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NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University Singapore, SingaporeCancer Science Institute of Singapore, National University of Singapore, 117599 SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600 Singapore
NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University Singapore, SingaporeCancer Science Institute of Singapore, National University of Singapore, 117599 SingaporeDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600 SingaporeThe N.1 Institute for Health, National University of Singapore, 117456 SingaporeDepartment of Biomedical Engineering, National University of Singapore, 117583 SingaporeThe Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, National University of Singapore, 117456 Singapore
Advances in nanotechnology have great potential to address many unmet clinical and biomedical needs. Nanodiamonds, as a class of carbon nanoparticles with unique properties, may be useful towards a versatile range of biomedical applications from drug delivery to diagnostics. This review describes how these properties of nanodiamonds facilitate their application in different fields of biomedicine, including delivery of chemotherapy drugs, peptides, proteins, nucleic acids and biosensors. Additionally, clinical potential of nanodiamonds, with studies in both preclinical and clinical stages, is also reviewed here, highlighting the translational potential of nanodiamonds in biomedical research.
As an emerging and rapidly developing technology, nanotechnology has been widely applied in biomedical research, including drug delivery and diagnostics. Nanomaterials in the nanoscale range offer unique benefits when delivering therapeutics to disease sites or performs diagnostics. Moreover, various surface modifications endow nanoparticles with enhanced capabilities to address unmet clinical needs.
1.1 Properties of nanoparticles in biomedical applications
Utilizing nanoparticles in drug delivery and bioimaging can 1) protect therapeutic and imaging modalities from rapid elimination and clearance, and prolong the circulation time in the body; 2) improve the physiochemical properties of therapeutic and imaging modalities, for example, increase the water solubility of insoluble drugs; 3) enable sustained release of therapeutics and imaging modalities, leading to reduced side effects; 4) achieve passive tumor targeting through the enhanced permeability and retention (EPR) effect.
EPR effect has been a fundamental concept of tumor-targeted delivery in nanomedicine since its discovery in 1980s [
A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.
]. The EPR effect is caused by the aberrant vascular architecture and defective lymphatic drainage in tumor sites. These pathophysiological characteristics enable the nanoparticles with size under 200 nm to progressively accumulate with prolonged retention period at the tumor sites. The EPR effect and prolonged circulation time in the body mediated by nanoparticles make nanoparticles have a higher chance to accumulate and stay at tumor sites, thus achieve passive tumor targeting.
1.2 Surface modifications for functional nanoparticles
Apart from the common properties of nanoparticles, more modifications have been designed for nanoparticles to achieve additional functions, including active targeting, stimuli-responsive controlled drug release, and nanotheranostics, which integrates diagnosis and therapeutics into a single nanoparticle system.
1.2.1 Active tissue targeting
Active tissue targeting is a popular method in nanoparticles functionalization. While EPR effect has been accepted as one of the universal concepts in cancer nanomedicine, unsatisfactory target localization by EPR-mediated passive targeting remains a concern in some applications. Therefore, active targeting has been developed as a complementary strategy to passive targeting for enhanced tumor targeting. It is usually based on the molecular targets specifically overexpressed on the surface of tumor cells. Examples include nanoparticles decorated by the monoclonal antibody of human epidermal receptor-2 (HER-2), which is overexpressed in some breast tumor cells [
Aberrant disease microenvironment allows for stimuli-responsive controlled drug release and theranostics at disease sites. For example, the stimuli conditions at the tumor sites include low pH conditions and acidic environment, elevated reactive oxygen species (ROS) level, and enzymes activated in tumorigenesis. Previous work from our laboratory utilized a peptide sequence that can be specifically cleaved by matrix metalloproteinases (MMP) 9 enzymes and loaded the peptide with nanodiamond to form a nanodiamond-based biosensor. Since MMP9 has been found to be overexpressed in various types of cancer and has been identified as a biomarker of cancer metastasis [
]. Besides the endogenous stimuli factors mentioned above, there also are exogenous stimuli strategies such as thermal, magnetic field, ultrasound, light, and weak electric field that can be harnessed to improve nanomedical applications.
With unique properties and versatile surface functionalization mentioned above, nanoparticles including lipid nanoparticles, polymeric nanoparticles, metal nanoparticles, and carbon nanoparticles have shown valid evidence for improving both drug delivery and diagnosis efficiency preclinically and clinically. Among the different types of nanoparticles, carbon-based nanoparticles have been of particular interest due to their tunable characteristics. In this review, we will mainly focus on a specific type of carbon nanomaterials, nanodiamonds, which have emerged as a promising candidate in biomedical applications. Nanodiamonds possess unique optical, electronic, and mechanical properties that make them attractive for a range of biomedical applications, such as therapeutic agent delivery, bioimaging, and diagnostics. Furthermore, the surface of nanodiamonds can be functionalized with various molecules to enhance their specificity and efficacy. Therefore, nanodiamonds hold great potential as a versatile platform for developing advanced nanomedicines.
2. Nanodiamonds
Carbon nanomaterials are a diverse class of inorganic nanomaterials, including carbon nanotubes, graphene, carbon dots, fullerenes, and nanodiamonds. Among them, nanodiamonds (NDs) are a relatively recent yet increasingly studied type of carbon nanomaterials. The structure of a nanodiamond particle is a faceted truncated octahedron, with electrostatic fields on the facet surfaces. Depending on the synthesis methods, there are two major classes of nanodiamonds in biomedical applications, detonation nanodiamonds (DNDs) and high-pressure high-temperature nanodiamonds (HPHT NDs). The high-pressure high-temperature method is typically used to introduce nitrogen-vacancy (NV¯) centers in nanodiamond particles to synthesize fluorescent nanodiamonds (FNDs). The advantages of FNDs lie in their photostability with negligible photobleaching and photoblinking [
]. Generally, larger sizes of FND particles exhibit higher fluorescence intensities. To achieve efficient brightness suitable for biomedical applications, the particle size of FNDs should be larger than 40 nm [
]. Meanwhile, the HPHT synthesis method may be inefficient and requires further improvements to achieve better cost-efficient production. In comparison, the detonation method allows for large-scale synthesis with relatively low synthesis cost. The resulting product, DND particles, is chemically stable, with a single particle size around 5 nm [
] (Fig. 1). Such aggregation is the equilibrium of the electrostatic attractions between faceted nanodiamonds and the repulsion force from the hydrogen-bond network of water molecules [
]. The resulting nanoparticles possess a high surface area-to-volume ratio that is beneficial for drug loading, and the appropriate particle size also meets the requirements for in vivo nanoparticles delivery.
Fig. 1Structure of DNDs and corresponding transmission electron microscopy (TEM) images. (A) The structure of a nanodiamond particle is a faceted truncated octahedron. The size of a single ND particle is around 5 nm, with diverse functional groups on the surface. In aqueous solution, NDs tend to form aggregates with size around 50-200 nm. (B) Corresponding TEM images. (Left) High magnification image shows that the size of a single ND particle is around 5 nm. Scale bar, 5nm. (Right) Low magnification image shows that ND aggregates exhibit self-assembled lace-like networks. Scale bar, 100nm. TEM images (B) are reproduced from ref
As indicated in Fig. 2, NDs possess unique surface electrostatic fields that are beneficial to drug delivery and imaging applications. Moreover, there are diverse functional groups on the surface of nanodiamonds including phenols, pyrones, hydroxyl, and epoxide groups, enabling the covalent and hydrogen binding with the therapeutic agents [
]. Additionally, the surface of nanodiamonds can be further modified with other functional groups, such as amine and carboxyl groups, allowing for more feasible conjugation capacity and drug-delivery capability [
Oxidized and amino-functionalized nanodiamonds as shuttle for delivery of plant secondary metabolites: Interplay between chemical affinity and bioactivity.
Fig. 2Schematic diagram of the nanodiamond particle structure and applications in biomedicine. The structure of nanodiamond particles is a faceted truncated octahedron, with diverse electrostatic fields on the different facet surfaces. the square facets in red color are positively charged, the hexagonal facets in blue color are negatively charged, the hexagonal facets in green color are neutrally charged. The unique electrostatic fields on the surface enable the wide biomedical applications of nanodiamonds as listed on the figure. Reproduced with permission, A from ref
Compared to other carbon nanoparticles like carbon nanotubes, nanodiamonds possess good water solubility due to surface functional groups and strong electrostatic fields on the facet surfaces that contribute to the hydrogen-bond network with water molecules and form a hydration shell in aqueous dispersions [
]. As a result, nanodiamonds are highly dispersible and stable in water. This property also contributes to the outstanding biocompatibility of nanodiamonds.
Another noteworthy property of nanodiamonds is their ability to induce nano-mediated endothelial leakiness. In vivo application of nanoparticles meets several physiologic barriers before reaching the disease sites. Vascular barrier posed by endothelium cells is one barrier that nanoparticles will encounter in their way to disease sites. Besides relying on the EPR effect, nanodiamond was reported to cause endothelial leakiness at the intended site by increasing intracellular oxidative stress within endothelial cells and activating the downstream pathways, leading to loss of VE-cadherin interconnection and cytoskeleton remodeling [
]. The resulting endothelial leakiness effect enabled nanoparticles to have higher chances to reach the disease sites. This effect was temporary with minimal damage and inflammation. Meanwhile, Xu et al. also reported that small interfering RNA (siRNA) delivered by nanodiamonds presented deeper penetration in 3D tumor models that resulted in enhanced therapeutic efficiency [
]. As such, nanodiamonds possess outstanding advantage as a delivery platform in vivo, particularly for solid tumor therapy.
2.2 Biocompatibility of nanodiamonds
One attractive characteristic of nanodiamonds in biomedical application is demonstrated biocompatibility. Toxicity tests of nanodiamonds have been conducted in many studies, both in vitro and in vivo, with minimal toxicity effect observed [
]. In the rats study, rats were given 1 or 2 mg dosage of nanodiamonds in 5% BSA saline solution weekly for two weeks. Serum chemistry, hematology, and urine evaluations were conducted 3 days after nanodiamonds administration. By the end of the study, blood samples and selected organs were collected for further toxicity evaluations. Results showed no systemic inflammatory, toxic, or pro-coagulant responses appeared during treatment, though moderate decreased of red blood cell count occurred. In addition, liver function and renal system were not affected by the nanodiamonds treatment. Histological study in the main organs also did not show observed histopathology alterations. The non-human primate study lasted for six months with two dosage groups, one clinically relevant dosage and one elevated dosage. Following a comprehensive evaluation including body weight, complete blood count, serum chemistry, urinalysis, and histopathology, the good biocompatibility of nanodiamonds was confirmed; nanodiamonds at clinically relevant dosages were well-tolerated.
Biodistribution analysis of nanodiamonds in mice has also been investigated in different studies. Chow et al. traced nanodiamonds biodistribution in mice using fluorescence dye-conjugated nanodiamonds [
]. Results showed that nanodiamonds accumulated mainly in liver, followed by kidney, spleen, and lung. The clearance duration of nanodiamonds in different organs differed, specifically, four days in lung, seven days in spleen and kidney, ten days in liver. Other studies also indicated that liver was the main organ that nanodiamonds accumulated in after being intravenously administrated [
]. In addition, both fluorescence dye-labelled and 18F radionuclide labelled nanodiamonds tracing results indicated that nanodiamonds could be excreted into the bladder/ urinary tract for in vivo clearance [
As shown in Fig. 2, various studies have been completed to interrogate the capability of nanodiamonds in biomedical applications. The unique properties of nanodiamonds addressed above make nanodiamonds an attracting class of nanomaterials in drug delivery and bioimaging. Therapeutic agents including chemotherapy drugs [
Development of multi-drug loaded PEGylated nanodiamonds to inhibit tumor growth and metastasis in genetically engineered mouse models of pancreatic cancer.
Biofunctionalization of scaffold material with nano-scaled diamond particles physisorbed with angiogenic factors enhances vessel growth after implantation.
Harnessing subcellular-resolved organ distribution of cationic copolymer-functionalized fluorescent nanodiamonds for optimal delivery of active siRNA to a xenografted tumor in mice.
] have been successfully delivered by nanodiamonds with improved efficacy.
2.3.1 Delivery of chemotherapy drugs
The application of nanodiamonds for enhanced chemotherapy drugs delivery has been reported by many studies. Besides the typical advantages of nano-based drug delivery systems such as enabling sustained release, reducing systemic toxicity, and extending circulation time, nanodiamonds show the capacity to overcome chemoresistance against cancer cells, especially cancer stem cells. Chemoresistance is a hurdle in clinical therapy for metastatic cancer. One common mechanism is mediated by the ATP binding cassette (ABC) transporters, which are capable of effluxing anthracycline class of anti-cancer chemotherapy drugs. Anthracycline drugs, typically with aromatic rings, can be linked with nanodiamonds by electrostatic interactions and π-π stacking. This is because, besides the electrostatic potential on the facet surface, nanodiamonds are also decorated with a graphitized, sp2 hybridizing surface that enables interactions with aromatic rings through π-π stacking.
Doxorubicin is an anthracycline that is used as a standard chemotherapy drug for many cancers [
]. However, severe side effects at the clinical dosage and chemoresistance occur in its clinical application. A study showed that when delivered by nanodiamonds, the resulting nanodiamond-doxorubicin (NDX) complexes were able to overcome drug efflux mediated by ABC transporters [
]. This significantly improved the therapeutic efficacy and reduced the toxicity of drugs in murine liver cancer and breast cancer models, both in vitro and in vivo. Furthermore, a more specific study of nanodiamond-mediated overcoming of chemoresistance in hepatic cancer stem cells was conducted using another anthracycline class drug, epirubicin [
]. The anti-chemoresistant effect could be explained by the sustained intratumoral drug release of epirubicin-nanodiamond (EPND) complexes after being internalized by cancer cells, leading to prolonged drug retention within cancer cells, preventing immediate drug efflux by ABC transporters (Fig. 3A). Since the side population cells that are enriched for cancer stem cells possess strong tumor initiation capacity, the preferential killing of nonside population cells by epirubicin treatment led to the selection and enrichment of cancer stem cells, whereas EPND treatment showed a significant decrease in side population cells, both in vitro and in vivo hepatic cancer models (Fig. 3B, 3C). As a result, EPND treatment was able to inhibit tumor initiation and prevent secondary allograft tumor formation in vivo (Fig. 3D). In vitro and in vivo evaluations confirmed the enhanced therapeutic effect of EPND, suggesting that nanodiamonds could be a useful platform in clinic, especially in treating cancer stem cells with anthracycline drugs.
Fig. 3Enhanced epirubicin (Epi) delivery by nanodiamonds against cancer stem cells. (A) epirubicin-nanodiamond (EPND) complexes showed increased cellular retention in liver tumor cells. Red signals denote Epirubicin, blue signals denote nuclei staining. Scale bar, 50 μm. Epirubicin treatment induced a significantly increase in side population cells while EPND treatment showed a significantly decrease in side population cells both in vitro (B) and in vivo in murine liver tumor models (C). Data are showed as mean ± SD; *p < 0.05; **p < 0.01. (D) EPND inhibited the tumor initiation and prevented secondary allograft tumor formatting. Reproduced with permission
Besides delivery of traditional small molecular drugs, nanodiamonds have also been utilized to deliver other emerging therapeutic modalities such us peptides and proteins, to increase stability and improving intracellular efficacy [
]. Peptides are highly versatile and can be designed as multifunctional smart materials. One example in biomedical application is stimuli-responsive peptides.
Gu et al. developed a nanodiamond-based stimuli-responsive delivery platform for therapeutic peptides delivery [
]. The ND-peptide complexes were composed of nanodiamonds, a SALL4-inhibitory peptide sequence, and a peptide linker (Fig. 4A). The peptide linker was designed to be specifically targeted by the endopeptidase cathepsin B (CTSB). CTSB is a lysosomal peptidase enzyme and has been found to be overexpressed in various cancers [
]. Based on this design, intracellular-specific controlled release could be achieved that the SALL4-inhibitory peptide was only released from the ND-peptide complexes within the cancer cells that overexpressed CTSB. Meanwhile, a Förster resonance energy transfer (FRET)-based dye pair was decorated on the ND-peptide complexes to monitor the cleavage activity. The designed ND-peptide complexes exhibited increased stability and prolonged retention in cells, leading to improved therapeutic efficacy in hepatocellular carcinoma (HCC) cells with high SALL4 expression (Fig. 4B). In vivo evaluation in the orthotopic SALL4-driven HCC mouse model further verified the enhanced therapeutic effect of ND-peptide complexes (Fig. 4C, 4D). Specifically, ND-peptide complexes displayed more tumor uptake and longer retention period in the tumor locations compared to the naïve peptide group. Moreover, increased tumor volume reduction was observed in the ND-peptide-treated group with no notable weight loss. Meanwhile, significantly increased apoptosis level by terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) analysis further indicated the enhanced therapeutic efficacy mediated by this ND-based delivery platform.
Fig. 4Stimuli-responsive therapeutic peptide delivered by nanodiamonds showed enhanced therapeutic effect. (A) Design of the stimuli-responsive therapeutic peptide. The peptide is composed of three parts, a SALL4-inhibitory sequence, a cleavable linker that is specifically respond to CTSB, and a FRET-based dye pair. (B) ND-peptide treatment led to increased apoptosis in cells with high SALL4 expression. (C) ND-peptide treatment in SALL4-driven HCC mouse model displayed improved therapeutic effect. (D) Quantification of luciferase signals of tumor in different treatment groups also confirmed the enhanced therapeutic effect of ND-peptide. mean ± SD, PBS group n=9, ND group n=7, peptide group n=8, ND-peptide group n=9. *p < 0.05, **p < 0.01, ***p < 0.005. Reproduced with permission
Apart from the therapeutic peptides, nanodiamonds have also been investigated to conjugate recombinant peptide as a vaccine formulations. Bilyy et al. developed a nanodiamond-pancoronavirus peptide conjugates to improve the stability and solubility of the peptide [
]. Animal studies in mice and rabbits both showed capacity of stimulating a robust immune response and exhibited strong and lasting immune response against new and emerging infections. Meanwhile, this nanodiamond-based formulations were safe and did not cause any tissue damage at the injection site.
With these studies, the preparation process of ND-peptide/protein conjugates is now well-developed and can be quickly adapted to deliver other peptides/proteins. With the great versatility of peptides/proteins design, nanodiamond-peptide/protein conjugates possess strong application potential toward biomedical field.
2.3.3 Delivery of nucleic acids
The potential of nanodiamonds as a delivery platform for genetic materials has also been explored. Gene therapy that controls the expression of cancer-related proteins has attracted increasing attention in cancer medicine and is considered as a promising next generation of cancer therapy. Besides, nucleic acid-based genetic materials have been considered a powerful tool for specific gene editing in biomedical research and rare inherited genetic diseases. However, nucleic acids have certain barriers that limit their application. For example, they are unstable in the physiological environment and tend to be degraded [
To overcome those challenges, nanodiamonds have been applied as a vector for enhanced nucleic acid delivery. Oxidized nanodiamonds modified with low molecular weight polyethyleneimine (PEI800) have been used for the delivery of plasmid and small interfering RNA (siRNA) [
]. The transfection efficiency of ND-PEI800 was comparable to ND-PEI25k, with significantly reduced toxicity. More interestingly, under cell culture medium with serum conditions, the transfection efficiency mediated by ND-PEI800 complexes was better than by Lipofectamine, which was considered the gold standard for transfection. This indicated that ND-PEI800 possessed great potential for in vivo gene delivery. The authors also proposed that with high density of amino groups coated on the surface, ND-PEI800 nanoparticles might be capable of performing endosomal escape, which is essential for successful intracellular nucleic acid delivery.
Besides PEI800, other cationic polymers have also been reported to decorate nanodiamonds surface for gene delivery. Examples include polyamidoamine (PAMAM) [
]. Those modifications endowed the nanodiamonds with positive charge and good dispersion, so that negatively charged nucleic acids could be effectively linked. Nevertheless, the safety issue of those surface modifications should be addressed and carefully evaluated for clinical translation, since none of these polymers have been clinically used.
2.3.4 Nanodiamond-based biosensors
FNDs, thanks to their superior optical properties and high biocompatibility, have been applied in bioimaging and biosensing with proven effectiveness [
]. The fluorescence of FNDs is stable and is not affected by environmental factors including pH, viscosity, molecular interaction, and organic solvents [
]. Meanwhile, studies have shown that FNDs are highly sensitive to the thermal changes and can be utilized as thermosensors under biological environment [
]. Wu et al. used FNDs as a nanothermometer, integrated with a photothermal agent, to establish an intracellular heating and temperature self-reporting photothermal system [
]. The designed nanoparticles were able to induce programmed cell death in live cancer cells and report the local temperature changes at the same time. Strikingly, they found that cells could tolerate large intracellular temperature changes and thermal inhomogeneity that cell viability was not affected under a 30°C local temperature increase.
In addition, long-term photostability and high biocompatibility and hemocompatibility properties of FNDs enable their application in in vivo bioimaging and long-term tracking. Kvakova et al. prepared mannose-modified near-infrared-emitting FND (FND-p-Man) as a probe for in vivo lymph node imaging [
]. Since the mannose receptor is highly expressed on the membrane surface of lymphatic macrophages, mannose-modified FND could specifically target to these lymphatic macrophages. This mannose receptor-mediated cell targeting was proved by the in vitro live cell internalization assay. Meanwhile, in vivo test in healthy mice confirmed that after injection at the footpad, FND-p-Man exhibited higher target-to-nontarget lymph node ratios compared to the non-modified FND (FND-p) in popliteal lymph nodes. Moreover, a murine footpad melanoma model (induced by B16-F10 cell line) was also used as the lymphangiogenesis and cancer-related lymphatic metastasis model. Lymph nodes imaging evaluation and subsequent histological analysis based on this model further showed the lymph node-specific targeting and accumulation mediated by FND-p-Man (Fig. 5). This work demonstrated that mannose-modified FND could be applied as near-infrared fluorescence imaging tracers for lymph node visualization. Advantages of FND as a nanoprobe include great stability with shelf life of more than one year, low background noise, high tissue compatibility, robust and low-cost preparation methods.
Fig. 5Enhanced lymph node-specific targeting and accumulation mediated by mannose-modified near-infrared-emitting FND (FND-p-Man). (A) Fluorescence images of excised popliteal lymph nodes from B16-F10 tumor-bearing mice after injection with non-modified FND (FND-p) or FND-p-Man. (B) Quantification of fluorescence intensity of excised lymph nodes. (mean ± SD, n = 4). **p < 0.005. (C) Histological analysis of excised lymph nodes. Lymph nodes are showed in neutral red. Blue arrows denote FND-p or FND-p-Man accumulation within the lymph nodes. Reproduced with permission
Besides FND, DND has also been investigated to develop bioimaging and diagnosis tools, mainly by delivery of contrast agents. Nanodiamonds, due to their unique facet-specific surface potentials and the resulting coordination of water molecules on the surface facets, have been reported to increase the interactions between paramagnetic ions and water molecules. As a result, when magnetic resonance imaging (MRI) contrast agents were delivered by nanodiamonds, their relaxivity value could be improved. Hou et al. developed a nanodiamond-manganese (NDMn) contrast agent through covalent conjugation [
]. The resulting NDMn conjugates exhibited improved both longitudinal (T1) and transverse (T2) relaxivity efficiency that outperformed the clinical Mn chelates, and meanwhile maintained minimal cytotoxicity towards THLE-2, an immortalized normal liver epithelial cell line. Further in vivo evaluation in a murine hepatic tumor model also showed that after systemic administration of NDMn in mice, significantly increased contrast-to-noise ratio between tumor and normal tissue could be observed at the tumor sites in both T1- and T2-weighted images. Compared to the clinical contrast agents, NDMn group exhibited higher resolution that showed clearer delineation between tumor and normal liver tissue. Together with other properties such as high molecular loading efficiency, low cytotoxicity, good stability and appropriate particle size, nanodiamonds served as an attractive platform for delivery of contrast agents. Meanwhile, the capability of multi-functional decorations of nanodiamonds expands the potential of nanodiamonds in biomedical applications, in both drug delivery and diagnosis, which may eventually benefit to clinical application.
2.3.5 Clinical potentials of nanodiamonds
While there have been wide applications of nanodiamonds demonstrated preclinically, clinical translation remains a hurdle but has shown promising early evidence. Clinical studies of nanodiamonds are currently limited to the topical application for root canal therapy. One clinical study utilized nanodiamond-modified gutta percha (NDGP) as the root canal filling material, with comparison of standard of care treatment of gutta percha. A randomized, interventional, parallel assignment clinical trial was conducted (ClinicalTrials.gov Identifier: NCT02698163), with the active comparator of gutta percha group and experimental NDGP group. The endpoints of the study have been achieved in experimental NDGP group, including healed lesion, reduced postoperative pain, and prevented reinfection [
]. Based on the observations of the NDGP study, another clinical trial that utilizing nanodiamonds and amoxicillin modified gutta percha (NDGX) as the filling material for root canal has also been conducted (ClinicalTrials.gov Identifier: NCT03376984). The study loaded the NDGP with the broad-spectrum antibiotic, amoxicillin, so as to inhibit the bacterial growth and reduce the likelihood of reinfection [
]. This study is currently under recruitment process for phase 2 and phase 3 clinical trials.
Though there is no systemic application of nanodiamonds under clinical trial, substantial preclinical assessments related nanodiamonds have been conducted in many studies. The selected in vivo biomedical applications of nanodiamonds under clinical or preclinical stages are summarized in Table 1.
Table 1Selected in vivo biomedical applications of nanodiamonds.
Safety studies and nonclinical risk assessment of detonation nanodiamond in large animal models with comprehensive hematologic, urine, and histological analysis
Preclinical studies including but not limited to these listed above serve as a foundation for the clinical translation of nanodiamond-based biomaterials. Meanwhile, more precise and comprehensive in vivo studies of nanodiamonds, such as quantitative evaluations of clearance of nanodiamond in body, need to be done.
3. Conclusion
The biomedical application and clinical potential of nanodiamonds in drug delivery and diagnostics fields have been comprehensively discussed in this review. Unique properties of nanodiamonds confer the ability to develop outstanding platforms in biomedical research. Common properties such as large surface ratio-to-volume ratio, good water solubility and stability, diverse facet surface electrostatic potentials, and tunable surface modifications make nanodiamond a competitive candidate in developing the delivery platform. Plenty of successful application examples have been reported that utilize nanodiamonds as the vehicle to deliver therapeutic and imaging agents in vivo or in vitro, with proven enhancement of efficacy. Meanwhile, nanodiamonds possess additional advantages that make them distinguished from other nanoparticles. Nanodiamond-mediated endothelial leakiness effect and enhanced solid tumor penetrative capacity enable nanodiamond effectively deliver therapeutic or imaging modalities to the tumor sites with deeper tumor penetration. Moreover, chemotherapy drugs delivered by nanodiamonds exhibited increased retention in cancer cells, thus avoided active efflux of drugs. Nanodiamond-mediated overcoming chemoresistance capacity makes nanodiamond especially suitable in delivering chemotherapy drugs against chemoresistant cancers. In addition, FNDs, with their superior inherent fluorescent properties, expand their biomedical application in drug delivery and bioimaging, allowing further design as muti-functional nanomaterials.
It is also noteworthy that nanodiamonds are highly biocompatible, which has been demonstrated in many animal studies. Meanwhile, two ongoing clinical trials for nanodiamond-based therapeutics further extend the application of nanodiamonds to clinical aspects and encourage more nanodiamond-related translational research. Continued research into the use of nanodiamonds towards biomedical and clinical applications should yield promising innovations towards improved human health through nanomedicine.
Funding sources
This work was supported by grants from the National Research Foundation Cancer Science Institute of Singapore RCE Main Grant, the Ministry of Education Academic Research Fund (MOE AcRF Tier 2 [MOE2019-T2-1-115]), and the Singapore Ministry of Health's National Medical Research Council under its Open Fund-Large Collaborative Grant (‘OF-LCG’) (MOH-OFLCG21Jun-0016).
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.
Oxidized and amino-functionalized nanodiamonds as shuttle for delivery of plant secondary metabolites: Interplay between chemical affinity and bioactivity.
Development of multi-drug loaded PEGylated nanodiamonds to inhibit tumor growth and metastasis in genetically engineered mouse models of pancreatic cancer.
Biofunctionalization of scaffold material with nano-scaled diamond particles physisorbed with angiogenic factors enhances vessel growth after implantation.
Harnessing subcellular-resolved organ distribution of cationic copolymer-functionalized fluorescent nanodiamonds for optimal delivery of active siRNA to a xenografted tumor in mice.
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