Category Archives: Nano Medicine

Global Healthcare Nanotechnology (Nanomedicine) Market is valued approximately USD 196.47 billion in 2019 and is anticipated to grow with a healthy growth rate of more than 11.9 % over the forecast period 2020-2027. Healthcare Nanotechnology (Nanomedicine) is the product which is nano-formulations of the existing drugs or new drugs or nanomaterials. Nanomedicine helps in improving human health by providing solutions for various life-threatening diseases, like cancer, Parkinsons disease, Alzheimers disease, diabetes, orthopedic diseases, and infections blood, lungs, and cardiovascular system.

For instance: according to the Alzheimers Disease International, there were around 50 million people globally with dementia in 2020, which is expected to double every 20 years. According to the Globocan 2020, the global cancer burden increased to 19.3 million cases and 10 million cancer deaths in 2020. This will increase the demand for effective nanomedicines in the management of the diseases. Further, increasing investments in urgent care, increasing geriatric population and strategic development between hospitals and the manufacturers has led the adoption of Healthcare Nanotechnology (Nanomedicine) across the forecast period. The market has seen positive growth due to investments in new products by research & development.

For Instance: in 2020, Medtronic PLC launched navigated titanium spinal implant, its new Adaptix Interbody System which is with the Titan nanoLOCK Surface Technology. In 2019, Nanobiotix, a clinical stage nanomedicine company had obtained the CE approval for its Hensify (NBTXR3), nanoparticles designed for injection directly into a tumor. However, stringent regulatory issues and high cost of nano-medicines compared to the traditional medicines along with low awareness among consumers in low income countries impedes the growth of the market over the forecast period of 2020-2027. Also, with the increasing prevalence of diseases, technological advancements for early disease diagnosis & preventive intervention the adoption & demand for Healthcare Nanotechnology (Nanomedicine) is likely to increase.

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The regional analysis of global Healthcare Nanotechnology (Nanomedicine) market is considered for the key regions such as Asia Pacific, North America, Europe, Latin America and Rest of the World. North America is the leading/significant region across the world in terms of market share owing to the growing geriatric population and promptness & affordability of nano-medicines coupled with the well-established healthcare infrastructure along with the huge investments in research & development activities. For instance: according to the http://www.acc.org, in 2018, coronary heart disease was the leading cause of deaths attributable to cardiovascular disease in the United States with 43.8% of total CVD deaths. Whereas, Asia-Pacific is also anticipated to exhibit highest growth rate / CAGR over the forecast period 2020-2027. Factors such as rise in research grants, increasing venture capital investors from developing economies of this region and increasing international research collaborations along with the improving healthcare infrastructure would create lucrative growth prospects for the Healthcare Nanotechnology (Nanomedicine) market across Asia-Pacific region.

Major market player included in this report are:Abbott LaboratoriesCombiMatrix CorporationGE HealthcareSigma-Tau Pharmaceuticals, Inc.Johnson & JohnsonMallinckrodt plcMerck & Company, Inc.Nanosphere, Inc.Pfizer, Inc.Celgene Corporation

The objective of the study is to define market sizes of different segments & countries in recent years and to forecast the values to the coming eight years. The report is designed to incorporate both qualitative and quantitative aspects of the industry within each of the regions and countries involved in the study. Furthermore, the report also caters the detailed information about the crucial aspects such as driving factors & challenges which will define the future growth of the market. Additionally, the report shall also incorporate available opportunities in micro markets for stakeholders to invest along with the detailed analysis of competitive landscape and product offerings of key players. The detailed segments and sub-segment of the market are explained below:By Diseases:Cardiovascular DiseasesOncological DiseasesNeurological DiseasesOthersBy Application:Drug DeliveryBiomaterialsActive ImplantsOthersBy Region:North AmericaU.S.CanadaEuropeUKGermanyFranceSpainItalyROE

Asia PacificChinaIndiaJapanAustraliaSouth KoreaRoAPACLatin AmericaBrazilMexicoRest of the World

Furthermore, years considered for the study are as follows:

Historical year 2017, 2018Base year 2019Forecast period 2020 to 2027

Send a request to Report Ocean to understand the structure of the complete report @https://www.reportocean.com/industry-verticals/sample-request?report_id=bw2116

Target Audience of the Global Healthcare Nanotechnology (Nanomedicine) Market in Market Study:

Key Consulting Companies & AdvisorsLarge, medium-sized, and small enterprisesVenture capitalistsValue-Added Resellers (VARs)Third-party knowledge providersInvestment bankersInvestors

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Healthcare Nanotechnology (Nanomedicine) Market will generate massive revenue by 2027 according to forecasts by Report Ocean The Manomet Current -...

Global Nanomedicine Market is valued at approximately USD 160 billion in 2019 and is anticipated to grow with a healthy growth rate of more than 12.6% over the forecast period 2020-2027. Nanomedicine is one of the most significant applications of nanotechnology used in the treatment, diagnosis, control, and monitoring of biological systems. Nanomedicine utilizes nanoscale manipulation of materials to enhance medicine delivery. Thus, nanomedicine has enabled the treatment alongside various diseases, such as cancer, cardiovascular diseases, and so on. Nanomedicine is the most promising mode of treatment of cancer. This expanding field of medical research can be utilized to discover improved personalized treatment for cancer in the present scenario. With the benefit of the properties of issue at nanoscale, nanomedicine pledges to create innovative drugs with larger efficacy and reduced side-effects than regular therapies. Thus, the surge in prevalence of cancer may act as a major driving factor for the growth of the market all over the world.

According to the National Cancer Institute (NIH), the prevalence of cancer has a major impact on society in the world and across the United States. As of January 2019, around 16.9 million cancer survivors were reported in the United States and is projected to increase to almost 22.2 million by the year 2030. Also, in 2020, an estimated 1,806,590 new cases of cancer were found and will be diagnosed in the United States. Furthermore, the rise in government approvals for the products developed by the manufacturers, along with the increased emergence of newer technologies for drug delivery are the few factors responsible for the high CAGR of the market during the forecast period. For instance, in February 2017, the Celgene International Srl granted approval for its REVLIMID (lenalidomide) from the European Commission, as monotherapy for patients treatment with multiple myeloma. This, in turn, is expected to strengthen the market growth all over the world. However, the high cost of nanomedicine, coupled with strict government norms for product approval are the few major factors inhibiting the market growth over the forecast period of 2020-2027.

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The regional analysis of the global Nanomedicine market is considered for the key regions such as Asia Pacific, North America, Europe, Latin America, and the Rest of the World. North America is the leading/significant region across the world in terms of market share owing to the rise in government funding for the nanoscale technology and nanomedicine, and the presence of a significant number of market vendors in the region. Whereas Asia-Pacific is anticipated to exhibit the highest growth rate / CAGR over the forecast period 2020-2027. Factors such as the rise in prevalence of chronic diseases such as cancer, along with the increasing number of venture capital investors in developing countries, such as China and India, would create lucrative growth prospects for the Nanomedicine market across the Asia-Pacific region.

Major market player included in this report are:Abbott LaboratoriesCombiMatrix Corp.General ElectricJohnson & JohnsonMallinckrodt PharmaceuticalsMerck & Co., Inc.Luminex CorporationPfizer Inc.Leadiant Biosciences, Inc.Teva Pharmaceutical Industries Ltd.

The objective of the study is to define market sizes of different segments & countries in recent years and to forecast the values to the coming eight years. The report is designed to incorporate both qualitative and quantitative aspects of the industry within each of the regions and countries involved in the study. Furthermore, the report also caters the detailed information about the crucial aspects such as driving factors & challenges which will define the future growth of the market. Additionally, the report shall also incorporate available opportunities in micro markets for stakeholders to invest along with the detailed analysis of competitive landscape and product offerings of key players. The detailed segments and sub-segment of the market are explained below:

By Modality:DiagnosticsTreatments

By Application:Drug DeliveryVaccinesDiagnostic ImagingRegenerative MedicineImplantsOthers

By Indication:Oncological DiseasesInfectious DiseasesCardiovascular DiseasesOrthopedic DisordersNeurological DiseasesOthers

By Region:North AmericaU.S.CanadaEuropeUKGermanyFranceSpainItalyROE

Asia PacificChinaIndiaJapanAustraliaSouth KoreaRoAPACLatin AmericaBrazilMexicoRest of the World

Furthermore, years considered for the study are as follows:

Historical year 2017, 2018Base year 2019Forecast period 2020 to 2027

Send a request to Report Ocean to understand the structure of the complete report @https://www.reportocean.com/industry-verticals/sample-request?report_id=bw2007

Target Audience of the Global Nanomedicine Market in Market Study:

Key Consulting Companies & AdvisorsLarge, medium-sized, and small enterprisesVenture capitalistsValue-Added Resellers (VARs)Third-party knowledge providersInvestment bankersInvestors

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Nanomedicine Market to Remain Competitive | Major Giants Continuously Expanding Market The Manomet Current - The Manomet Current

DUBLIN--(BUSINESS WIRE)--The "The Global Market for Multi-Walled Carbon Nanotubes 2021-2031" report has been added to ResearchAndMarkets.com's offering.

There has been a resurgence of industrial interest in multi-walled carbon nanotubes (MWCNT) over the last two years, after producers had previously reduced or abandoned production. LG Chem has recently launched the world's largest MWCNT manufacturing plant in Korea (1,700 tons total).

At the end of 2020, Carbice Corporation raised $15 million to develop CNTs for thermal management in electronics. Cabot Corporation acquired Shenzhen Sanshun Nano New Materials Co., Ltd (SUSN) for approximately $115 million.

MWCNTs are mainly used as substitute additives of carbon black in conductive plastics and composites applications and as additives in lithium-ion battery electrodes. MWCNT powders, arrays, sheets, flakes, films and yarns have found applications in semoconductors, power cables, automotive coatings, polymer composites, coatings, aerospace, sensors, heaters, filters and biomedicine.

Report contents include:

Key Topics Covered:

1 Executive Summary

1.1 The global market for carbon nanotubes in 2021

1.1.1 Demand for Multi-walled carbon nanotubes (MWCNTs) increasing

1.1.2 Industry developments 2020-2021

1.2 Exceptional properties

1.3 Commercial products

1.3.1 Applications

1.3.2 Key players

1.3.3 Production capacities in 2021

1.3.4 Market demand, metric tons (MT)

1.4 Carbon nanotubes market challenges

2 Ovewview of Carbon Nanotubes

2.1 Properties

2.2 Comparative properties of CNTs

3 Carbon Nanotube Synthesis And Production

4 Carbon Nanotubes Patents

5 Carbon Nanotubes Pricing And Price Drivers

6 3D Printing

7 Adhesives

8 Aerospace

9 Automotive

10 Batteries

10.2.1 Cnts In Electric Vehicle Batteries

10.2.2 Nanomaterials In Lithium-Sulfur (Li-S) Batteries

10.2.3 Nanomaterials In Sodium-Ion Batteries

10.2.4 Nanomaterials In Lithium-Air Batteries

10.2.5 Flexible And Stretchable Batteries In Electronics

10.2.6 Flexible And Stretchable Libs

10.2.6.1 Fiber-Shaped Lithium-Ion Batteries

10.2.6.2 Stretchable Lithium-Ion Batteries

10.2.6.3 Origami And Kirigami Lithium-Ion Batteries

10.2.6.4 Fiber-Shaped Lithium-Ion Batteries

10.3.1 Materials

11 Composites

12 Conductive Inks

13 Construction

13.3.1 Cement

13.3.2 Asphalt Bitumen

14 Filtration

15 Fuel Cells

16 Life Sciences And Medicine

16.3.1 Drug Delivery

16.3.2 Imaging And Diagnostics

16.3.3 Implants

16.3.4 Medical Biosensors

16.3.5 Woundcare

17 Lubricants

18 Oil And Gas

19 Paints And Coatings

20 Photovoltaics

21 Rubber And Tires

22 Sensors

23 Smart Textiles And Apparel

24 Supercapacitors

25 Other Markets

26 Collaborations

27 Company Profiles

28 Research Methodology

29 References

Companies Mentioned

For more information about this report visit https://www.researchandmarkets.com/r/2z3fem

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Multi-Walled Carbon Nanotubes Market Report 2021 - Global Production Capacities for MWCNTS Historical and Forecast to 2031 - ResearchAndMarkets.com -...

SHELTON, CT / ACCESSWIRE / February 8, 2021 / NanoViricides, Inc.. (NYSE American: NNVC) (the "Company") a global leader in the development of highly effective broad-spectrum antiviral therapies based on a novel nanomedicines platform has announced today that its broad-spectrum anti-coronavirus drug candidate for the treatment of COVID-19 infections was well tolerated in safety pharmacology studies required for progressing to human clinical trials.

The Company reports that its drug candidate NV-CoV-2 was found to be safe in the GLP safety pharmacology studies performed by an external contract research organization (CRO) in both rat and non-human primate (NHP) models. Additionally, multiple injections of NV-CoV-2 were also well tolerated in an extensive non-GLP study in rats that was performed by AR Biosystems, Inc., FL.

Based on the safety of NV-CoV-2 in these studies, the Company believes that projected dosages would be safe in human clinical trials. With these findings, the Company believes that it will be possible to administer repeated dosages of NV-CoV-2 in a human clinical trial, if needed, to achieve control over the coronavirus infection from SARS-CoV-2 or its variants.

In a GLP neuro-pulmonary safety pharmacology study in rats, the following conclusion was drawn: The intravenous administration of NV-CoV-2 at doses of 25, 50 and 100 mg/kg did not affect respiratory function in rats.

In a GLP cardiovascular function study in the NHP cynomolgus monkeys, the following conclusion was drawn: Intravenous infusion of NV-CoV-2 at 25, 37.5, and 50 mg/kg did not have any toxicologic effects on cardiac rhythm or ECG morphology in cynomolgus monkeys in this study. No significant effects on blood pressure and heart rate were observed after the intravenous infusion of NV-CoV-2.

These results were consistent with a more extensive, multiple injection non-GLP safety and tolerability study in Sprague-Dawley male and female rats. In this non-GLP study, NV-CoV-2 was injected intravenously (via tail vein) on each of days 0, 1, 2, 3, 4, and 5. Two different doses were used: 320mg/kg BW per injection, and 160 mg/kg BW per injection. Clinical observations, body weight, urine, blood chemistry, post-mortem findings, and organ histology were studied. In all parameters, NV-CoV-2 was well tolerated at both dosages throughout the study.

The Company has received draft reports from all of these studies. We anticipate receiving final audited reports on the GLP studies shortly.

The Company is preparing to submit a pre-IND application to the US FDA with safety tolerability and effectiveness data to obtain guidance regarding human clinical trials. Additionally, we are actively seeking opportunities to engage appropriate sites for human clinical trials. Further, we are engaged in the preparation of clinical trial protocols and other activities that would be necessary for submitting an IND application to the US FDA.

The need for the broad-spectrum, pan-coronavirus nanoviricide drug treatment cannot be overstated for combating the COVID-19 pandemic given the current circumstances and the present status of the pandemic. New virus variants continue to develop in the field. The variants that have advantages in terms of transmissibility, infectivity, and escape from drugs and vaccines will continue to evolve and spread, replacing prior variants. This is already well documented.

Several vaccines have been found to be substantially less effective in protecting against infection by the South African variant, N501Y-V.2 (also called lineage B.1.351) than the earlier variants. A mutation present in B.1.351 as well as Brazilian variant P.1 that is thought to be possibly linked to evasion from antibody drugs and vaccines, E484K, has also been reported in UK in a further differentiated mutant of the variant of concern lineage B.1.1.7. The available monoclonal antibody drugs and convalescent plasma antibodies have been reported to be less effective against several variants.

By the very nature of how they work, vaccines and antibodies tend to be highly specific to the target virus variant, and do not afford strong protection against differentiated variants that are evolutionary distant from the target variant. This scientific fact is now well demonstrated for the COVID-19 pandemic.

It is therefore clear that an effective broad-spectrum anti-coronavirus drug will be needed before the world can return to normal activity.

The Company previously had advanced NV-CoV-1 and had continued to work further with additional drug candidates. One of these drug candidates, namely, NV-CoV-2 was found to have several advantages over NV-CoV-1 in terms of manufacturability and dose formulation. Therefore the Company has advanced NV-CoV-2 into GLP safety/pharmacology studies.

NanoViricides is developing a broad-spectrum antiviral drug where the potential for escape of virus variants is minimized by the very design of the drug for the treatment of COVID-19 infected sick persons. In contrast, vaccines are not treatments for sick persons, and must be administered to healthy individuals, and further require several weeks for the recipient's immune system to become capable of protecting against the target virus strain which still may not protect against new virus variants circulating by that time.

NanoViricides has a strong advantage in that the Company has its own cGMP-capable manufacturing facility in Shelton, CT. This facility is capable of producing approximately 4kg of the COVID-19 drug per batch. We anticipate that this would be sufficient for human clinical trials, and possibly for initial introduction under Compassionate Use, Emergency Use Authorization or similar regulatory approval.

"We are pleased with the results of the safety pharmacology studies, and now we are confident that our COVID-19 drug candidate can advance into human clinical trials," said Anil R. Diwan, PhD, President and co-Founder of NanoViricides, Inc., and co-Inventor of its platform technologies and drug candidates.

About NanoViricides

NanoViricides, Inc. (the "Company")(www.nanoviricides.com) is a development stage company that is creating special purpose nanomaterials for antiviral therapy. The Company's novel nanoviricide class of drug candidates are designed to specifically attack enveloped virus particles and to dismantle them. Our lead drug candidate is NV-HHV-101 with its first indication as dermal topical cream for the treatment of shingles rash. In addition, we are developing a clinical candidate for the treatment of COVID-19 disease caused by SARS-CoV-2 coronavirus. The Company cannot project an exact date for filing an IND for this drug because of its dependence on a number of external collaborators and consultants.

The Company is now working on tasks for completing an IND application. The Company is currently pursuing two separate drug candidates for the treatment of COVID-19 patients. NV-CoV-2 is our nanoviricide drug candidate that does not encapsulate remdesivir. NV-CoV-2-R is our other drug candidate that is made up of NV-CoV-2 with remdesivir encapsulated in it. The Company believes that since remdesivir is already US FDA approved, our drug candidate encapsulating remdesivir is likely to be an approvable drug, if safety is comparable. Remdesivir is developed by Gilead. The Company has developed both of own drug candidates NV-CoV-2 and NV-CoV-2-R independently.

The Company intends to re-engage into an IND application to the US FDA for NV-HHV-101 drug candidate for the treatment of shingles once its COVID-19 project moves into clinical trials, based on resources availability. The NV-HHV-101 program was slowed down because of the effects of recent COVID-19 restrictions, and re-prioritization for COVID-19 drug development work.

The Company is also developing drugs against a number of viral diseases including oral and genital Herpes, viral diseases of the eye including EKC and herpes keratitis, H1N1 swine flu, H5N1 bird flu, seasonal Influenza, HIV, Hepatitis C, Rabies, Dengue fever, and Ebola virus, among others. NanoViricides' platform technology and programs are based on the TheraCour nanomedicine technology of TheraCour, which TheraCour licenses from AllExcel. NanoViricides holds a worldwide exclusive perpetual license to this technology for several drugs with specific targeting mechanisms in perpetuity for the treatment of the following human viral diseases: Human Immunodeficiency Virus (HIV/AIDS), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Rabies, Herpes Simplex Virus (HSV-1 and HSV-2), Varicella-Zoster Virus (VZV), Influenza and Asian Bird Flu Virus, Dengue viruses, Japanese Encephalitis virus, West Nile Virus and Ebola/Marburg viruses. The Company has executed a Memorandum of Understanding with TheraCour that provides a limited license for research and development for drugs against human coronaviruses. The Company intends to obtain a full license and has begun the process for the same. The Company's technology is based on broad, exclusive, sub-licensable, field licenses to drugs developed in these areas from TheraCour Pharma, Inc. The Company's business model is based on licensing technology from TheraCour Pharma Inc. for specific application verticals of specific viruses, as established at its foundation in 2005.

As is customary, the Company must state the risk factor that the path to typical drug development of any pharmaceutical product is extremely lengthy and requires substantial capital. As with any drug development efforts by any company, there can be no assurance at this time that any of the Company's pharmaceutical candidates would show sufficient effectiveness and safety for human clinical development. Further, there can be no assurance at this time that successful results against coronavirus in our lab will lead to successful clinical trials or a successful pharmaceutical product.

This press release contains forward-looking statements that reflect the Company's current expectation regarding future events. Actual events could differ materially and substantially from those projected herein and depend on a number of factors. Certain statements in this release, and other written or oral statements made by NanoViricides, Inc. are "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. You should not place undue reliance on forward-looking statements since they involve known and unknown risks, uncertainties and other factors which are, in some cases, beyond the Company's control and which could, and likely will, materially affect actual results, levels of activity, performance or achievements. The Company assumes no obligation to publicly update or revise these forward-looking statements for any reason, or to update the reasons actual results could differ materially from those anticipated in these forward-looking statements, even if new information becomes available in the future. Important factors that could cause actual results to differ materially from the company's expectations include, but are not limited to, those factors that are disclosed under the heading "Risk Factors" and elsewhere in documents filed by the company from time to time with the United States Securities and Exchange Commission and other regulatory authorities. Although it is not possible to predict or identify all such factors, they may include the following: demonstration and proof of principle in preclinical trials that a nanoviricide is safe and effective; successful development of our product candidates; our ability to seek and obtain regulatory approvals, including with respect to the indications we are seeking; the successful commercialization of our product candidates; and market acceptance of our products.

FDA refers to US Food and Drug Administration. IND application refers to "Investigational New Drug" application. cGMP refers to current Good Manufacturing Practices. CMC refers to "Chemistry, Manufacture, and Controls". CHMP refers to the Committee for Medicinal Products for Human Use, which is the European Medicines Agency's (EMA) committee responsible for human medicines.

Contact:NanoViricides, Inc.info@nanoviricides.com

Public Relations Contact:MJ ClyburnTraDigital IRclyburn@tradigitalir.com

SOURCE: NanoViricides, Inc.

View source version on accesswire.com:https://www.accesswire.com/628273/NanoViricidess-Broad-Spectrum-Antiviral-Drug-Candidate-for-the-Treatment-of-COVID-19-Infections-was-Well-Tolerated-in-GLP-and-non-GLP-Animal-Safety-Studies

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NanoViricides's Broad-Spectrum Antiviral Drug Candidate for the Treatment of COVID-19 Infections was Well Tolerated in GLP and non-GLP Animal Safety...

Introduction

Cancer remains one of the greatest challenges to human health. World Health Organization (WHO) reported that about 8.8 million deaths worldwide were due to cancer in 2015, and the deaths are expected to break through 13 million in 2030 according to the report by the International Agency for Research on Cancer (IARC). To reduce the deaths from cancer, several strategies have been developed in recent years to improve cancer therapy including surgery, radiotherapy, chemotherapy, immunotherapy, targeted therapy, hormone therapy, stem cell transplant and precision medicine.1 Among them, radiotherapy (RT) is considered as one important and effective modality to kill or control tumors since Marie Curie, the Nobel Prize winner, discovered radioactivity.2 Typically, RT is a treatment modality to cancer cells by using high-energy photon radiation such as X-rays, gamma ()-rays, and others. RT can take effect via direct and indirect mechanisms to destroy cancer cells and tumor tissue (Figure 1).

Figure 1 Schematic of the mechanism of ionizing radiation (IR) in RT. In the case of direct effect, IR directly damages the DNA, which, if unrepaired, results in cell death or permanent growth arrest. In the case of indirect effect, ROS are formed by the radiolysis of a large amount of water and oxygen, and then the ROS damage the DNA. There are many types of DNA damage, such as base change, SSB, DSB, cross-linkage with protein or with other DNA molecules.

In the direct action, radiation directly induces single-strand breaks (SSB) and double-strand breaks (DSB) in DNA, resulting in the termination of cell division and proliferation, or even cell necrosis and apoptosis. In the case of indirect action, radiation induces the generation of ROS, which can induce cellular stress in, and injure biomolecules, and and ultimately alter cellular signaling pathways. Clinical studies have shown that more than half (about 70%) of patients need to receive RT, and in some cases RT is the only kind of cancer treatment.3 Therefore, there is a great need to develop approaches to improve radiosensitivity.

Innovative technologies can provide alternative strategies to improve RT efficiency. For example, image-guided radiation therapy (IGRT) is the use of imaging during radiation therapy to improve the precision and accuracy of treatment delivery. IGRT can be used to treat tumors in areas of the body that move, such as the lungs. RT machines are equipped with imaging technology to allow your doctor to image the tumor before and during treatment. By comparing these images to the reference images taken during simulation, the patients position and/or the radiation beams may be adjusted to more precisely target the radiation dose to the tumor. To help align and target the radiation equipment, some IGRT procedures may use fiducial markers, ultrasound, MRI, X-ray images of bone structure, CT scan, 3D body surface mapping, electromagnetic transponders or colored ink tattoos on the skin.4 Intensity-modulated radiation therapy (IMRT) is an advanced mode of high-precision RT that uses computer-controlled linear accelerators to deliver precise radiation doses to a malignant tumor or specific areas within the tumor.5 Although the abovementioned innovative technologies greatly improve the therapeutic effect, there are still obstacles such as cancer stem cells and tumor heterogeneity making it difficult to use RT alone to cure tumors. Radiosensitizers with the ability to increase the radiosensitivity of tumor tissue and pharmacologically decrease normal tissue toxicity are expected to be an efficient way to improve RT.6

Radiosensitizers are compounds that, when combined with radiation, achieve greater tumor inactivation than would have been expected from the additive effect of each modality. G E Adams, a pioneer in the field of RT, classified radiosensitizers into five categories: (1) suppression of intracellular thiols or other endogenous radioprotective substances; (2) formation of cytotoxic substances by radiolysis of the radiosensitizer; (3) inhibitors of repair of biomolecules; (4) thymine analogs that can incorporate into DNA; and (5) oxygen mimics that have electrophilic activity.7,8 This classification was based on the mechanism of DNA damage and repair and indicated the direction for radiosensitizers at the early stage. However, with the continuous technological innovation, more and more materials and drugs with radiotherapy sensitization have been defined as radiosensitizers. In addition, some in-depth mechanisms for radiosensitization have also been discovered.9,10 According to the latest research, radiosensitizers can be classified into three categories based on their structures: small molecules (Figure 2), macromolecules (Table 1), and nanomaterials (Table 2).11 In the following part, the applications, the main role, and influencing factors of these three types of radiosensitizers are first summarized, especially those have currently entered clinical trials. Second, the development status and the mechanism of action of the radiosensitizer are also summarized. Third, the future development and application of the radiosensitizer was presented.

Figure 2 Molecular structures of some representative small-molecule radiosensitizers discussed in this paper.

Table 1 Some Macromolecule Radiosensitizers Discussed in This Paper

Table 2 The List of Nanomaterials Used for Radiosensitization

Hypoxia in tumor microenvironment is one of the major limitations to radiotherapy. Tumor cells in the hypoxic microenvironment are much more resistant to radiation than in the normal oxygen microenvironment.1214 Oxygen enhancement ratio (OER) or oxygen enhancement effect in radiobiology refers to the enhancement of the therapeutic or detrimental effect of ionizing radiation due to the presence of oxygen. This so-called oxygen effect is most notable when cells are exposed to an ionizing radiation dose.15,16 Oxygen, a potent radiosensitizer, promotes free radical formation through its unique electronic configuration. As the most electrophilic cellular molecule, oxygen is easily reduced by electrons formed from the incident radiation. After oxygenated tumor irradiation, energy transfer results in the radiolysis of water with the initial formation of an ion radical that then forms the highly reactive hydroxyl radical after reaction with another water molecule. Oxygen leads to the formation of peroxide after reaction with the hydroxyl radical. Then, the peroxide results in permanent cellular and DNA damage.13

Accompanied with solid tumor growth, the surrounding vasculatures are not in sufficient quantities to supply oxygen to the new cells, the cancer cell mass becomes heterogeneous gradually, and necrosis occurs following ischemia. Normally, cancer cells undergo apoptosis through the p53 pathway, while those heterogeneous cells adapt to the hypoxic environment efficiently by activation of additional signaling pathways, especially the hypoxia-inducible factor (HIF) pathway.1719 Studies showed that HIF-1 was associated with vascular endothelial growth factor (VEGF) signaling pathway, glucose transport, and glycolysis pathway, which could help the tumor to build vasculature.1921 Under hypoxia, the cancer cells are more aggressive and resisted radiotherapy significantly. Thus, hypoxia often occurs in most solid tumors and leads to radioresistance both through increasing free radical scavenging and changing patterns of gene expression.22,23

More and more research has been devoted to overcoming hypoxia problems, from using high-pressure oxygen tanks and blood substitutes that carried oxygen, to using intricate, accurate approaches that proportionated differences in partial pressure of oxygen (PO2) between tumors and healthy tissue.24,25 Hyperbaric oxygen is the most direct method to ameliorate hypoxia in tumor cells, while this method is inconvenient and may increase complications sometimes.26,27 A new radiosensitizer, Kochi oxydol-radiation therapy for unresectable carcinomas (KORTUC), is being evaluated by a Phase I/II clinical trial (NCT02757651) for the treatment of malignant tumors that contain numerous hypoxic cancer cells and/or large quantities of antioxidative enzymes.28

Oxygen mimetics, using the chemical properties of molecular oxygen as a template, have higher electron affinity and better diffusion properties to anoxic tissue than oxygen. As oxygen mimetics can theoretically substitute for oxygen in fixing radiation-induced damage of DNA, making it nonrepairable and hence lethal. Therefore, oxygen mimetics are considered as true radiosensitizers. The most representative oxygen mimetics are nitro-containing compounds and nitric oxide (NO).13

The prototype of electron-affinity radiosensitizers is nitrobenzene, and then researchers focus on nitroimidazole and its derivatives.2931 Nitroimidazoles, which undergo enzymatic and radiation-induced redox reactions. These agents are intrinsic inactive, their effect becomes evident only in the presence of ionizing radiation to fix or stabilize DNA radical lesions in oxygen-deficient cells.32 Misonidazole, a 2-nitroimidazole, is one of the earliest developed nitroimidazoles. In preclinical studies, misonidazole showed better radiosensitizing effect than 5-nitro imidazole or metronidazole (Flagyl) in the majority of solid murine tumors.3335 However, the results were unsatisfactory in clinical trials, since severe neurotoxicity was caused by misonidazole.3639 Metronidazole, a 5-substituted nitroimidazole, which has less electron-affinic was proven as an inferior radiosensitizer.40,41 In conclusion, because of the dose-limiting toxicity at clinically tolerable doses, misonidazole and metronidazole are not the ideal candidates in radiotherapy.42

In view of the issues discussed above, further efforts have been made to improve the pharmacokinetic properties of nitroimidazoles. Second-generation nitroimidazole radiosensitizers, such as etanidazole or nimorazole, are designed to increase the hydrophilicity of the reagents and thereby reduce neurotoxicity. For example, etanidazole has better hydrophilicity than misonidazole because its side chain is modified by hydroxyl.43 Although etanidazole presents lower preclinical toxicity and higher efficacy, it shows no obvious benefit for head and neck cancer patients in randomized studies.44 Nimorazole, a 5-nitroimidazole, is recommended for the treatment of head and neck cancers in Denmark since its beneficial effects in several clinical trials. Moreover, it has been further explored in an EORTC international trial.4551 Notably, the DAHANCA 28 trial demonstrated that hyperfractionated, accelerated radiotherapy with concomitant cisplatin and nimorazole (HART-CN) for patients was feasible and yielded favorable tumor control.52 Other nitro compounds have also been exploited for hypoxia radiosensitization. Dinitroazetidine, RRx-001, has been evidenced as an effective radiosensitizer with low toxicity and is now being evaluated in the NCT02871843 clinic trial.53

Nitrogen oxides, in particular, NO, act as radiosensitizers through many direct and indirect mechanisms. Similar to the oxidative stress induced by oxygen, NO can fix or stabilize radiation-induced DNA damage through nitrosative stress pathways.54 Oxidative and nitrosative stress pathways involve the generation of reactive species. For example, nitrous acid, peroxynitrite (ONOO), and nitric acid produce cytotoxic effects through mechanisms including DNA cross-linking, protein nitrosylation, glutathione depletion, and inhibition of mitochondrial respiration.5558 As an uncharged free radical, NO can diffuse across cell membranes freely and bind to soluble guanylate cyclase (sGC) to induce cyclic GMP production, thereby regulating vascular physiology.5961 Researchers have reported that 5-nitroimidazoles and sanazole can release NO.62,63

A phase I study of non-small-cell lung cancer (NSCLC) patients suggested that NO donation increased tumor perfusion and, therefore, promoted tumor growth.64 However, a phase II study of prostate cancer patients claimed that low-dose NO had no direct cytotoxic effect, but could decrease hypoxia through improving blood flow in tumor tissue.65 Some anticancer drugs approved by US Food and Drug Administration (FDA), such as bevacizumab, sorafenib, and etaracizumab played their roles by blocking the VEGF pathway to some extent.66 VEGF is overexpressed in anoxia environment, which leads to endothelial cell proliferation and neovascularization. In angiogenesis, there is a positive and negative feedback regulation relationship between VEGF and NO, which maintains vascular homeostasis precisely.67 In addition, Liebmann et al proved that pretreatment with NO improved the survival of mice after irradiation.68

In recent years, more and more researchers reported that active compounds from Chinese herbs such as curcumin,6971 resveratrol,7274 dihydroartemisinin7577 and paclitaxel,7880 could enhance tumor radiotherapy sensitivity (Figure 2). Curcumin is a polyphenolic active compound extracted from turmeric. Curcumin exerts anti-inflammatory effect by inhibiting the transcription factor NF-B, which is involved in both tumorigenesis and radioresistance.81 In a preclinical study, Chendil et al reported that when treated with RT and curcumin together, the human prostate cancer cell line, PC3 presented threefold fewer surviving and the mechanism was supposed to have a relationship with NF-B.82 In addition, nanocurcumin as a radiosensitizer is being evaluated by a Phase II clinical trial (NCT02724618). Other relevant research on mutant p53 Ewings sarcoma cells proved that radiosensitivity of curcumin was associated with other p53-response genes.83

Resveratrol is an active compound extracted from grapes, knotweed, peanuts, mulberry and other plants. Tan et al proved that resveratrol enhanced the radiosensitivity in nasopharyngeal carcinoma cells by downregulating E2F1.73 Liao et al found that resveratrol enhanced radiosensitivity in human NSCLC NCI-H838 cells by inhibiting NF-B activation.84 Dihydroartemisinin is a derivative of artemisinin, which can shorten the G2/M phase, while increases the G0/G1 and S phase, thereby reducing the radiation resistance.85 Although the relevant clinical research has not yet been carried out, researchers have demonstrated that resveratrol8689 and dihydroartemisinin9092 possessed radiosensitization on cancer cells in vitro.

Paclitaxel is widely known as a very good natural anticancer drug.93,94 As a new type of antimicrotubule drug, paclitaxel can inhibit the microtubule networks formation and prevent the tumor cells proliferation to achieve radiosensitization.95 Results showed that paclitaxel could obviously enhance the radiosensitivity of inoperable patients with locally advanced esophageal cancer and improve the prognosis of patients with acceptable therapeutic effect.96 A three-arm randomized Phase III trial (NCT02459457)comparison of paclitaxel-based three regimens concurrent with radiotherapy for patients with local advanced esophageal cancer and a Phase III study (NCT01591135) of comparing paclitaxel plus 5-fluorouracil vs cisplatin plus 5-fluorouracil in chemoradiotherapy for locally advanced esophageal carcinoma are underevaluated.

Some bioreductive agents, such as aromatic N-oxides, transition metal complexes, quinones, aliphatic N-oxides and nitro compounds, have radiosensitization effects by virtue of their preferential cytotoxicity toward hypoxic cells.11 Tirapazamine (TPZ), a hypoxia-selective radiosensitizer, has shown promising results in clinical trials.97,98 Under hypoxic environments, TPZ can be reduced by reductase in cells to a metabolite that produces free radical and then leads to SSB, DSB, and base damage on DNA.99 A Phase I clinical trial of TPZ with cisplatin and radiotherapy in small cell lung cancer showed prolonged survival of patients.100 A Phase II study of TPZ with chemoradiotherapy in locally advanced head and neck cancer reported improvements in failure-free survival and response of patients.101 However, further phase III trials of TPZ with chemoradiotherapy in locally advanced head and neck cancer concluded that there was no obvious improvement in patient survival.102 In addition, SN30000 (previously known as CEN-209), an analog of TPZ, with more favorable diffusion property that provides greater toxicity in hypoxic cancer cells than TPZ, is currently under development by the Drug Development Office of Cancer Research UK.103

AQ4N, a representative to aliphatic N-oxide, can be reduced to AQ4 by cytochrome P450 isoenzymes or nitric oxide synthase 2A.104 In vivo experiments showed that combined utilization of AQ4N with radiotherapy resulted in increased antitumor efficacy, as well as negligible toxicity to normal tissue compared with radiation alone.105 Positive results were also evidenced in Phase I clinical trials.106 A Phase I clinical trial in glioblastoma and head and neck tumor patients proved that AQ4N could be specifically activated in hypoxic regions of solid tumors.107 Unfortunately, a Phase II clinical trial of AQ4N with radiotherapy and temozolomide in glioblastoma began in 2006, was in a pending status (NCT00394628).

TH-302 (evofosafamide), a similar compound that can be reduced to bromo-isophosphoramide mustard in hypoxic conditions, has radiosensitization activity, especially in hypoxic cells.108,109 In preclinical models of rhabdomyosarcoma (skeletal muscle) and NSCLC, TH-302 combined with radiotherapy treatment resulted in significant tumor growth delay.110 In addition, in a study in patient-derived xenograft models of pancreatic cancer, combination treatment of TH-302 and radiotherapy was more efficient than either treatment alone.111 TH-302 can specifically target the hypoxic tumor cells and induce DNA damage simultaneously in adjacent tumor tissue of the hypoxic zone, and thus holds potential radiosensitization effects in solid tumor treatment.112 However, on the database of US National Institutes of Health clinical trials, only one of the 26 trials listed proposed combination treatment of TH-302 with radiotherapy (NCT02598687), and it was withdrawn because two phase III trials did not meet their primary endpoint.113

Mitomycin C, a quinone-based anticancer therapeutic, can be activated via DNA cross-linking. In preclinical study, mitomycin C showed only slight toxicity in hypoxic cells, which promotes the development of other hypoxia-sensitive quinones selection.114 Among them, porfiromycin (POR) and apaziquone (EO9) are bioreductive prodrugs, represent the leading candidates.104 Preclinical studies concluded that POR held higher hypoxic selectivity than mitomycin C.115 Although preclinical trials proved POR had acceptable toxicity, the following Phase 3 trial demonstrated that POR had a poorer therapeutic effect than mitomycin C.116 Preclinical studies indicated that EO9 had greater antitumor property than mitomycin C, indicating EO9 can be a ideal radiosensitizer.117

Other types of chemical radiosensitizers have also seen some progress and some of them are in preclinical evaluations. For example, chemicals that influence cell signaling, suppress radioprotective substances, pseudosubstrates and targeted delivery systems are exploited. With the development of research on radioresistance mechanism, it has been found that multiple signal pathways are related to radioresistance, providing more targets for radiosensitization, such as PI3KAktmTOR,118 Wnt,119 MAPK,120 MDM2121 and c-METPI3KAkt.122 For example, BKM120, the oral PI3K inhibitor, can inhibit the activity of PI3K/Akt by targeting the PI3K-Akt pathway, thereby increasing cell apoptosis and inhibiting DNA double-strand break repair in liver cancer cells.123 BEZ235, a dual PI3KmTOR inhibitor, can improve the radiosensitivity of colorectal cancer cells.124 AMG 232, a picomolar affinity piperidinone inhibitor of MDM2, can suppress tumor growth on a mouse model.121

Suppression of radioprotective substances, such as glutathione (GSH), is another strategy of radiosensitization. Inhibition of GSH can prevent DNA damage repair and lead to increased damage in tumor cells, which improves the efficacy of radiotherapy in turn.125 In addition, pseudosubstrates lead cells undergoing DNA synthesis unable to distinguish thymidine and its halogenated analogs efficiently. It is a new area of clinical research to use halogenated pyrimidine analogs, like bromodeoxyuridine (BrdUrd) and iododeoxyuridine (IdUrd), as potential clinical radiosensitizers.126 One study demonstrated that electron affinities of 5-halogenated deoxyuridine led to enough ability to bind a radiation-produced secondary electron, thereby increasing the sensitivity of radiotherapy.127

In addition, research on new indications for existing drugs provides a new paradigm for the development of radiosensitizers. For instance, papaverine, an ergot alkaloid first isolated from Papaver somniferum in 1848, has been used for treatment of vasospasm, cerebral thrombosis, pulmonary embolism and erectile dysfunction.128 Denko et al identified papaverine as an inhibitor of mitochondrial complex I and proved that papaverine could increase oxygenation and enhance radiation response.128 A phase I trial (NCT03824327) study on papaverine and stereotactic body radiotherapy (SBRT) for NSCLC or lung metastases is under evaluation. In summary, small-molecule chemicals as radiosensitizers initiated in the past five years under clinical trials are summarized in Table 3.

Proteins and peptides, such as antibodies and short peptides, have high affinity with antigens and receptors overexpressed on the surface of tumor cells, making them usable as radiosensitizers.129 For instance, HER3-ADC, a maytansine-based antibody-drug conjugate targeting HER3, which induces cell arrest in the G2/M phase to inhibit DNA damage repair and thereby improves radiosensitivity of HER3-positive pancreatic cancer cells.130 SYM004, a epidermal growth factor receptor targeting antibody, can inhibit DNA double strand breaks repair and induces apoptosis via downregulating MAPK signaling, and thereby improves radiosensitivity in tumor cells.120 Cetuximab and nimotuzumab, binding the epidermal growth factor receptor (EGFR), can increase radiation-induced apoptosis and DNA damage, and thereby improve the radiosensitivity of human epidermal-like A431 cells.131 The hepatocyte growth factor (HGF)/Met signaling pathway which mediates DNA double-strand break repair is upregulated in the majority of cancers. AMG102, a monoclonal antibody against HGF, can inhibit DNA damage repair and increase radiosensitivity of glioblastoma multiforme.132 In addition, proteins and peptides in serum, such as C-reactive peptide,133 HSP134 and paraoxonase-2135 contribute to radioresistance and can be used as radiotherapy targets. ECI301, a mutant derivative of macrophage inhibitory protein-1a, can be assisted by HSP-70 and HMGB1, thereby enhancing the effect of radiotherapy.134 Other proteins, like DNAzyme (DZ1)136 and NKTR-214,137 can also improve the effect of radiotherapy.

MicroRNAs (miRNAs), which encode by endogenous genes are noncoding single-stranded RNA molecules containing about 22 nucleotides. Studies have shown that some specific miRNAs can be used to improve radiotherapy efficacy138,139 and some miRNAs can be used as radiotherapy sensitization targets.140 For example, miR-621 targets SETDB1 in hepatocellular carcinoma can be used as a tumor radiosensitizer directly.141 miR-205 targets zinc finger E-box binding homeobox 1 (ZEB1) and the ubiquitin-conjugating enzyme Ubc13 to enhance the radiosensitivity of breast cancer cells.142 miR-144-5p targets ATF2 to enhance radiosensitivity of NSCLC.143 miR-146a-5p enhances radiosensitivity in hepatocellular carcinoma through activation of DNA repair pathway.144 miR-150 modulates AKT pathway in NK/T cell lymphoma to enhance radiosensitivity.145 miR-99a targets mTOR pathway to enhance the radiosensitivity of NSCLC.146 miR-139-5p modulates radiotherapy resistance in breast cancer by repressing multiple gene networks of DNA repair and ROS defense.147 Transcriptional activation of miR-320a induces cancer cell apoptosis under ionizing radiation conditions.148 However, inhibition of miR-21-5p promotes the radiation sensitivity of NSCLC.149 Inhibition of miR-630 enhances radiotherapy resistance in human glioma by directly targeting CDC14A.150 Furthermore, a clinical study included 55 atypical meningioma patients found in seven upregulated miRNAs (miR-4286, miR-4695-5p, miR-6732-5p, miR-6855-5p, miR-7977, miR-6765-3p, miR-6787-5p) and seven downregulated miRNAs (miR-1275, miR-30c-1-3p, miR-4449, miR-4539, miR-4684-3p, miR-6129, miR-6891-5p) in patients. Those miRNAs may induce radioresistant and radiosensitive, respectively.

siRNA, known as short interfering RNA or silencing RNA, is a class of double-stranded RNA, noncoding RNA molecules, typically 2027 base pairs in length, similar to miRNA, and operating within the RNA interference (RNAi) pathway.151 HuR is a protein related to radiotherapy resistance, knockdown of HuR by siRNA resulting DNA damage and enhanced radiosensitivity.152 S100A4, a member of the S100 family of transcription factors, modulates various activities of malignant tumor cells through different mechanisms. A short siRNA against S100A4 enhances the radiosensitivity of human A549 cells.153 NBS1 plays an important role in the radiation-induced DNA double-strand breaks reparation, siRNA targets NBS1 can increase radiation sensitivity of cancer cells.154 Survivin, a member of the inhibitor of apoptosis (IAP) protein family, is overexpressed in most cancers resulting in aggressive behavior of tumor and therapy resistance. Downregulation of survivin by siRNA can enhance radiosensitivity in head and neck squamous cell carcinoma.155 Therefore, numerous siRNAs can be used as radiosensitizers by silencing genes related to radioresistance.

Similar to siRNAs, oligonucleotides also play important roles in gene expression regulation. Since they are easy to design and synthesize, antisense oligonucleotides have great potential to develop as radiosensitizers.11 Telomerase expresses in many kinds of tumors (>85%), while the expression of telomerase is restricted in normal tissues. A study indicated that expression of telomerase could be inhibited by radiolabeled oligonucleotides, which targeted the RNA subunit of telomerase, thereby inducing DNA damage in telomerase-positive tumor cells.156 In addition, the phosphorothioate-modified antisense oligonucleotides (PS-ASODN) against human telomerase reverse transcriptase were reported to promote radiotherapy effect in liver cancer.157 Furthermore, Park et al reported that inhibition of cyclic AMP response element-directed transcription using decoy oligonucleotides enhanced tumor-specific radiosensitivity.158 Yu et al demonstrated that antisense oligonucleotides targeted human telomerase RNA (hTR ASODN) could improve the radiosensitivity of nasopharyngeal carcinoma cells.159 The radiosensitization mechanism of macromolecules was summarized in Figure 3.

Figure 3 Radiosensitization mechanism of macromolecules. (A) Proteins and peptides. (a1) Direct interaction of key proteins. (a2) Loading of radioactive seeds. (a3) Radiosensitizers delivery. (a4) Conjugation with nanomaterials. (B) miRNAs can then bind with mRNAs to implement radiosensitization. (b1) Downregulation by inhibitors. (b2) Upregulation. (C) siRNAs can improve radiosensitivity by binding and degrading complementary mRNAs. (D) Oligonucleotides improve the radiosensitivity by complementary binding with DNAs.

The X-ray absorption coefficient () represents the relationship between the X-ray absorption phenomenon (E) and atomic number (Z), =Z4/(AE3), where is the density and A is the atomic mass of the element.160 Therefore, the change of atomic number (Z) causes a significant change of X-ray absorption coefficient (). Noble metal nanomaterials, such as gold (Au, Z=79), silver (Ag, Z=47) and platinum (Pt, Z=78) can effectively absorb X-ray energy and interact with radiation in tumor cells, and then emit photoelectrons, auger electrons, compton electrons and other secondary electrons. These secondary electrons not only interact with DNA directly, but also react with water to increase the production of ROS and further increase the sensitivity of tumor cells to radiation. This process is a physical sensitization mechanism.161 Furthermore, functionalized noble metal nanomaterials promote the generation of ROS, transfer the cell cycle into a radiosensitive state, and inhibit p53 signaling pathway to induce cell autophagy and lysozyme body function disorder, thereby increasing radiotherapy sensitivity. This process is a biochemical sensitization mechanism.162,163

Gold nanoparticles with good chemical stability, easy preparation, controllable size and shape, easy surface functionalization, high biocompatibility, and low toxicity have proven satisfactory radiosensitizing effects in various tumors.164167 Silver nanoparticles and platinum nanoparticles are also commonly used in biomedicine.168,169 Research found that silver nanoparticles combined with radiotherapy could enhance the radiosensitivity of human glioma cells in vitro and extended the survival time of glioma mice.170,171 Liu et al demonstrated that silver nanoparticles could induce apoptosis of cancer cells through G2/M phase arrest after radiation, and they suggested that silver nanoparticles could be used as a nanoradiosensitizer for hypoxic glioma radiotherapy.172 Recently, Fathy reported that thymoquinone-capping silver nanoparticles represented a promising engineered nanoformulation for enhancing cancer radiosensitivity.173 Li et al demonstrated that platinum nanoparticles could enhance radiosensitivity through increasing DNA damage, ROS stress, and cell cycle arrest.163 They also proved that platinum nanoparticles could convert endogenic H2O2 to O2 in cancer cells, thus significantly improving radiosensitivity without apparent toxicity to animals in vivo.163

Similar to noble metal nanomaterials, gadolinium (Gd, Z=64), hafnium (Hf, Z=72), tantalum (Ta, Z=73), tungsten (W, Z=74), and bismuth (Bi, Z=83) are also metal elements with large atomic coefficients and have a great X-ray attenuation capability.174176 Based on this, numerous studies have focused on these heavy metal nanomaterials to investigate their radiotherapy sensitization. However, they usually cause damage to healthy tissues with direct contact.177 Therefore, their stable forms such as oxides, sulfides, and selenides are explored as the radiosensitizers.178180

Gadolinium-based nanoparticles are usually known as magnetic resonance imaging (MRI) contrast agents. It should be noted that researchers discovered a family of gadolinium-based nanoparticles called AGuIX for combined MRI and radiosensitization.181 Results showed that AGuIX could interact with X-rays and -rays at a certain concentration. After internalization through the enhanced permeability and retention (EPR) effect, AGuIX could be resident in the tumor for a long time before being cleared by the kidneys.182 Preclinical animal experiments proved that AGuIX held obvious radiosensitization effects in several tumor models without obvious toxicity.183 A Phase I clinical trial (NCT03308604) to evaluate the optimal dose of AGuIX combined with chemoradiation in patients with locally advanced cervical cancer; a Phase II clinical trial (NCT03818386) using AGuIX gadolinium-chelated polysiloxane based nanoparticles and whole brain radiotherapy in patients with multiple brain metastases; and a single-arm phase II trial (NCT04094077) aiming to evaluate the efficacy of AGuIX during fractionated stereotactic radiotherapy of brain metastasis are being evaluated.

Hafnium, in the same family as titanium and zirconium, is chemical inertness. The oxidation state of hafnium, hafnium dioxide (HfO), was usually used in radioactive protective coatings, biosensors, and X-ray contrast agents.184,185 Jayaraman et al demonstrated that HfO2 nanoparticles had excellent biocompatibility.185 Researchers from France discovered that HfO can be used as a radiosensitizer with low cytotoxicity.186 A Phase I trial (NCT03589339) combining hafnium oxide nanoparticles (NBTXR3) with anti-PD-1 therapy in microsatellite instability-high solid malignant tumour and a Phase III clinical trial (NCT02805894) of NBTXR3 in prostate adenocarcinoma are under evaluation.

Tantalum is a nontoxic, biologically inert element with good biocompatibility.187 Studies found that TaOx and Ta2O5 could be used as CT imaging contrast agents.188190 Brown et al found Ta2O5 nanoparticles showed a radiasentizition effect on radioresistant glioma cells.191 Song et al showed hollow shell tantalum oxide (HTaOx) had a large X-ray attenuation capability and could enhance radiation therapy effects by Compton scattering and Auger effect.192 In addition, TaOx can be used as functional group carrier to load drugs, thereby improving tumor hypoxic environment. For example, HTaOx loaded with catalase, which reacted with H2O2 in the tumor microenvironment, then improved the oxygen content and overcame the radiotherapy tolerance of hypoxic tumor cells, thereby improving the radiotherapy effect.193

Tungsten and bismuth also have significative applications in medicine.194,195 Hossain et al concluded that bismuth nanoparticles had stronger radiosensitizing effect than gold and platinum nanoparticles at the same physical and chemical conditions.196 Yu et al found that the ultra-small semi-metallic Bi nanoparticles with LyP-1 peptide modified at 3.6 nm showed obvious radiosensitization effect.197 Recently, a large number of studies shown that some nanomaterials of tungsten and bismuth had excellent photothermal absorption conversion performance and strong X-ray absorption capacity, therefore they can be used for tumor radiosensitization as well as synergistic therapy of hyperthermia and radiotherapy.198201

In addition, research about several high Z metal elements combined together to further improve the radiosensitization effect were also explored. For example, SiBiGdNP chelated Bi and Gd in organosilane to improve the sensitivity of radiotherapy.202 GdW10O36 contained both W and Gd to expect they had better radiotherapy sensitization effect.203

Ferrite-based nanomaterials can catalyze the generation of free radicals through Fentons reaction (1) and HaberWeiss reaction (2) to enhance the effect of radiosensitization.204

Fe2+ + H2O2 Fe3+ + OH + OH

Fe3+ + H2O2 Fe2+ + OOH + H+ (1)

Fe3+ + O2 Fe2+ + O2

Fe2+ + H2O2 Fe3+ + OH + OH (2)

Studies proved that Fe3O4 had a dose-enhancing effect for radiotherapy, especially superparamagnetic Fe3O4 nanoparticles (SPIONS) possessing MRI imaging property had good application prospects in image-guided tumor radiotherapy.205

The composition of the spinel structure ferrite is usually stated as MFe2O4, where M=Fe, Zn, Co, Mn, Ni.206 Among them, ZnFe2O4, MnFe2O4, CoFe2O4 nanoparticles were widely investigated.207 For example, Meidanchi et al confirmed that ZnFe2O4 nanoparticles interacted with -rays to produce photoelectric effect resulting in a higher release level of electron in radioresistant cells.208 Studies also indicated that ZnFe2O4 nanoparticles could be used as radiosensitizers.208,209 Salunkhe et al demonstrated that MnFe2O4 and CoFe2O4 nanoparticles could improve the therapeutic efficacy of cancer through multimodal image-guided combination therapy.210

Semiconductor quantum dots have unique properties, such as quantum dimension effect, surface effect, and quantum confinement effect, making them great candidates in biomedicine applications.211 Until now, numerous studies focused on using semiconductor quantum dots as photosensitizers and radiosensitizers for tumor treatment have been reported.212214 When the electronic energy levels are in the range of 15 eV, the semiconductor nanomaterials can absorb the photon energy and perform as photosensitizers, showing photocatalytic properties. When the electronic energy levels are at keV and MeV (X-rays and -rays), semiconductor nanomaterials can enhance absorption of high-energy photons acting as radiosensitizers and causing damage to cancer cells.212 Nakayama et al synthesized a semiconductor nanomaterial PAA-TiOx to generate hydroxyl radicals under the irradiation of X-rays, which increased DNA damage and inhibited tumor growth significantly.215 Morita et al clarified the radiosensitization mechanism of PAA-TiOx nanoparticles by releasing H2O2 to relieve hypoxia in tumor cells.216 TiO2 nanotubes have been reported to enhance the radiosensitization effect through regulating G2/M cycle arrest and reducing DNA repair of tumor cells.177 The mechanism of radiosensitization of metal-based nanomaterials is shown in Figure 4.

Figure 4 Radiosensitization mechanism of metal-based nanomaterials. The process contains physical and biochemical sensitization mechanism.

Many nonmetallic nanomaterials also possess the function of radiosensitization.217 For example, C60, fullerene, has potent anticancer activities, however, the potential toxicity to normal tissues limits its further use. Therefore, nanocrystals of C60 (Nano-C60) with negligible toxicity to normal cells have been developed as a radiosensitizer.218 In addition, nanodiamonds and carbon nanotubes can reduce radioresistance of tumor cells by promoting ROS generation, destroying DNA double-strands, and regulating the cell cycle.219,220 Selenium (Se) nanoparticles not only work as chemotherapeutic drugs, but also improve the antitumor effect of X-rays by activating ROS to induce DNA damage in cancer cells.221

Nano-based delivery systems are efficient approaches for drug targeted transportation, which can deliver radiosensitizers, such as chemicals, oxygen carriers, siRNAs and catalases to the tumor sites and have attracted wide interest of researchers recently.222 More importantly, nanobased delivery systems can precisely deliver radioactive particles like223 Ac (releasing a-particles), 131I, and 125I to tumor sites.223 With the development of nanotechnology, nanobased delivery systems have great potential for radiosensitizer delivery.

However, there is still a challenge to achieve clinical translation of nanobased delivery systems, factors like physicochemical properties of the nanoformulations, radiation sources, and indications block their clinical translation.223 In addition, long circulation lifetime of nanodelivery systems may increase the risk of long-term toxicity.224 Another critical factor is stability in body fluid of nanodelivery systems. Because the aggregation of nanoparticles in body fluid will influence the pharmacokinetics and the cellular response and generate serious side effects such as blocking the blood vessels.222 Therefore, attention should be paid to these factors when designing the nanodelivery systems. Size is also an important factor, small size and high Z nanoparticles often hold better radiosensitizing effect than larger-size ones.223 In particular, the small size nanoparticles with positive charge can bind to negative charged DNA and can be eliminated by renal clearance conveniently. In addition, functional modification of nanostructures using biocompatible materials can improve their stability and targeting.225

Radiosensitizers have been developed for decades from the earliest free radical damage and fixation strategies to gene regulation, from chemicals to biological macromolecules and nanomaterials. Although each radiosensitizer has dialectical advantages and limitations, the mechanisms of sensitization are similar. The main mechanisms include: (I) inhibiting radiation-induced repair of DNA damage, increasing the degree of DNA damage; (II) disturbing the cell cycle and organelle function to improve cytotoxicity; and (III) inhibiting the expression of radiation resistance genes or promoting the expression of radiation sensitive genes.

Although small molecules, macromolecules, and nanomaterial radiosensitizers are being developed, and some nanoradiosensitizers have been used for clinical research (Table 4), the result still cannot meet clinical translation needs. Therefore, there is an urgent need to find new targets of radiotherapy and new mechanisms of sensitization, and after that to develop more effective radiosensitizing drugs. First of all, multitarget radiosensitizers often have more obvious efficacy than single target, researchers can focus on screening multitarget radiosensitizers or drug combinations. New approaches, in particular, nanotechnology based as radiosensitizers have shown promise. Nanomaterials with low cytotoxicity, good biocompatibility, and ease of functionalization need to be explored. In addition, other technologies, such as molecular structure analysis, molecular cloning technology, and bioinformatics analysis can accelerate the development of new radiosensitizers. Moreover, development of new drug delivery systems can also improve radiosensitization efficacy. Finally, the application of artificial intelligence and machine learning in new drug discovery and clinical trials, may guide development of new radiosensitizers and optimization of existing radiosensitizers.

Table 4 Clinical Translation of Some Nanoradiosensitizers

This work was supported by Innovation Capacity Support Plan of Shaanxi Province (2018TD-002), the National Natural Science Foundation of China (No. 82000523), the Natural Science Foundation of Shaanxi province (Grant No. 2020JQ-087, 2020JQ-095), the Young Talent Support Plan of Xian Jiaotong University (YX6J001), the Fundamental Research Funds for the Central Universities (xzy012019070).

The authors report no conflicts of interest in this work.

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Nanopharmaceuticals Market: Overview

Nanopharmaceuticals are revolutionizing medical science by leveraging nanomedicine to render effective healthcare, especially in developing countries. The technology is yet in evolution stages and promises to bring advancement not only in therapeutics but also in detecting diseases and targets. Also, one factor that is making it popular is its cost-effectiveness.

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Rise in the incidence of chronic diseases such as infectious diseases, cancer, and cardiovascular diseases, is paving way for expansion of nano-pharmaceuticals market. Nanopharmaceuticals are also referred to as nanotechnology-based pharmaceuticals. The advancement is becoming an integral part of medical science and has potential to treat diseases at cellular level.

Primarily, nanopharmaceuticals are particles in the size range 10 to 1,000 nanometers of specific matter used to manufacture drugs. As a result of composition and shape, the medicines have several benefits to offer over the normal medicines.

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The report on nanopharmaceuticals market offers insights about the latest developments in the field. Besides, it targets the potential drivers which will help in the expansion of the market in the tenure of forecast period. Later, the market intelligence offers details about particular segments dominating in specific regions.

Nano-pharmaceuticals Market: Trends and Opportunities

Increase in the incidence of chronic diseases such as cancer, infectious diseases, and cardiovascular diseases, is one of the main factors fuelling nano-pharmaceuticals market. Prominent players in the nano-pharmaceuticals market are investing on large scale in order to introduce improved medicines in the market.

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The advancements in the nanopharmaceuticals are likely to address therapeutics for critical diseases, which are yet to be explored. This can be explained by an example of Jazz Pharmaceuticals, a key player of nano-pharmaceuticals market. In August 2017, the company received FDA approval for Vyxeos. Vyxeos is basically used for the treatment of acute myeloid leukemia.

Registering the pace of research and developments underway for nanopharmaceuticals, global nano-pharmaceuticals market is projected to grow at a significant pace in the course of the forecast period.

On the other side, factors such as less solubility of nano-pharmaceuticals, toxicity issues, and its functioning need to be addressed on a wider scale. If not, these factors may hinder the growth of the nanopharmaceutical market in the tenure of forecast period.

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Nanopharmaceuticals Market: Regional Outlook

As a result of substantial advancement in the research and development activities in North America, the region is expected to dominate in the global nano-pharmaceuticals market. Besides, the region is witnessing rapid adoption rate of nano-pharmaceuticals for advanced therapeutics. Also, presence of prominent players is another main factor which is fuelling the expansion of nano-pharmaceutical market.

Due to presence of large number of players in the nano-pharmaceuticals market, the competition is also intense. These players are bringing several strategies and developments in the market to gain foothold in the market. Prominent players are expanding their reign by acquisitions, merging and collaborations. Some of the prominent players in the market are- Teva Pharmaceuticals Industries Limited, JOHNSON & JOHNSON, Shire Plc., Novartis AG, Hoffmann-La Roche AG, Pfizer Inc., Merck & Co., and Sanofi S.A.

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Nano-pharmaceuticals Market: Competitive Analysis

Some of the key players in the nanopharmaceuticals market are JOHNSON & JOHNSON, Sanofi S.A, Hoffmann-La Roche AG, Teva Pharmaceuticals Industries Limited, Novartis AG, Merck & Co., Shire Plc., and Pfizer.

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