refolding after fusion. Researchers at MIT and Harvard Medical School have developed a new kind of NP delivery systems by using siRNA delivery to tumor cells, which can eliminate tumors by destroying the mRNA (Dahlman et al., 2014). The outside of this kind of NP has a layer of membrane and inside is a mixture of siRNA and protein. After entering into the tumor cells, NPs with a protein and siRNA mixture can destroy the targeted mRNA. Ren et al. (2012) found that most of the tumors can be eliminated in ovarian tumor-bearing mice by using RNAi (RNA interfere) NP treatment. Scientists at the University of Kentucky have developed thermodynamically stable X-shaped RNA NPs for carrying therapeutic RNA motifs by self-assembly of re-engineered small RNA fragments, which is considered useful for cancer treatments at the RNA and DNA level (Haque et al., 2012).

Nanovaccine is a novel approach for vaccinations (Zaman et al., 2013). It consists of nano-sized particles of a biodegradable polymer, which encapsulates an antigen of a pathogen, or the active ingredient. Nanovaccines are more efficient than conventional vaccines in that they induce both a humoral and a cell-mediated immune response. Most nanovaccines are noninvasive, delivered by oral or nasal routes, thus allowing no-pain delivery with minimal damage. In addition, nanovaccines can control the delivery of the associated antigens to a specific location and for prolonged times (Cordeiro et al., 2015). No-pain delivery might be the biggest advantage of nanovaccines over conventional vaccines, which are usually multi-injection and multi-dose delivery systems (Nandedkar, 2009). The disadvantages of nanovaccines may include difficulty in reproducibility of formulation during manufacturing (Sharma et al., 2009) and potentially toxicity induced by a prolonged clearance time of the NPs in the body. Therefore, evaluation of the safety of nanovaccines should be equally essential as the study of their efficacy (Nandedkar, 2009). Nanomaterials can be used for nanovaccines including natural nanocarriers (i.e. as bacterial spores, virus-like particles, exosomes and bacteriophages) and synthetic nanocarriers (i.e. proteosomes, liposomes, virosomes, SuperFluids and nanobeads) (Gill, 2013). Nanomaterials are frequently evaluated as the nanocarriers for nanovaccines, which are in the experimental stage at present, including liposomes (Ghaffar et al., 2014; Hu et al., 2014; Marasini et al., 2016), polysaccharide (Cordeiro et al., 2015; Vicente et al., 2014), polyanhydride (Carrillo-Conde et al., 2011; Chavez-Santoscoy et al., 2012), polymeric (Guo et al., 2015b; Vicente et al., 2013), chitosan (Danesh-Bahreini et al., 2011; Doavi et al., 2016; Hunsawong et al., 2015) and silica NPs (Mahony et al., 2014; Mody et al., 2015), etc.

Nanovaccines stimulate the human body’s immune system curing infections, preventing infections and diseases from spreading (Zaman et al., 2013) and possibly promising chronic disease treatments, such as cancers (Nandedkar, 2009; Paulis et al., 2013), HIV (Vela Ramirez et al., 2014), influenza (Petukhova et al., 2013) and others.

Along with the rapid development of nanotechnology, the potential value of NPs as novel radiosensitizers in radiation therapy has been investigated in recent years (Su et al., 2014). Radiation therapy is one of the most commonly used non-surgical interventions in tumor treatment but is often hindered by low efficacy (Bergs et al., 2015). Research evidence shows that NPs can enhance the efficacy of the radiation therapy by acting as both a therapeutic and a carrier for other therapeutics. NPs, particularly high atomic number metal NPs such as gold, can either sensitize cancer cells to ionizing radiation via their physicochemical properties, or encapsulate radiation sensitizing agents, thereby protecting them from degradation (Bergs et al., 2015; Kwatra et al., 2013). At present, the most commonly investigated nanoparticulate radiosensitizers in preclinical models include gold (Botch way et al., 2015; Dorsey et al., 2013; Hainfeld et al., 2008; Her et al., 2015; Jain et al., 2012; Lee et al., 2014; Yamada et al., 2015), Ag (Swanner et al., 2015; Wu et al., 2015; Yamada et al., 2015) and iron oxide (Bhana et al., 2015; Klein et al., 2014; Sun et al., 2016; Zhao et al., 2012) NPs.

In conclusion, due to the potential fora better therapeutic index with radiation therapy, NPs are being widely investigated for cancer therapy.

Nanomaterials are being widely developed for medical and pharmaceutical purposes with the rapid development of nanotechnology. Despite the many proposed advantages of nanomaterials, increasing concerns have been expressed on human biosafety (Zhao and Castranova, 2011). First, as stated above, NPs possess different physicochemical properties compared to their bulk analogues due to extremely small size and large surface area, which makes the particles more reactive and catalytic. Second, in the field of nanomedicine, exogenous NPs may be delivered into the human body without passing through the normal gastrointestinal absorption process after intravenous or interstitial injections. Third, in the human body, NPs have the potential to interact with biological molecules or to accumulate in human tissues or organs. Therefore, human biosafety evaluation is the key point for the safe use of nanomaterial products in clinical practice. However, it is worthy to note that, until now, most published data related to nanomaterial products in nanomedicine are still staying at in vitro cell culture or in vivo animal experiment stages. Human clinical trials should be the last but the most important step for clinical translation of nanomaterial products. However, the transition probability might be low because clinical translation in nanomedicine is a long, arduous, resource intensive process (Satalkar et al., 2016). In addition, human biosafety uncertainty raises a variety of ethical concerns in clinical trials for nanomedicine products (Resnik and Tinkle, 2007).

Under conditions of occupational and environmental exposures, inhalation of NPs is normally the primary route of entry into the human body. However, intravenous and interstitial injections of nanoparticulate carriers represent the specific exposure routes in nanomedicine. In a previous article entitled as “Toxicology of nanomaterials used in nanomedicine” (Zhao and Castranova, 2011), we reviewed biosafety evaluation data related with animal studies of NPs. The research data on the acute and chronic toxicity, genotoxicity, carcinogenicity, as well as reproductive and developmental toxicity of NPs in animal studies are expanding but are not yet complete. Animal experiments suggest that some of the NPs may potentially exhibit adverse health effects on the human body. For example, TiO₂ and carbon black NPs are classified as possibly carcinogenic to humans by WHO/International Agency for Research on Cancer based solely on carcinogenicity data in experimental animals (Baan, 2007). Limited results are reported for the carcinogenicity of multiwalled carbon nanotubes in animal experiments after intraperitoneal injections (Sakamoto et al., 2009), but no data are available for lung inhalation exposure. Research reports related to the genotoxicity of NPs are still limited (Zhao and Castranova, 2011). In addition, no data are available to confirm carcinogenicity among other NPs (Tsuda et al., 2009). However, Sargent et al. (2014) have shown that inhalation of multiwalled carbon nanotubes can cause tumorigenesis in mice. Whether human exposure to NPs designed for medical use induces cancer also remains unclear (Zhao and Castranova, 2011). All these animal experimental results do have certain implications for human biosafety evaluation of nanomaterials designed for nanomedicine. However, animal experiments generally employ high dose and short exposure time, which is quite different from human administration routes in clinical practice. In addition, due to the profound differences in anatomy, physiology and genetics between humans and animals, results from animal experiments cannot directly be extrapolated to humans and in most instances animals have been poor predictors for how humans will respond to drugs.

Accordingly, in this paper, we mainly focus on human clinical trials and try to provide a general perspective on the current landscape related to human biosafety of nanomedicine products used or will be used in clinical practice. We try to answer: During the clinical trials, are there any adverse health effects or toxicities after human exposure?

In 2013, Etheridge et al. (2013) did a detailed search of the literatures with the keywords of “clinical trial and nanomedicine” through websites such as PubMed, Google and Google Scholar, etc. They identified a total of 247 applications and products, which were approved or in various stages of a clinical study, and all of the actively targeted products are aimed at diagnosing or treating various forms of cancer. In 2015, Marchal et al. (2015) identified 145 clinical studies for the terms “nanoparticles” and “cancer” through the US National Institute of Health database, which was much lower than the number of 45 139 clinical studies at the same time in oncology registered by this website. This reflects a big gap between NP design, quoting more than 9000 publications in PubMed, and clinical translation. Of course, a large number of companies developing NPs published the detailed clinical trial information on approved systems or nanoparticulate systems on their websites instead of open journals, which might be a reason for such a low number in clinical studies for nanomedicine products (Schütz et al., 2013). In phase III failures of clinical trials reported between 2007 and 2010, Thomson Reuters Life Science Consulting found that 21% of the failures were due to safety issues (Arrowsmith, 2011). However, most of these clinical trial failures also cannot be found in open scientific literature.

Nanoconstructions are used for anticancer drug delivery, including liposomes, spherical structures ranging from 100 to 400 nm in size, and polymer-based chemical entities (less than 100 nm). Specific structures such as albumin-bound NPs or antibody-drug conjugates are also used. After extensive reviewing on clinical trial articles of nanomedicine in public journals, we found that most of them focused mainly on reporting the findings of the therapeutic effectiveness of the drugs (Wagner et al., 2006), but not on evaluating the human biosafety of the nanomaterials. Although all the materials assigned for clinical trials have demonstrated biocompatibility using current standards, it remains unclear whether persistence in the human body will produce acute or chronic adverse effects (Etheridge et al., 2013).

Unique properties of nanomaterials make them available to be used as effective antitumor agents or as a compound of combined therapy for improving the therapeutic effectiveness of existing antitumor drugs. However, despite considerable amounts of described nanotechnology-based formulations, only a limited number of them have been introduced into clinical trials (Piktel et al., 2016).

NP albumin-bound paclitaxel (nab-paclitaxel) (Abraxane®) is a colloidal suspension of 130 nm particles homogenized in human serum albumin bound to paclitaxel (Al-Hajeili et al., 2014), which has been approved for the treatment of metastatic breast cancer, based on a phase III clinical trial in 460 patients. A significant difference was reported in the overall survival in patients receiving nab-paclitaxel vs. solvent-based paclitaxel. Subsequently, a number of clinical trials have examined different schedules, doses, and combinations in an effort to optimize nab-paclitaxel-based therapy for metastatic and early stage breast cancer (Martin, 2015). No significant adverse effects related to human serum albumin nanocarriers were reported in these clinical trials. However, in a pivotal comparative randomized phase III study for the treatment of breast cancer, Yamamoto et al. (2011) found that the nab-paclitaxel-treated group showed a higher incidence of sensory neuropathy than the solvent-based paclitaxel group. Nab-paclitaxel is a novel formulation of paclitaxel that does not require solvents such as polyoxyethylated castor oil and ethanol. Use of these solvents has been associated with a toxic response, including hypersensitivity reactions and prolonged sensory neuropathy, as well as a negative impact in relation to the therapeutic index of paclitaxel (Yamamoto et al., 2011).The reason for the phenomenon, why the human serum albumin nanocarrier group showed a higher incidence of sensory neuropathy than the solvent-based paclitaxel group was not reasonably explained in this clinical trial. The authors only mentioned that these adverse side effects rapidly resolved after interruption of treatment and dose reduction. Animal studies indicate that alterations in coagulation, renal, cardiovascular and pulmonary functions were mainly involved as potentially causing adverse effects following high-dose administration of human serum albumin (Gales and Erstad, 1993). It remains unclear if there is any relationship between a higher incidence of sensory neuropathy and ***human serum albumin nanocarriers.

In a clinical study, 66 patients (59 with recurrent glioblastoma) received neuronavigationally controlled intratumoral instillation of an aqueous dispersion of iron oxide (magnetite) NPs (Nano-Cancer® therapy) and subsequent heating of the particles in an alternating magnetic field. Treatment was combined with fractionated stereotactic radiotherapy. The side effects of this therapeutic approach were moderate, and no serious complications were observed. They concluded that thermotherapy using magnetic NPs in conjunction with a reduced radiation dose is safe and effective (Maier-Hauff et al., 2011). Another clinical trial of 14 patients with glioblastoma multiforme received three-dimensional image guided intratumoral injection of aminosilane-coated iron oxide NPs (core diameter: 15 nm) dispersed in water, with an iron concentration of 112 mg ml⁻¹. Patients received 410 (median: 6) thermotherapy treatments following instillation of 0.1–0.7ml (median: 0.2) of magnetic fluid per ml tumor volume and single fractions (2 Gy) of a radiotherapy series of 16–70Gy (median: 30). They concluded that thermotherapy using magnetic NPs was tolerated well by all patients with minor or no side effects (Maier-Hauff et al., 2007).

In a prospective phase I clinical trial, the treatment-related morbidity and quality of life following intraprostatic injection of a NP dispersion and thermotherapy using superparamagnetic NPs were investigated in 10 patients with biopsy-proven locally recurrent prostate cancer. Results showed that NP deposits were detectable in the prostates 1 year after thermal therapy. At a median follow-up of 17.5 months (3–24), no systemic toxicity was observed (Johannsen et al., 2007). This clinical trial indirectly reminds us that therapeutic or carrier NPs may stay in the human body for a long time (more than 1 year).

Maeda et al. (2016) developed a tumor-targeted nanoprobe, N-(2-hydroxypropyl)methacrylamide copolymer-conjugated pirarubicin (P-THP). They found this tumor-targeted nanoprobe exhibited prolonged blood circulation time, thereby resulting in good tumor-selective accumulation. In a clinical pilot study of a patient with stage IV prostate cancer with multiple metastases in the lung and bone, P-THP (50–75 mg administered once every 2–3 weeks) was shown to clear the metastatic nodules in the lung almost completely after three treatments. In this study, the patient retained an excellent quality of life during the treatment without any apparent adverse side effects.

With the rapid development of nanotechnology, Ag nanoproducts have broadened their application as an antibacterial, antiviral and anti-inflammatory therapy (Munger et al., 2014). In an in vivo human time–exposure study, Munger et al. (2014) conducted a prospective, controlled, parallel design systematic study with two oral doses (10 and 32 ppm, 5–10 nm and 25–40 nm, respectively) of a commercial Ag NP solution over a 3–14 day monitored exposure in 60 healthy volunteers (between 18 and 80 years of age). They found that this colloidal elemental Ag particulate formulation produces detectable Ag ions in human serum, but does not demonstrate any clinically significant changes in metabolic, hematologic, urine, physical findings, sputum morphology or imaging. Their results asserted that the Ag detected in the serum of the human subjects is absorbed in the upper gastrointestinal tract into the blood stream in an ionic form, but not in an intact Ag metallic particle form. Therefore, the fate of nanomaterials through different administration routes, for example, orally, or intravenous or interstitial injections, are entirely different. If there is any toxicity of Ag nanoproducts through intravenous injections into the human body it is still unknown.

Oleanolic acid and ursolic acid are considered relatively nontoxic, and have been used in cosmetics and health products through oral administration (Liu, 1995). Liu (1995) evaluated the single- and multiple-dose pharmacokinetics (PK) as well as the safety of ursolic acid nanoliposomes (UANL) in healthy volunteers and in patients with advanced solid tumors. Twenty-four healthy volunteers in the single dose PK study were divided into three different groups, which received 37, 74 and 98 mg m⁻² of UANL via a 4 h intravenous infusion, respectively. Eight patients in the multiple dose PK study were administered 74 mg m⁻² of UANL daily for 14 days. No drug accumulation was observed with repeated doses of UANL. Nausea, diarrhea and abdominal distention were the common adverse effects that were observed. Most UANL-associated adverse effects were either grade 1 or 2. Only one patient developed grade 3 adverse effects in the form of elevated aspartate aminotransferase and alanine aminotransferase levels with diarrhea at the same time after receiving 74 mg m⁻² of UANL (Liu, 1995). The size (nm) of the UANLs was not clearly stated in this paper.

A novel hard solid nanoparticulate formulation, CYT-6091, constructed by simultaneously binding recombinant human TNF alpha (rhTNF) and thiolated PEG to the surface of 27 nm colloidal gold NPs was tested in a phase I dose escalation clinical trial in 29 patients with advanced stage cancer (Libutti et al., 2010). This formulation was injected intravenously (50–600 μg m⁻²), and one cycle of treatment consisted of two treatments administered 14 days apart. Biopsies (punch, core or excisional) were obtained from 20 subjects from both tumor and adjacent healthy tissue 24 h post-administration of CYT-6091. Adverse events were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (version 3.0). Results showed that the half-life for rhTNF and gold were quite similar (182 and 217 min, respectively), suggesting that the CYT-6091 nanoconstruction remains intact in the circulation. Electron micrographs of the patient biopsies, taken 24 h after administration, indicated that the gold NPs travel to tumors having fenestrations of 200–400 nm in size. Gold NPs were also found in healthy liver tissue, but were not detected in healthy skin or breast tissue. The most frequent grade 3 and 4 adverse events were lymphopenia (26 of 29 patients), hypoalbuminemia (five of 29), hypokalemia (five of 29), hypophosphatemia (five of 29), hyperbilirubinemia (five of 29) and increased aspartate aminotransferase (five of 29). In addition, redistribution in circulating lymphocytes and neutrophils that was dose dependent was observed. All other adverse events were not considered as dose-limiting toxicities. Depending on the results, it is difficult to distinguish which adverse events were induced by gold NPs, rhTNF, or both of them. However, from this clinical trial we can get the following conclusions: First, a certain dose of hard solid gold NPs can be administrated through the intravenous injection route into the human body without severe acute adverse effects. Second, the human body can tolerate nanoparticulate formulation of gold NPs in sizes of 200–400 nm. Third, gold NPs will be distributed to not only tumor tissue, but also normal tissues or organs. Therefore, the chronic potential adverse effects should be further evaluated even if this therapeutic formulation is approved for clinical use.

In conclusion:

In summary, unique chemical and physical properties, potential applications and human biosafety in clinical trials of NPs are reviewed in this paper. The unique chemical and physical properties of NPs include small size, surface area, quantum size, chemical reaction properties, catalytic properties, optical properties and other properties. The potential applications of NPs in medicine mainly include medical diagnosis, drug carriers, medical instruments, tissue engineering, therapeutic drugs, nanogene medicine, gene therapy of cancer, nanovaccines and radiosensitizers. Nanotechnology allows a quicker, more accurate and more credible diagnosis process. Drug carrier NPs can be easily delivered and absorbed, greatly increase the time of the drug half-life and reduce the drug dosage. In the gene therapy of cancer, more accurate targeting can avoid drugs causing too much damage to normal tissue/cells. In tissue engineering, nanotechnology may also play an irreplaceable role. Liposomal and polymer-conjugated formulations are the NPs frequently used for nanomedicine products at present. Human biosafety information from open published clinical trials is limited. Most clinical trial reports for nanomedicine products focused mainly on the therapeutic effectiveness of drugs without paying enough attention to the human biosafety or adverse effects.

To help optimize development of nanomedicine, we summarized the following strategies as suggestions for future work in nanomedicine research.