Chaoliang Tang, Heng Li, Junmou Hong,Xiaoqing Chai*

Application of nanoparticles in the early diagnosis and treatment of tumors: current status and progress

Chaoliang Tang1, Heng Li2*, Junmou Hong3*,Xiaoqing Chai1*

1Department of Anesthesiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.2Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China.3Department of Vascular Surgery, Zhongshan Hospital, Xiamen University, Xiamen, 361004, China

Malignant tumors pose a serious threat to human life and health. Despite recent developments in modern medical techniques, the early diagnosis and treatment of tumors remain difficult due to their asymptomatic nature in the early stages of disease and the limitations in current clinical diagnostic methods. Advancements in nanotechnology, particularly in the area of multi-functional diagnostic nanomaterials, can help effectively resolve present inadequacies via concurrently achieving early diagnosis, image-guided intervention, and real-time monitoring and treatment of tumors. The development of nanomaterials and nanotechnology may also aid in the area of anti-cancer drug development by improving the safety and side-effect profile, as well as by enhancing the targeted specificity of the drugs, which are two of the long-standing challenges in Western medicine. The progress in the field of nanomaterials has also uncovered novel approaches for the clinical application of traditional Chinese medicine because the combination of traditional Chinese medicine components with nanoparticles overcomes various drawbacks, including poor water solubility, low bioavailability, and short half-life, of the former. Moreover, nanoparticles also enhance the biological effectiveness and targeted specificity of these medicines. In this review, we discuss the application of nanoparticles in the early diagnosis and treatment of tumors, through modern and traditional medicine.

Tumors, Nanomaterials, Chinese medicine, Diagnosis, Treatment

The present review discusses the application of nanoparticles in the early diagnosis and treatment of tumors, through Western and traditional Chinese medicine, indicating the potential enhancement of biological effectiveness and target-specificity of the combination of nanoparticles and Western or Chinese medicine.

In the classical ancient Chinese medicine book of(Yellow Emperor's Classic of Medicine) (221 B.C.E.–220 C.E.), the earliest known documents on traditional Chinese medicine (TCM), a set of theories has already been established on the diagnosis and treatment of tumors. However, the traditional formulations of TCM, including decoctions, pills, and powders are associated with various shortcomings, including poor water solubility, low bioavailability, and short half-life, which limit their effectiveness in the treatment of tumors. Early research efforts in this area were dedicated to improving the targeted delivery of the active components of TCM monomers. By combining the active TCM monomers with nanomaterials, the bioavailability and targeted specificity of TCMs can be effectively increased.

Background

Over the past few decades, a significant progress has been made in the diagnosis and treatment of tumors. However, diagnosis and treatment still mainly rely on the use of invasive procedures (e.g., biopsy and surgical treatment), which are inconvenient, and noninvasive methods (e.g., radiotherapy and chemotherapy), which have poor specificity. Therefore, these methods lead to unsatisfactory treatment outcomes [1, 2]. In recent years, scientists have been actively engaged in the quest for a noninvasive, high-specificity tumor diagnosis methods to improve the survival rate and quality of life of tumor-affected patients, and nanotechnology has provided a breakthrough in this arduous task.

Nanotechnology refers to a multidisciplinary field of applied science and technology that involves the study of material characteristics and interactions (including molecular and atomic manipulation) at the nanometer scale (1–100 nm), and the utilization of these characteristics for practical applications. Nanomedicine, an emerging interdisciplinary field, is the application of the principles and methods of nanotechnology in medical research and clinical treatment, to enable accurate diagnosis and treatment of diseases with complex pathogenic mechanisms at the molecular level [3]. Nanomaterials can be broadly defined as materials with at least one dimension in the nanoscale regime, or materials obtained through the arrangement of the basic units in the nanoscale regime in a certain pattern [4, 5]. In particular, the use of nanoparticles as nanoprobes in early tumor detection and early tumor-tissue imaging has received increasing attention from researchers. Nanoparticles can serve as good drug delivery platforms because of their surface modifiability. The synthesis of aqueous injectable solutions and the development of passive or active targeted drug-delivery systems has allowed nanoparticles to become an accurate means of early tumor diagnosis and imaging [6]. The improvement in the side-effect profile and targeted specificity of antitumor drugs has always been a key aim in modern medical research. Rapid developments in the area of nanomaterials and nanotechnology have uncovered novel research approaches for the targeted delivery of antitumor drugs, enabling substantial progress in basic research and clinical applications. In the classical ancient Chinese medicine book of(Yellow Emperor's Classic of Medicine) (221 B.C.E.–220 C.E.), the earliest known documents on traditional Chinese medicine (TCM), a set of theories has already been established on the symptoms, diagnosis, treatment, and prognosis of tumors. However, the traditional formulations of TCM, including decoctions, pills, and powders are associated with various shortcomings, such as those of poor water solubility, low bioavailability, and short half-life, which limit their effectiveness in the treatment of tumors. Early research efforts in this area were dedicated to improving the targeted delivery of the active components of TCM monomers. By combining the active TCM monomers with nanomaterials, the bioavailability and targeted specificity of TCMs can be effectively increased.

This review discusses the applications of nanoparticles in the early diagnosis and treatment of tumors in modern and traditional medicine.

Nanoparticles and early tumor diagnosis

Application of quantum dots for early tumor diagnosis

Quantum dots (QDs) are semiconductor nanocrystals with a diameter of 2–10 nm. The size-dependent optical properties, superior photostability, and modifiable surface properties of QDs enable the use of these nanoparticles as unique probes in optical imaging, highlighting the potential application of QDs in early tumor diagnosis [7, 8]. Inorganic-organic hybrid nanomaterials composed of QDs are capable of unobstructed entry into the circulatory system, as well as navigation to specific sites for interaction between targeted molecules and tumor markers [9]. In 2004, Gao et al. first reported the use of QDs in cancer targeting and imaging analysis in living animals [10]. The application of QDs in near-infrared (NIR) imaging was described by Gao et al. in 2010 [11]. Because NIR QDs effectively increase the tissue-penetration depth, photon detection can be achieved with a higher accuracy and sensitivity. Allen et al. also demonstrated that the use of QDs resulted in greater clarity and penetration depth in tumor vasculature imaging [12]. In general, good photostability, high surface modifiability, and strong tissue penetration ability of QDs enable their binding with specific tumor markers and facilitate signal transmission to detection devices, demonstrating the great potential of QDs in early tumor diagnosis.

Application of nanoparticles in magnetic resonance imaging for early tumor diagnosis

Decades of clinical trials have proven that magnetic resonance imaging (MRI) is a highly effective noninvasive imaging tool for disease diagnosis and monitoring. With significant progress achieved in MRI techniques over recent years, many researchers are now dedicating their efforts to the application of nanoparticles to enhance the tumor-diagnostic capabilities of MRI. In particular, ultrasmall superparamagnetic iron oxide nanoparticles have demonstrated the widest applications among magnetic nanoparticles. Besides serving as contrast agents for MRI, iron oxide nanoparticles have also been utilized by researchers as carriers for targeted drug delivery of chemotherapeutic agents [13, 14]. Superparamagnetic iron oxide (SPIO) nanoparticles were the first to be applied in clinical tumor imaging [15]. Previous studies have shown that SPIO nanoparticles are readily taken up by Kupffer cells—specialized macrophages located in the hepatic parenchyma. Because most hepatic tumors lack macrophages, the specific uptake of SPIO nanoparticles by macrophages increases the contrast between healthy and diseased tissue, enabling the detection of primary or metastatic hepatic lesions as small as 2–3 mm [16, 17]. To increase the specificity of magnetic nanoparticles, researchers have conjugated chlorotoxin (a small peptide present in scorpion venom and a highly specific marker for glioma cells) with magnetic nanoparticles to guide the targeting of tumors in animals [18]. Meng et al. conjugated SPIO nanoparticles with chlorotoxin and fluorescein isothiocyanate, which provided both MRI and optical imaging abilities and enabled fluorescence emission [19]. Gadolinium (Gd)-based complexes are the most commonly used MRI contrast agents used in clinical settings. However, the applications of these complexes are limited due to their relatively low sensitivity. With nanotechnology, major progress has been made in overcoming the low sensitivity of Gd-based complexes [20, 21]. Researchers have also found that chitosan-loaded nanoparticles have a longer residence time in tumor tissues [22]. Xu et al. synthesized a Gd(III)-1B4M-DTPA chelated G2 PAMAM dendrimer, labeled with rhodamine green, which could be used for targeted detection of ovarian cancer through MRI and fluorescence. Validation in mice bearing ovarian cancer xenografts demonstrated that the dendrimer bound effectively and specifically to the tumor tissue, and delivered sufficient amounts of chelated Gd(III) and fluorophores to the ovarian tumor to produce visible changes detectable by both, MRI and optical imaging [23].

Application of nanoparticles in positron emission tomography for early tumor diagnosis

The use of positron emission tomography (PET) for disease diagnosis has become increasingly common in clinical settings due to its noninvasive nature, high patient compliance, and high diagnostic accuracy. PET imaging provides effective diagnosis of tumors and cardiovascular diseases. Previous research has indicated that the sensitivity of PET imaging in tumor diagnosis can be further enhanced using a radioactive nucleotide-labeled nanoparticle carrier system [24]. The use of nanoparticles allows for the development of multimodal imaging probes for image-guided targeting. Different types of imaging probes may be combined with a single nanoparticle for the evaluation of its effectiveness in tumor targeting [25, 26]. Cai et al. recently developed a multifunctional probe for PET and NIR fluorescence imaging. A QD with an amine-functionalized surface was modified with Arg-Gly-Asp (RGD) peptides and 1, 4, 7, 10-tetraazacyclodocecane-N, N’, N”, N”’-tetraacetic acid chelators and subsequently labeled with 64Cu for PET imaging. Such nanoparticle agents (RGD peptide-conjugated QDs) were applied to mice bearing U87MG human glioblastoma cells (integrin αvβ3-positive). Results indicated that the dual-function probe enabled the imaging of tiny tumor tissue in the mice, thus demonstrating the promising prospects of the application of such probes in early tumor diagnosis [27, 28]. The combination of different imaging modalities (e.g., PET and optical imaging), through the application of nanoparticles, offers great potential in effective clinical diagnosis [29]. For example, while PET imaging provides useful high-level information on the full-body macroenvironment, optical imaging provides valuable molecular-grade information on the tumor microenvironment. By incorporating tumor-specific targeting agents with the help of nanotechnology, the sensitivity and diagnostic ability of these imaging methods can be combined and enhanced further [30].

Nanoparticles as drug carriers for early tumor treatment

The improvement of the safety and tolerability profile and target-selectivity of antitumor agents has always been a key aim of researchers. Recent developments in nanotechnology have uncovered novel research approaches for the targeted delivery of antitumor drugs, enabling substantial progress in basic and applied research in this area. Gold nanoparticles (AuNPs), inorganic nanomaterials, can have different functions and morphologies conferred to them by their unique biochemical characteristics. AuNPs can be classified into Au nanospheres, Au nanorods, and Au nanocrystals, based on the morphology, and were mainly used for the photothermal ablation of tumors in the early years [31]. Subsequent research revealed that various drugs and targeted molecules can readily bind to the AuNPs, upon appropriate surface modifications of the latter. Exploiting the unique properties of the nanoparticles, Khutale and Casey developed a multifunctional AuNP-based drug delivery system (Au-PEG-PAMAM-DOX) for the delivery of doxorubicin (DOX). Results of the study indicated that the drug-delivery system efficiently achieved the targeted delivery of the antitumor drug DOX to tumor sites, enabling the targeted killing and growth inhibition of tumor cells [32]. To improve the accuracy of targeted antitumor-drug delivery, Ren designed a coordinated release system based on the photothermal and infrared-response characteristics of AuNPs [33]. In another study, Yang et al. reported the development of a novel nanomaterial for tumor diagnosis and treatment by wrapping a bovine-serum-albumin-based Gd/Au complex on the surface of biodegradable mesoporous silica nanoparticles. Biodegradable mesoporous silica nanoparticles have previously been successfully used as nanoscale drug carriers for tumor treatment, through disulfide linkages. This was followed by the addition of folate as the targeting ligand. Researchers found that the degradation rate of bMSN-ss-COOH was significantly higher under acidic conditions than that under normal conditions, which prevented the rapid excretion from the body and favored the swift release of the antitumor drug after entering the tumor cells. In addition, the target-specificity of bMSN-ss-GABA towards the tumor demonstrated that the folate modification enhanced the endocytosis of the nanoparticles and further promoted the anti-tumor activity of the drug [34].

The combination of various types of chemotherapeutic agents with functional nanoscale radiosensitizers to attain synergy between chemotherapy and radiotherapy also serves as an effective means of killing tumor cells. Werner et al. found that Genexol-PM, a polymeric nanoparticle micelle formulation of paclitaxel, achieved sensitivity enhancement ratios of 1.12 and 1.23, in H460 cells and A549 cells, respectively, which was indicative of better radiosensitivity compared with Taxol [35]. Shi et al. found that tocopheryl polyethylene glycol 1000 succinate-emulsified docetaxel-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles had a significantly higher radiosensitization effect on radioresistant tumor cells, A549 and CNE-1, compared with docetaxel alone. The improved radiosensitization effect was associated with the enhancement of cell-cycle arrest in the G2/M phase and promotion of apoptosis by the nanoparticles. This also led to the improvement of cell uptake and inhibition of multiple drug resistance by tocopheryl polyethylene glycol 1000 succinate [36]. Certain polymers, block copolymers, liposomes, organic silanes, hydrogels, and mesoporous or easily modifiable nanomaterials are commonly used as carriers for chemotherapeutic drugs and radiosensitizers. Examples include polydopamine loaded with the radioactive nuclide 131I and the chemotherapeutic drug DOX [37], block copolymers loaded with docetaxel [38], organic silanes loaded with a cisplatin prodrug [39], mesoporous silicon dioxide loaded with mitomycin C [40], topotecan [41] or selenocysteine [42], and carbon nanotubes loaded with catechin [43]. Such methods not only improve the biocompatibility of nanomaterials and their target-specificity towards tumor cells, overcoming the multidrug resistance associated with chemotherapeutic drugs, but also enhance the synergistic treatment effects of chemotherapy and radiotherapy. Chang et al. showed that RGD- and adrenocortico polypeptide-modified Au@Se-R/A nanocomposites could be used for synergistic radiochemotherapy [44]. In a study by Song et al., hollow tantalum oxide nanoshells were used as radiosensitizers, and cell-cycle arrest into radiation-sensitive phases was induced through the loading of the chemotherapeutic agent SN-38 [45]. Another study by Liu et al. demonstrated the effective inhibition of hypoxic tumor-cell growth through the utilization of upconversion nanoparticles as radiosensitizers, and loading of the nanoparticles with the chemotherapeutic agent tirapazamine [46]. Novel inorganic nanomaterials such as selenium nanoparticles [47] are capable of achieving synergy between chemotherapy and radiotherapy. Researchers have also found that cysteine-modified Fe Pt nanoparticles can serve the dual function of chemotherapeutic agents and radiosensitizers, wherein Pt ions can provide chemotherapeutic effects by reacting with DNA, while the strong radioactive decay of Pt, a heavy metal, promotes the generation of reactive oxygen species, making the nanoparticles suitable for use as radiosensitizers. This results in the realization of synergistic chemoradiotherapy [48].

Nanomaterials are of great significance to tumor treatment, and substantial progress has been attained in basic research on the use of nanomaterials in tumor treatment. However, there are relatively few reports on the application of nanomaterials in the clinical treatment of tumors. Further research in the form of meticulously conducted large-scale clinical trials is needed to validate the clinical safety and efficacy of nanomaterials in the treatment of tumors.

Nanoparticles as drug carriers for application in tumor treatment with TCM monomers

Relevant studies have shown that TCM monomers play an active role in the treatment of tumors. With the increasing application of nanomaterials in the field of tumor research, many attempts have been made to combine the TCM monomers with nanomaterials for tumor treatment. Early research efforts in this area had been dedicated to enhancing the targeted delivery of the active components of TCM monomers. Solid lipid nanoparticles (SLNs) are nanomaterials comprised of solid lipids, with have diameters ranging between 50 and 1000 nm [49]. To enhance the effects of tetrandrine (TET), which is extracted from Han Fang Ji (S. Moore), in the treatment of arthritis, silicosis, hypertension, and fibrosis, Li et al. extracted the lipophilic active components of TET and utilized SLNs as a carrier, which increased the bioavailability and targeted-specificity of TET [50]. Chen et al. found that zedoary turmeric oil (ZTO), a volatile oil extracted from the dry rhizome of E Zhu (Val.), possessed antitumor activity and provided protection against liver injury [51]. However, ZTO has low bioavailability and limited clinical applications, as it causes irritation of the upper gastrointestinal tract and has poor water solubility. Zhao et al. found that the loading of ZTO onto SLNs prepared by a melt-emulsification technique significantly alleviated the side effects and improved the targeted-specificity of ZTO in the treatment of diseases [52].

The polysaccharides found in TCM play a crucial role in the regulation of many physiological processes in the human body, and possess antitumor, anti-inflammatory, and antioxidant properties. Chinese yam polysaccharide (CYP) which is extracted from Shan Yao (Thunb.), the major constituent of Chinese yam, has been proven to have antitumor activity, by Kim et al. However, the shortcomings of CYP, including strong dose dependence and short half-life, limit its applications in the clinical treatment of tumors [53]. To overcome this, Li et al. selected PLGA nanoparticles, believed to possess high biocompatibility and biodegradability characteristics, to encapsulate CYP and increase its biological activity [24]. PLGA mainly comprises lactic acid and glycolic acid, and is ultimately metabolized to carbon dioxide and water in the human body. When used as a drug carrier, PLGA’s biocompatibility and biodegradability favors a sustained and effective release of drugs in the body [54]. Therefore, PLGA-based nanomaterials can potentially serve as suitable carriers for enhancement of the bioavailability of active TCM components.

Chuan Xin Lian ((Burm. f.) Nees, APN) is an important medicinal plant in TCM. Studies have indicated that the monomer andrographolide of APN possesses a wide spectrum of anticancer activities; however, the agent has a low bioavailability due to its poor water solubility [55, 56]. Zhang utilized glyceryl tribehenate as a carrier material and poloxamer as an emulsifier for the preparation of an andrographolide derivative, ATC-II-SLNs, by high-pressure homogenization. When a tumor formation experiment was conducted with nude mice, ATC-II-SLNs were found to provide stronger inhibitory effects towards tumor growth and increase targeted-specificity of the drug in the liver, compared with ATC-II, indicating good prospects for the clinical application of these nanoparticles [57]. In another study by Yao et al., the effective components of APN (mainly diterpene lactones) were encapsulated using methoxy poly(ethylene glycol)-poly(D.L-lactic acid) (mPEG-PLA) nanomaterials. Results showed that the mPEG-PLA-APN particles were stable against salt dissociation, protein adsorption, and anion substitution. Cytotoxicity testing in vitro demonstrated that the inhibitory effect of mPEG-PLA-APN on cell viability in the mouse mammary carcinoma cell line 4T-1 was more significant than that of free APN [58].

Luteolin (Lu), which is extracted from Mu Xi Cao (), a flavonoid, can inhibit tumor cell proliferation, promote the activation of cell cycle checkpoints, and induce apoptosis in early mutant cells, thereby preventing tumor formation and development [59]. However, the clinical applications of Lu have been considerably limited due to its poor water solubility. Qiu et al. used monomethoxy poly (ethylene glycol)-poly(e-caprolactone) (MPEG-PCL) micelles to encapsulate Lu by a self-assembly method to obtain water-soluble Lu/MPEG-PCL micelles. This enabled the slow release of Lu from the Lu/MPEG-PCL micelles, leading to its sustained effects in the body. Results of in vivo and in vitro experiments also indicated that the inhibitory effects of Lu/MPEG-PCL on tumor growth were more significant than those of Lu [60].

Quercetin (2-(3, 4-dihydroxyphenyl)-3, 5, 7-trihydroxychromen-4-one), a natural flavonoid commonly found in fruits and vegetables,such as onions, apples and strawberries, can regulate multiple biological pathways, including induction of apoptosis, and inhibition of angiogenesis and cell-proliferation. Quercetin has also been reported to protect against oxidative stress and mutagenesis in normal cells [61, 62]. However, the poor water solubility of quercetin necessitates the use of solvents such as dimethyl sulfoxide or ethanol, during administration, which can cause dose-dependent hemolysis as well as liver and kidney impairments. Quercetin’s low bioavailability also limits its use as a pharmaceutical agent [63]. Hu et al. developed a quercetin prodrug through the phosphorylation of its hydroxyl groups, which not only increased its water solubility but also facilitated its precipitation with calcium to form an amorphous nanoparticle core, used in the formulation of lipid calcium phosphate nanoparticles. The targeted lipid calcium phosphate nanoparticle formulation was shown to have a high loading efficiency and a particle size of approximately 35 nm, which significantly improved the bioavailability and metabolic stability of quercetin. Following the systemic administration of the quercetin phosphate nanoparticles, quercetin phosphate was released and was found to convert back to the quercetin under physiological conditions. In a stroma-rich bladder carcinoma model, a significant downregulation of Wnt16 expression and a synergistic antitumor effect was observed with cisplatin nanoparticles, suggesting that quercetin phosphate alone significantly remodeled the tumor microenvironment, thereby increasing the penetration of the second-wave nanoparticles into the tumor nests. Therefore, quercetin phosphate nanoparticles may be a safe and effective alternative to improve the treatment outcomes for desmoplastic tumors [64].

Curcumin (Cur), a natural polyphenol derived from Jiang Huang (L.), possesses a broad range of therapeutic properties, and can provide antioxidant, anti-inflammatory, antitoxic, antimicrobial and antitumor effects [65]. Besides having superior pharmacological characteristics, Cur is also an ideal chemosensitizer, as it downregulates multidrug- resistance proteins and inhibits cancer cell proliferation through the inhibition of human epidermal growth factor receptor 2 activity and activation of nuclear factor kappa B [66, 67]. In addition, high doses of Cur can provide cardiac protection without causing systemic side effects [68]. However, the clinical utility of Cur is low because of its insolubility in water and poor bioavailability [69]. P-glycoprotein-mediated drug efflux is considered to be the major obstacle limiting the success of cancer chemotherapy. To effectively overcome multidrug resistance, enhance the antitumor effects, and reduce the side effects of drugs, Wang et al. prepared DOX and Cur co-encapsulated pegylated polymeric micelles. These micelles had a high loading efficiency, high stability, and the ability to simultaneously deliver a chemotherapeutic drug along with a multidrug-resistance modulator to the tumor sites. As a chemosensitizer, Cur enhanced the absorption of DOX by MCF7/Adr cells, thereby enhancing the latter’s anticancer activity. Results also indicated that the DOX and Cur co-encapsulated pegylated polymeric micelles significantly increased the cellular uptake and cellular apoptosis in vitro, as well as enhanced the antitumor activity and reduced the systemic side effects in vivo of DOX. Therefore, the concomitant use of anticancer agents and chemosensitizers may be a promising approach in tumor treatment [70].

Cornus officinalis is a widely distributed woody plant native to China, Japan, and Korea. Its fruit, known as Shan Zhu Yu () in China, is considered a valuable herb and tonic, mainly used by the Chinese for the improvement of kidney function [71]. Shan Zhu Yu () extract possesses antidiabetic, antioxidant, immunoregulatory, and antihyperglycemic effects, and can be used for the treatment of cancer and shock [71, 72]. Through phytochemical research, more than 150 different compounds with diverse structures have been isolated from Shan Zhu Yu (), including iridoid glycosides, anthocyanidin, flavonoids, saccharides, and tannins [73]. In particular, compounds such as anthocyanidin have attracted widespread attention, as they possess a broad range of biological properties, including anti-inflammatory, antioxidant, antitumor, and antidiabetic properties [74, 75]. In consideration of the wide range of biological activity and chemical components of Shan Zhu Yu (), He et al. prepared Ag NPs with the use of the aqueous extract of Shan Zhu Yu () and obtained uniformly dispersed nanoparticles with an average size of 11.7 nm, with potential pharmacological effects. Water-soluble biological molecules such as flavonoids and/or anthocyanidin play a key role in the reduction and stabilization of Ag NPs. The Ag NPs synthesized using the aqueous Shan Zhu Yu () extract exhibited remarkable anticancer properties against human prostate cancer (PC-3) and human liver cancer (HepG2) cells. The results of this study provided a low-cost, nontoxic, and eco-friendly method for the synthesis of metal nanoparticles as well demonstrated as a novel approach for future anticancer research [76].

Prospects

With the current lack of effective diagnostic and treatment measures, tumors remain a colossal threat to human health globally. With the help of recent experimental research, significant progress has been made in the application of nanomaterials in tumor diagnosis and treatment. However, researchers still face substantial challenges in the effective application of these materials in clinical settings. In particular, the biosafety of nanomaterials remains a critical challenge, as there is a lack of clear evidence indicating that nanomaterials can be effectively metabolized in the body, without causing significant side effects of toxicity through accumulation. Furthermore, the determination of safe-dose levels of the nanoparticle-based drugs is difficult, due to a lack of definite evaluation criteria. However, it is an indisputable fact that the combination of nanomaterials and biological diagnostic techniques can effectively assist in the diagnosis and prevention of diseases. Nanomedical techniques can contribute positively to the further development of clinical medicine and basic medicine. In general, the application of TCM in the treatment of tumors is limited by the biochemical characteristics of the therapeutic agents. However, the advent of nanomaterials has uncovered novel approaches to overcome these limitations, through combining the active TCM components with nanomaterials, thereby effectively enhancing the formers’ biological efficacy and target-specificity. When used concomitantly with other chemotherapeutic agents, nanomaterials can also help resolve the problem of tumor drug resistance. In addition, the side effects caused by the poor target-specificity of TCM may also be greatly avoided with the help of nanomaterials.

1. Ghosn M, Kourie HR, Abdayem P, et al. Anal cancer treatment: current status and future perspectives. World J Gastroenterol 2015, 21: 2294–2302.

2. Moriguchi M, Umemura A, Itoh Y. Current status and future prospects of chemotherapy for advanced hepatocellular carcinoma. Clin J Gastroenterol 2016, 9: 184–190.

3. Jain AK, Thareja S. In vitro and in vivo characterization of pharmaceutical nanocarriers used for drug delivery. Artif Cells Nanomed Biotechnol 2019, 47: 524–539.

4. Nel A, Xia T, Madler L, et al. Toxic potential of materials at the nanolevel. Science 2006, 311: 622–627.

5. Medina C, Santos-Martinez MJ, Radomski A, et al. Nanoparticles: pharmacological and toxicological significance. Br J pharmacol 2007, 150: 552–558.

6. Suk KH, Gopinath SCB. Drug Encapsulated Nanoparticles for Treating Targeted Cells. Curr Med Chem 2017, 24: 3310–3321.

7. Clementino A, Sonvico F. Development and validation of a RP-HPLC method for the simultaneous detection and quantification of simvastatin's isoforms and coenzyme Q10 in lecithin/chitosan nanoparticles. J Pharm Biomed Anal 2018, 155: 33–41.

8. Zhao Y, Sun Q, Zhang X, et al. Self-assembled selenium nanoparticles and their application in the rapid diagnostic detection of small cell lung cancer biomarkers. Soft Matter 2018, 14: 481–489.

9. Geszke M, Murias M, Balan L, et al. Folic acid-conjugated core/shell ZnS:Mn/ZnS quantum dots as targeted probes for two photon fluorescence imaging of cancer cells. Acta Biomater 2011, 7: 1327–1338.

10. Gao X, Cui Y, Levenson RM, et al. In vivo cancer targeting and imaging with semiconductor quantum dots. Nat Biotechnol 2004, 22: 969–976.

11. Gao J, Chen X, Cheng Z. Near-infrared quantum dots as optical probes for tumor imaging. Curr Top Med Chem 2010, 10: 1147–1157.

12. Allen PM, Liu W, Chauhan VP, et al. InAs (ZnCdS) quantum dots optimized for biological imaging in the near-infrared. J Am Chem Soc 2010, 132: 470–471.

13. Smits LP, Tiessens F, Zheng KH, et al. Evaluation of ultrasmall superparamagnetic iron-oxide (USPIO) enhanced MRI with ferumoxytol to quantify arterial wall inflammation. Atherosclerosis 2017, 263: 211–218.

14. Philips BWJ, Stijns RCH, Rietsch SHG, et al. USPIO-enhanced MRI of pelvic lymph nodes at 7-T: preliminary experience. Eur Radiol 2019, 29: 6529–6538.

15. Reimer P, Tombach B. Hepatic MRI with SPIO: detection and characterization of focal liver lesions. Eur Radiol 1998, 8: 1198–1204.

16. Li YW, Chen ZG, Wang JC, et al. Superparamagnetic iron oxide-enhanced magnetic resonance imaging for focal hepatic lesions: systematic review and meta-analysis. World J Gastroenterol 2015, 21: 4334–4344.

17. Corot C, Robert P, Idee JM, et al. Recent advances in iron oxide nanocrystal technology for medical imaging. Adv Drug Deliv Rev 2006, 58: 1471–1504.

18. Lyons SA, O'Neal J, Sontheimer H. Chlorotoxin, a scorpion-derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin. Glia 2002, 39: 162–173.

19. Meng XX, Wan JQ, Jing M, et al. Specific targeting of gliomas with multifunctional superparamagnetic iron oxide nanoparticle optical and magnetic resonance imaging contrast agents. Acta Pharmacol Sin 2007, 28: 2019–2026.

20. Ichikawa H, Uneme T, Andoh T, et al. Gadolinium-loaded chitosan nanoparticles for neutron-capture therapy: influence of micrometric properties of the nanoparticles on tumor-killing effect. Appl Radiat Isot 2014, 88: 109–113.

21. Deagostino A, Protti N, Alberti D, et al. Insights into the use of gadolinium and gadolinium/boron-based agents in imaging-guided neutron capture therapy applications. Future Med Chem 2016, 8: 899–917.

22. Park H, Kim MH, Yoon YI, et al. One-pot synthesis of injectable methylcellulose hydrogel containing calcium phosphate nanoparticles. Carbohydr Polym 2017, 157: 775–783.

23. Xu H, Regino CA, Koyama Y, et al. Preparation and preliminary evaluation of a biotin-targeted, lectin-targeted dendrimer-based probe for dual-modality magnetic resonance and fluorescence imaging. Bioconjug Chem 2007, 18: 1474–1482.

24. Lu J, Sun XD, Yang X, et al. Impact of PET/CT on radiation treatment in patients with esophageal cancer: A systematic review. Crit Rev Oncol Hematol 2016, 107: 128–137.

25. Cui L, Rao J. Semiconducting polymer nanoparticles as photoacoustic molecular imaging probes. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2017, 9: e1418

26. Li J, Rao J, Pu K. Recent progress on semiconducting polymer nanoparticles for molecular imaging and cancer phototherapy. Biomaterials 2018, 155: 217–235.

27. Cai W, Chen K, Li ZB, et al. Dual-function probe for PET and near-infrared fluorescence imaging of tumor vasculature. J Nucl Med 2007, 48: 1862–1870.

28. Deng H, Wang H, Li Z. Matching chelators to radiometals for positron emission tomography imaging-guided targeted drug delivery. Curr Drug Targets 2015, 16: 610–624.

29. Skovgaard D, Persson M, Kjaer A. PET imaging of urokinase-type plasminogen activator receptor (uPAR) in prostate cancer: current status and future perspectives. Clin Transl Imaging 2016, 4: 457–465.

30. Skovgaard D, Persson M, Kjaer A. Urokinase plasminogen activator receptor-PET with (68) Ga-NOTA-AE105: first clinical experience with a novel PET ligand. PET Clin 2017, 12: 311–319.

31. Li W, Cao Z, Liu R, et al. AuNPs as an important inorganic nanoparticle applied in drug carrier systems. Artif Cells Nanomed Biotechnol 2019, 47: 4222–4233.

32. Khutale GV, Casey A. Synthesis and characterization of a multifunctional gold-doxorubicin nanoparticle system for pH triggered intracellular anticancer drug release. Eur J Pharm Biopharm 2017, 119: 372–380.

33. Ren Y, Wang R, Gao L, et al. Sequential co-delivery of miR-21 inhibitor followed by burst release doxorubicin using NIR-responsive hollow gold nanoparticle to enhance anticancer efficacy. J Control Release 2016, 228: 74–86.

34. Yang S, Chen L, Zhou X, et al. Tumor-targeted biodegradable multifunctional nanoparticles for cancer theranostics. Chem Eng J 2019, 378: 122171.

35. Werner ME, Cummings ND, Sethi M, et al. Preclinical evaluation of Genexol-PM, a nanoparticle formulation of paclitaxel, as a novel radiosensitizer for the treatment of non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2013, 86: 463–468.

36. Shi W, Yuan Y, Chu M, et al. Radiosensitization of TPGS-emulsified docetaxel-loaded poly (lactic-co-glycolic acid) nanoparticles in CNE-1 and A549 cells. J Biomater Appl 2016, 30: 1127–1141.

37. Li Z, Wang B, Zhang Z, et al. Radionuclide imaging-guided chemo-radioisotope synergistic therapy using a (131)I-labeled polydopamine multifunctional nanocarrier. Mol Ther 2018, 26: 1385–1393.

38. Au KM, Min Y, Tian X, et al. Improving cancer chemoradiotherapy treatment by dual controlled release of wortmannin and docetaxel in polymeric nanoparticles. ACS Nano 2015, 9: 8976–8996.

39. Rocca JD, Werner ME, Kramer SA, et al. Polysilsesquioxane nanoparticles for triggered release of cisplatin and effective cancer chemoradiotherapy. Nanomedicine 2015, 11: 31–38.

40. Fan W, Shen B, Bu W, et al. Design of an intelligent sub-50 nm nuclear-targeting nanotheranostic system for imaging guided intranuclear radiosensitization. Chem Sci 2015, 6: 1747–1753.

41. Shen B, Zhao K, Ma S, et al. Topotecan-loaded mesoporous silica nanoparticles for reversing multi-drug resistance by synergetic chemoradiotherapy. Chem Asian J 2015, 10: 344–348.

42. He L, Lai H, Chen T. Dual-function nanosystem for synergetic cancer chemo-/radiotherapy through ROS-mediated signaling pathways. Biomaterials 2015, 51: 30–42.

43. Castro Nava A, Cojoc M, Peitzsch C, et al. Development of novel radiochemotherapy approaches targeting prostate tumor progenitor cells using nanohybrids. Int J Cancer 2015, 137: 2492–2503.

44. Chang Y, He L, Li Z, et al. Designing core-shell gold and selenium nanocomposites for cancer radiochemotherapy. ACS Nano 2017, 11: 4848–4858.

45. Song G, Chao Y, Chen Y, et al. All-in-one theranostic nanoplatform based on hollow TaOx for chelator-free labeling imaging, drug delivery, and synergistically enhanced radiotherapy. Adv Funct Mater 2016, 26: 8243–8254.

46. Liu Y, Bu W, et al. Radiation-/hypoxia-induced solid tumor metastasis and regrowth inhibited by hypoxia-specific upconversion nanoradiosensitizer. Biomaterials 2015, 49: 1–8.

47. Yu B, Liu T, Du Y, et al. X-ray-responsive selenium nanoparticles for enhanced cancer chemo-radiotherapy. Colloids Surf B Biointerfaces, 2016, 139: 180–189.

48. Sun Y, Miao H, Ma S, et al. FePt-Cys nanoparticles induce ROS-dependent cell toxicity, and enhance chemo-radiation sensitivity of NSCLC cells in vivo and in vitro. Cancer Lett 2018, 418: 27–40.

49. Uner M, Wissing SA, Yener G, et al. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for application of ascorbyl palmitate. Pharmazie 2005, 60: 577–582.

50. Li Y, Dong L, Jia A, et al. Preparation and characterization of solid lipid nanoparticles loaded traditional Chinese medicine. Int J Biol Macromol 2006, 38: 296–299.

51. Chen CC, Chen Y, Hsi YT, et al. Chemical constituents and anticancer activity of Curcuma zedoaria roscoe essential oil against non-small cell lung carcinoma cells in vitro and in vivo. J Agric Food Chem 2013, 61: 11418–11427.

52. Zhao XL, Yang CR, Yang KL, et al. Preparation and characterization of nanostructured lipid carriers loaded traditional Chinese medicine, zedoary turmeric oil. Drug Dev Ind Pharm 2010, 36: 773–780.

53. Kim SK, Lee SC, Shin DH, et al. Quantification of endogenous gibberellins in leaves and tubers of Chinese yam, dioscorea opposita thunb. cv. tsukune during tuber enlargement. Plant Growth Regulation 2003, 39: 125–130.

54. Kumari A, Yadav SK, Yadav SC. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B Biointerfaces 2010, 75: 1–18.

55. Wang W, Guo W, Li L, et al. Andrographolide reversed 5-FU resistance in human colorectal cancer by elevating BAX expression. Biochem Pharmacol 2016, 121: 8–17.

56. Mishra SK, Tripathi S, Shukla A, et al. Andrographolide and analogues in cancer prevention. Front Biosci (Elite Ed) 2015, 7: 255–266.

57. Zhang SJ. Research on anticipation system of andrographolide derivative ATC-Ⅱ solid crystal nanoparticles. Henan University, 2012.

58. Yao H, Song S, Miao X, et al. mPEG-PLA micelle for delivery of effective parts of andrographis paniculata. Curr Drug Deliv 2018, 15: 532–540.

59. Rao PS, Satelli A, Moridani M, et al. Luteolin induces apoptosis in multidrug resistant cancer cells without affecting the drug transporter function: involvement of cell line-specific apoptotic mechanisms. Int J Cancer 2012, 130: 2703–2714.

60. Qiu JF, Gao X, Wang BL, et al. Preparation and characterization of monomethoxy poly(ethylene glycol)-poly(epsilon-caprolactone) micelles for the solubilization and in vivo delivery of luteolin. Int J Nanomedicine 2013, 8: 3061–3069.

61. Aniya Y. Development of bioresources in Okinawa: understanding the multiple targeted actions of antioxidant phytochemicals. J Toxicol Pathol 2018, 31: 241–253.

62. Bongiovanni GA, Soria EA, Eynard AR. Effects of the plant flavonoids silymarin and quercetin on arsenite-induced oxidative stress in CHO-K1 cells. Food Chem Toxicol 2007, 45: 971–976.

63. Wu Q, Deng S, Li L, et al. Biodegradable polymeric micelle-encapsulated quercetin suppresses tumor growth and metastasis in both transgenic zebrafish and mouse models. Nanoscale 2013, 5: 12480–12493.

64. Hu K, Miao L, Goodwin TJ, et al. Quercetin remodels the tumor microenvironment to improve the permeation, retention, and antitumor effects of nanoparticles. ACS Nano 2017, 11: 4916–4925.

65. Mohajeri M, Sahebkar A. Protective effects of curcumin against doxorubicin-induced toxicity and resistance: a review. Crit Rev Oncol Hematol 2018, 122: 30–51.

66. Murakami M, Ohnuma S, Fukuda M, et al. Synthetic analogs of curcumin modulate the function of multidrug resistance-linked ATP-binding cassette transporter ABCG2. Drug Metab Dispos 2017, 45: 1166–1177.

67. Meiyanto E, Putri DD, Susidarti RA, et al. Curcumin and its analogues (PGV-0 and PGV-1) enhance sensitivity of resistant MCF-7 cells to doxorubicin through inhibition of HER2 and NF-kB activation. Asian Pac J Cancer Prev 2014, 15: 179–184.

68. Yang C, Wu K, Li SH, et al. Protective effect of curcumin against cardiac dysfunction in sepsis rats. Pharm Biol 2013, 51: 482–487.

69. Zhao X, Chen Q, Li Y, et al. Doxorubicin and curcumin co-delivery by lipid nanoparticles for enhanced treatment of diethylnitrosamine-induced hepatocellular carcinoma in mice. Eur J Pharm Biopharm 2015, 93: 27–36.

70. Wang J, Ma W, Tu P. Synergistically improved anti-tumor efficacy by co-delivery doxorubicin and curcumin polymeric micelles. Macromol Biosci 2015, 15: 1252–1261.

71. Huang J, Zhang Y, Dong L, et al. Ethnopharmacology, phytochemistry, and pharmacology ofJ Ethnopharmacol 2018, 213: 280–301.

72. Liu X, Han ZP, Wang YL, et al. Analysis of the interactions of multicomponents inwith human serum albumin using on-line dialysis coupled with HPLC. J Chromatogr B Analyt Technol Biomed Life Sci 2011, 879: 599–604.

73. Lin MH, Liu HK, Huang WJ, et al. Evaluation of the potential hypoglycemic and Beta-cell protective constituents isolated from Corni fructus to tackle insulin-dependent diabetes mellitus. J Agric Food Chem 2011, 59: 7743–7751.

74. Seeram NP, Schutzki R, Chandra A, et al. Characterization, quantification, and bioactivities of anthocyanins in Cornus species. J Agric Food Chem 2002, 50: 2519–2523.

75. Czerwinska ME, Melzig MF. Cornus mas and Cornus officinalis-analogies and differences of two medicinal plants traditionally used. Front Pharmacol 2018, 9: 894.

76. He Y, Li X, Wang J, et al. Synthesis, characterization and evaluation cytotoxic activity of silver nanoparticles synthesized by Chinese herbal Cornus officinalis via environment friendly approach. Environ Toxicol Pharmacol 2017, 56: 56–60.

:

This study was supported by grants from the National Natural Science Foundation of China (Grant No. 81801175), the Fundamental Research Funds for the Central Universities (Grant No. WK9110000044), the China Postdoctoral Science Foundation (Grant No. 2019M662179), and the Anhui Province Postdoctoral Science Foundation (Grant No. 2019B324).

:

TCM, traditional Chinese medicine; QDs, quantum dots; NIR, near-infrared; MRI, magnetic resonance imaging; SPIO, superparamagnetic iron oxide; Gd, gadolinium; PET, positron emission tomography; RGD, Arg-Gly-Asp; PLGA, poly (lactic-co-glycolic acid);SLNs, Solid lipid nanoparticles;TET, tetrandrine;ZTO, zedoary turmeric oil;CYP, Chinese yam polysaccharide;APN,(Burm. f.) Nees;mPEG-PLA, methoxy poly(ethylene glycol)-poly(D.L-lactic acid);Lu, luteolin;Cur, curcumin;DOX, doxorubicin;MPEG-PCL, monomethoxy poly(ethylene glycol)-poly(e-caprolactone); AuNPs, gold nanoparticles.

:

The authors declare that they have no conflict of interest. The authors alone are responsible for the content of the paper.

:

Chaoliang Tang, Heng Li, Junmou Hong, et al. Application of nanoparticles in the early diagnosis and treatment of tumors: current status and progress. Traditional Medicine Research 2020, 5 (1): 34–43.

:Nuo-Xi Pi.

:4 December 2019,

26 December 2019,

: 30 December 2019

Heng Li. Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No.1 Swan Lake Road, Shushan District, Hefei, 230036, China. Email: 13855133182@163.com. Junmou Hong. Department of Vascular Surgery, Zhongshan Hospital, Xiamen University, No.201–209 Hubinnan Road, Siming District,Xiamen, 361004, China. Email: hongjunmou101@163.com. Xiaoqing Chai. Department of Anesthesiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No.17 Lujiang Road, Luyang District, Hefei, 230001, China. Email: xiaoqingchai@163.com.