Abstract

Bacteria extracellular vesicles (BEVs), characterized as the lipid bilayer membrane-surrounded nanoparticles filled with molecular cargo from parent cells, play fundamental roles in the bacteria growth and pathogenesis, as well as facilitating essential interaction between bacteria and host systems. Notably, benefiting from their unique biological functions, BEVs hold great promise as novel nanopharmaceuticals for diverse biomedical potential, attracting significant interest from both industry and academia. Typically, BEVs are evaluated as promising drug delivery platforms, on account of their intrinsic cell-targeting capability, ease of versatile cargo engineering, and capability to penetrate physiological barriers. Moreover, attributing to considerable intrinsic immunogenicity, BEVs are able to interact with the host immune system to boost immunotherapy as the novel nanovaccine against a wide range of diseases. Towards these significant directions, in this review, we elucidate the nature of BEVs and their role in activating host immune response for a better understanding of BEV-based nanopharmaceuticals’ development. Additionally, we also systematically summarize recent advances in BEVs for achieving the target delivery of genetic material, therapeutic agents, and functional materials. Furthermore, vaccination strategies using BEVs are carefully covered, illustrating their flexible therapeutic potential in combating bacterial infections, viral infections, and cancer. Finally, the current hurdles and further outlook of these BEV-based nanopharmaceuticals will also be provided.

Introduction

Vesiculation is a crucial and fundamental process across all kinds of species to produce the extracellular vesicles that serve as essential mediators of basic physiological events [1]. These nanovesicles are filled with molecular patterns originated from parent cells, including metabolites, nucleic acids, proteins, and signaling molecules, to maintain cell growth and homeostasis [2, 3]. Biological regulation by extracellular vesicles is widespread across both prokaryotes and eukaryotes [4]. Notably, bacteria, as one of the major inhabitants in the human body, establish intricate relationships with host health and disease, wherein bacterial extracellular vesicles (BEVs) are indispensably involved in these processes [5, 6]. With the increasing and deep understanding of their biological function, BEVs are found to influence various cellular behaviors, including the transport of genetic information, phage infection, mediation of metabolism, as well as interaction between bacteria-bacteria and bacteria-host [7, 8].

Particularly, BEVs are characterized as nanosized nanoparticles, surrounded by lipid-bilayer membranes, ranging from 20 to 400 nm in diameter [7]. In account of the diversity of bacterial types and biogenesis mechanisms, the BEVs could carry versatile cargos inherited from mother cells, such as lipopolysaccharides (LPS), endotoxins, genetic information, cytosolic and membrane proteins [9]. By thanking the unique structure and intrinsic properties of BEVs, these naturally occurring nanovesicles attract the research interest to be developed as novel nanopharmaceuticals, prompting further exploration of their biomedical applications [10, 11]. Generally, BEVs are widely evaluated as biotherapeutics in different forms. Firstly, these nanovesicles with hollow structures could serve as novel drug delivery platforms, facilitating the transport of diverse bioactive molecules and therapeutic cargo to the recipient cells at the lesion site [12]. Thanks to the stability of naturally-occurring membrane structure, the BEVs-based drug delivery platform could carry the therapeutic genetic tools (e.g. siRNA, CRISPR-Cas9, etc.), protecting them from enzymatic degradation or hydrolysis in the complex physiological environment [13, 14]. Besides, benefiting from the ease of modification, BEVs-based drug delivery platforms could efficiently load the small molecular therapeutics [14], or directly produce the synthetic cargo (e.g. antigens, enzymes, therapeutic proteins, etc.) on the BEVs by editing the desired gene in parent bacteria. The BEVs-based drug carriers are also featured in their capability for targeting delivery toward the disease area to enhance drug accumulation and availability [15]. Moreover, the BEVs drug delivery platform can integrate with functional materials, to facilitate combinational therapy (e.g. photodynamic therapy, photothermal therapy, etc.) and maximize the synergistic therapeutic efficiency [16].

Conclusion and further perspective

In this review, we comprehensively summarize the development of BEV-based nanopharmaceuticals to facilitate disparate biomedical applications in recent years. Amongst the unique advantages and functions of BEVs, we demonstrated the tremendous potential of applying these naturally occurring nanovesicles to establish a myriad of innovative therapeutic strategies for new-generation pharmaceuticals evolution, especially in the versatile bioactive cargo delivery and powerful vaccination approaches.

Taking the unique merits of nanovesicles, the structural stability, ease of cargo loading, promising penetration across physiological barriers, and specific targeting capabilities endow the BEVs application to be beneficial in delivery for a wide range of therapeutics. Particularly, the naturally occurring membrane structure of BEVs enables targeting delivery of therapeutic genetic tools (e.g., siRNA, DNA, CRISPR-Cas9, etc.) in the physiological, preserving stability and bioactivity, thus enhancing gene therapy. Leveraging the ease of genetic modification in parent bacteria, protein cargo, such as enzymes and antigens, can also be directly expressed within BEVs, optimizing loading efficiency compared to conventional delivery platforms. Furthermore, advancements in nanotechnology and material science have witnessed the integration of functional materials with BEV delivery platforms to achieve combinational therapy, thereby further improving the synergistic therapeutic efficacy.

Abstract

Introduction

Polyacrylamide hydrogels and their polymerization

Polyacrylamide hydrogel in cell biology and drug delivery system

Classification of hydrogels: a broad overview

Homo-polymeric hydrogels

Co-polymer hydrogels

Semi-interpenetrating network

Interpenetrating network

Recent progress (2019–2022) of polyacrylamide-based hydrogel composites

Swelling and degradation behaviour of PAM hydrogels

Mechanical properties of PAM hydrogel composites

Tribological and rheological properties of PAM composites

Magnetic hydrogel composites

Biological properties of the PAM hydrogel composites

Applications of polyacrylamide hydrogels

Conclusions

Scope for the future work

Acknowledgements

References

Abstract

     Polyacrylamide hydrogels have made an immensely important place in various fields having bio-compatibility, high water-holding capacity, tunability and cheap synthesis, which has attracted researchers’ attention. Polyacrylamide can be chemically infused with other elements or compounds to find applications in magnetic biosensors, drug delivery, cartilage repair and wound dressing. This paper throws light on the brief introduction of hydrogels and their classification. The polymerization method of polyacrylamide hydrogel followed by its clinical uses (cell biology and drug delivery) is adorned in the report. Keeping at the centre, the recent highlights on the research work done on polyacrylamide hydrogel composites using various reinforcing additives are crucially explored first time in the present report. The improvement practice in the strength, bonding and self-healing of the polyacrylamide hydrogel is demonstrated by the encapsulation of nanoparticles like silicon, carbon nanotubes, gelatine, cellulose, etc. The clinical aspects of the polyacrylamide are corroborated by the cell viability, proliferation and migration. Thus, polyacrylamide hydrogels are emerging candidates, precisely illuminated in the review, which can be an influential highlight designed for upcoming research.

Introduction

     Hydrogels are flexible polymers with excellent biocompatibility. Due to their three-dimensional network, hydrogels have high water-holding capacity. Further, hydrogels have the ability to form blends by using more than one monomers and cross-linkers. Chemical infusion of hydrogels has also been tested with several biocompatible materials. These hydrogel composites are tested for a ‘new generational’ changes in existing applications. This infusion using corresponding salts followed by reduction using a suitable reducing agent forms nanoparticles suspended in the hydrogel. Research in magnetic bio-sensing materials has tested hydrogels infused with magnetic nanoparticles also called ferrogels. For applications like cartilage replacement as well, hydrogel-based composites are carefully prepared for specific cartilage-like properties [1, 2]. Gels are formed when crosslinker forms bonds laterally linking two polymeric chains. This is much like the two sugar phosphate DNA backbones that are joined by chromosome pairs. Except that, the polymeric chains are flexible, unlike DNA backbones! Without cross-linking, the polymeric chains will dissolve into the aqueous phase and only interaction between the chains is through a physical bond. Cross-linking also decides the strength-related properties of the gel. Optimizing the cross-linking method and the cross-linking ratio is essential for strength-related properties.

Conclusions

     Polyacrylamide hydrogels are emerging polymers due to their unique properties, which have made them useful in fields like cartilage repair, wound dressing, contact lenses, drug delivery and biosensors. The PAM hydrogel can be prepared by a monomer unit along with a cross-linker mixed in a suitable quantity. The PAM composites were fabricated by introducing some nanoparticles and reducing them to change these cations/anions into metal ions. The present review described the introduction of hydrogels with their different types, based on the polymeric network structure. The PAM hydrogels along with different nanoparticles like TiO2 and CNTs are turned with high strength ([ 0.43 and 2.340 MPa compressive strength and elastic modulus, respectively) composites. However, the puncture resistant of the PAM was also enhanced with these nanoparticles, estimated using the needle insertion technique. The tribological and magnetic investigations (magnetic saturation 1.41 emu/g) revealed an improved performance of PAM with encapsulation of nanoparticles due to the fine-grained structure and lubrication effects (created by CNTs). Furthermore, the biological activity of PAM composites was remarkably important and ideal for the implementation in biomedical research. Thus, in short, this review report is an important highlight for PAM hydrogel composites and can provide a prominent direction to future research based on the PAM hydrogels for biomedical applications.

Abstract

Keywords

1. Introduction

2. DNA damage response

3. DDR and radiotherapy failure

4. DDR inhibitors decrease radio-resistance

5. DDR roles in chemotherapy failure

6. DDR inhibitors decrease chemo-resistance

7. Conclusions

Funding

Availability of data and material

Ethics approval and consent to participate

Consent for publication

Declaration of Competing Interest

Acknowledgements

References

Abstract

Up to now, many improvements have been made in providing more therapeutic strategies for cancer patients. The lack of susceptibility to common therapies like chemo- and radio-therapy is one of the reasons why we need more methods in the field of cancer therapy. DNA damage response (DDR) is a set of mechanisms which identifies DNA lesions and triggers the repair process for restoring DNA after causing an arrest in the cell cycle. The ability of DDR in maintaining the genome stability and integrity can be favorable to cancerous cells which are exposed to radiation therapy or are treated with chemotherapeutic agents. When DDR mechanisms are error-free in cancer cells, they can escape the expected cellular death and display resistance to treatment. In this regard, targeting different components of DDR can help to increase the susceptibility of advanced tumors to chemo- and radio-therapy.

1. Introduction

DNA-damaging agents originating whether from endogenous or exogenous resources are known to threat the viability of every cell of our body [1]. Besides to the cellular issues arising from the great number of mutations and genome instability, the lack of proper responses can establish generations of these defective cells and put our whole body in danger [1]. DNA damage response or DDR is a precise mechanism which contains sensing the lesions, establishing signals, and finally initiating repair processes by the means of these signals [2]. During DDR, cell cycle is also affected by the mediators of DDR and is temporarily stopped in order to inhibit the replication of a defective DNA [3]. In some cases, DNA deteriorations are irreparable and thus, cell death is the only option on the table [3].

In addition to normal cells, cancerous cells are also able to use the same mechanisms for their chemotherapy- and/or radiotherapy-induced damaged DNA. Until DDR is working properly in a cancerous cell, DNA damages would not lead to cell death and thus, treatment would not be considered successful [1]. This means that despite all the advantageous impacts of DDR, it stands in the way of overcoming a great challenge in cancer therapy: resistance to our common methods, chemo- and radio-therapy. Recently, a great number of researchers have worked on targeting distinct components of DDR for enhancing the efficacy of cytotoxic treatments [4]. In this paper, we review the process of DDR briefly and explain the role of its key players in decreasing the susceptibility of cancer cells to common therapeutic procedures. Additionally, the usage of DDR inhibitors on different types of cancer would be discussed for giving an insight for the treatment of advanced stages of this lethal disease.

1- Introduction

2- Breast cancer

3- Drug resistance

4- miRNA biogenesis

5- miR-21 in BC

6- Expression of miR-21 in cancer tissues and cells

7- Role of miR-21 as a mediator in drug resistance in BC

8- Upstream pathway of miR-21

9- Potential targets of miR-21

10- Conclusion and future perspectives

References

Abstract

Breast cancer (BC) is the most common cancer among women that is responsible for the most of the cancer-related death in worldwide. Drug resistance is remaining as a significant clinical obstacle to treat BC patients effectively. Therefore, to help overcome this problem, it is necessary to understand the mechanisms of drug resistance. microRNAs classify as highly conserved non-coding RNAs (~22 nucleotides) and interact with mRNAs-coding genes for direct post-transcriptional repression. It has been reported that miR-21 is overexpressed and also acts as oncomiR in many human malignancies by targeting of several tumor suppressor genes–associated with apoptosis, proliferation and metastasis. Specifically, it has been reported that miR-21 is responsible for the drug resistance and its overexpression is related to the development of Multi Drug Resistance (MDR) in breast cancer. In this review, we discussed about the role of miR-21 on the drug resistance of breast cancer.

Introduction

Breast cancer (BC) is responsible for the death of approximately 500,000 women per year in the world. Also, more than one million new case of BC is diagnosed across the world per year. The occurrence of BC accounts for 7-8% of the entire number of malignant tumors. Chemotherapy is known as a principal strategy for cancer treatment; however, its application is limited due to drug resistance. Resistance to chemotherapeutics is mainly divided into two extensive categories: (i) intrinsic and (ii) acquired. Intrinsic resistance shows the presence of resistance-mediating factors in the tumor before starting of treatment process that makes chemotherapy ineffective. Acquired drug resistance, however, will be developed during of the treatment [1,2]. Drug resistance brings serious clinical obstacles to the prosperous treatment of BC patients. To overcome these problems, a well understanding of the drug resistance mechanisms is definitely required. The molecular mechanism of chemotherapeutic resistance in BC cells is completely complicated, and comprises multiple processes, including epigenetic changes, gene mutation, gene amplification and microRNA expression. miRNAs are short non-coding RNAs (~22 nucleotides) that could be found in all eukaryotic cells. They have a significant role in the progression of cancer by binding to the 3′ untranslated region (UTR) of the target genes, leading to the target mRNA degradation and inhibition of translation.

1- Introduction

2- pH-responsive polymeric nanocarriers

3- Temperature-responsive polymeric nanocarriers

4- Redox potential-responsive polymeric nanocarriers

5- Enzyme-responsive polymeric nanocarriers

6- Light-responsive polymeric nanocarriers

7- Dual-responsive polymeric nanocarriers

8- Future perspectives

9- Conclusions

References

Abstract

In the last decade, considerable attention has been devoted to the use of biodegradable polymeric materials as potential drug delivery carriers. However, bioavailability and drug release at the disease site remain uncontrollable even with the use of polymeric nanocarriers. To address this issue, successful methodologies have been developed to synthesize polymeric nanocarriers incorporated with regions exhibiting a response to stimuli such as redox potential, temperature, pH, and light. The resultant stimuli-responsive polymeric nanocarriers have shown tremendous promise in drug delivery applications, owing to their ability to enhance the bioavailability of drugs at the disease site. In such systems, drug release is controlled in response to specific stimuli, either exogenous or endogenous. This review reports recent advances in the design of stimuli-responsive nanocarriers for drug delivery in cancer therapy. In particular, the synthetic methodologies investigated to date to introduce different types of stimuli-responsive elements within the biomaterials are described. The sufficient understanding of these stimuli-responsive nanocarriers will allow the development of a better drug delivery system that will allow us to solve the challenges encountered in targeted cancer therapy.

Conclusions

In this review, it was focused on the most recent advances in the development of stimuli-responsive nanocarriers for drug delivery in cancer therapy. These smart drug delivery systems respond to the distinct changes in cancer cells, such as changes in pH gradient and elevated secretion of certain enzymes, rather than the conditions in normal cells. Targeting tumors with stimuliresponsive nanocarriers could not only increase the therapeutic benefit and minimize associated toxicity, but could also enhance the curative effect by specifically releasing the anti-cancer drug in a powerful precise mode, both temporally and spatially. The different approaches adopted to incorporate stimuli responsive elements within the polymeric nanocarriers were discussed, with a particular focus on polymeric materials with stimuliresponsive mechanisms in response to pH, redox potential, enzymes, temperature, and light. Despite the tremendous progress that has been made regarding the engineering of new stimuli-responsive materials, several challenges still remain to be addressed with respect to nanomedicine applications. For example, their biodegradability and biocompatibility profiles should be critically investigated prior to utilization in human clinical trials. Many of these systems have only been reported as an in vitro proof-of-concept and follow-up work in vivo preclinical models has been described for only a few. However, the translation of these stimuli-responsive delivery systems from the bench to the bedside might be facilitated, to some extent, if the regulatory requirements for human clinical trials are considered in light of the key features that render a biopolymer suitable for biomedical application, such as biocompatibility, biodegradability, high drug loading capability, programmable release, excellent in vivo stability, non-cytotoxicity, and ability to support effective targeting. Given the ongoing developments in the field of bionanotechnology along with the wide knowledge accumulated over recent years, it is convinced that the collaborative efforts of chemists, biologists, and medicinal and pharmaceutical scientists will revolutionize the design of responsive polymeric materials for cancer therapy to significantly improve both the quality and duration of the lives of patients with cancer.

1- Introduction

2- DDS for targeted BC treatment

3- Conclusion and outlook

References

Abstract

Bladder cancer is a severe disease that threatens human health. The high recurrence rate and severe side-effects of traditional bladder cancer therapy require more efficient and higher targeting treatment. Drug delivery systems especially being endowed with the targeting property may provide a feasible means to solve such problems. Herein, we have reviewed the recent progress of the drug delivery systems aiming at bladder cancer therapy especially focusing on their targeting strategies. Additionally, we give some outlook of the design on targeting strategy for more effective anti-cancer applications.

Introduction

Cancer is a category of disease originating from unregulated cell growth and such abnormal cells are able to spread or invade other parts of our body. It is a major public health problem and becomes the second leading cause of death worldwide. Among them, bladder cancer (BC) tops the list of the estimated new cases and deaths [1]. In Europe, BC is the 5th most common cancer type for both sexes affecting rather men than women [2]. In US, BC ranks the 4th most common caner and the 8th in mortality in men [1]. In principle, BC is a rather heterogeneous disease, resulting in a challenge in classification, staging and grading. Generally, 70% of bladder urothelial cell carcinomas represent a superficial disease called nonmuscle-invasive BC, while the other 30% develop a muscle-invasive disease bearing the risk of metastatic spread of the tumor [3]. The standard scheme for superficial BC treatment is surgical transurethal resection with an 80% early success rate. Unfortunately, among them, 70% of those patients develop tumor recurrence within 5 years after surgical transurethal resection [4]. Therefore, chemotherapy still plays an important role in the prevention of tumor recurrence and progression. Although systemic or intravesical chemotherapy using the first-line chemotherapeutic agents (cisplatin, taxanes, gemcitabine, etc.) enables long-term survival in some patients, the high recurrence rate and severe side-effects still hinder BC therapy. Thus, more efficient and higher targeting treatment is in urgent need to improve the quality of the BC patients’ lives.

Overcoming Target-Dependent Resistance

Overcoming Pathway-Dependent Resistance

Concluding Remarks

References

Coadministration of Allosteric and Orthosteric Drugs: A Novel Strategy to Tackle Drug Resistance

As a detrimental problem in modern biomedicine, the inevitable emergence of drug resistance poses a great challenge to pharmaceutics and threatens global health [1–7]. It is a sophisticated evolving process involving multiple events on the molecular pathway, and even organismal levels. Based on the underlying mechanism, drug resistance is classified as target-dependent resistance (see Glossary), caused by changes within the original targets, and pathway-dependent resistance, resulting from alterations in the relevant collateral pathways) [4,8,9]. Different methodologies are applicable for tackling different types of resistance; for example, structure-based drug design is more suitable against target-dependent resistance, whereas the multitargeted approach of polypharmacology may be a better choice against pathway-dependent resistance [10–12]. Many excellent reviews have already discussed various approaches to combat resistance, but most of them only focus on either drug optimization or combined treatments with different types of therapies [5,12–14]. Stemming from rapid developments in structural biology and protein allostery research [15–20], allosteric drugs can resensitize resistant targets and selectively target resistance-related signaling pathways, thereby restoring the efficacy of orthosteric drugs. Moreover, compared with monotherapy, double- or even multiple-drugging strategies can cover a broader therapeutic spectrum, achieve synergistic effects, and contribute to better clinical outcomes. Thus, combination therapy with allosteric and orthosteric drugs provides an unprecedented opportunity to overcome the notorious problem of drug resistance and boost the development of next-generation pharmacological agents. With the goal of forwarding this notion, this review first outlines typical examples of combined treatments to combat clinically relevant resistance, reviewing their modes of action and future perspectives in detail. Then, it discusses the current state of this combinatorial strategy, presenting the existent obstacles as well as possible solutions. This review highlights a promising tactic for overcoming the long-standing conundrum of drug resistance and will hopefully be instructive for future drug discovery and development.

1- Introduction

2- Mechanisms and conventional methods towards monitoring of drug resistance

3- Electrochemical and Electrochemiluminescent (ECL) sensing

4- Electrical sensing

5- Optical sensing

6- The role of nanomaterials for the screening of drug resistance

7- Electrochemical nanosensor for the monitoring of drug resistance

8- Optical nanosensors for the monitoring of drug resistance

9- Electrochemiluminescence nanosensors for the monitoring of drug resistance

10- Photoelectrochemical (PEC) Nanosensors for the monitoring of drug resistance

11- Conclusion

References

Abstract

Drug resistance is worldwide health care crisis which decrease drug efficacy and developing toxicities. Effective resistance detection techniques could alleviate treatment cost and mortality associated with this crisis. In this review, the conventional and modern analysis methods for monitoring of drug resistance are presented. Also, various types of emerging rapid and sensitive techniques including electrochemical, electrical, optical and nano-based methods for the screening of drug resistance were discussed. Applications of various methods for the sensitive and rapid detection of drug resistance are investigated. The review outlines existing key issues in the determination which must be overcome before any of these techniques becomes a feasible method for the rapid detection of drug resistance. In this review, the roles of nanomaterials on development of novel methods for the monitoring of drug resistance were presented. Also, limitations and challenges of conventional and modern methods were discussed.

Introduction

Drug resistance as an emerging health concern reducing the efficiency and potency of a drug to produce effective treatment of pathogenic microorganisms or cancer and decrease overall patient survival [1]. During the cancer invasion and metastasis, large number of failures in the chemotherapy is related with the resistance of tumor cells to anticancer agents [2]. Consequently, resistance to drugs led to many other problems including toxicity and huge costs for development of new drugs [3]. In contemporary clinical practice, resistance to anticancer drugs can only be detected after long treatment periods [3]. Various mechanisms including reduced influx or enhanced efflux of drug, drug detoxification, glutathione conjugation, disrupt in DNA repair introduced for resistance against some anticancer agents like cisplatin [4]. It is important to point out that resistant to anticancer agents already exists before of chemotherapy in about half of cancer cases [3]. Thus, diagnostic tests for drug resistance in individual prior to commencing treatment with chemotherapy agents are required to predict the efficacy of chemotherapy and avoid any toxicity in normal tissues [3]. Several in vitro test analysis methods have been developed to assessment of resistance or sensitivity [5-7].

The novel coronavirus (2019-nCoV) is an emerging pathogen that was first described in late December 2019 and causes a severe respiratory infection in humans. Since the outbreak of COVID-19, international attention has raised to develop treatment and control options such as types of immunotherapies. The immunotherapy is an effective method for fighting against similar viral infections such as SARS-CoV, and MERS-CoV. These methods include several types of vaccines, monoclonal antibody candidates, and etc. This systematic review article was designed to evaluate the existing evidence and experience related to immunotherapy for 2019-nCoV. Web of Science (ISI), PubMed, and Scopus databases were used to search for suitable keywords such as 2019-nCoV, novel coronavirus, Immunotherapy, interleukin, vaccine and the related words for relevant publications up to 24.3.2020. The present systematic review was performed based on PRISMA protocol. Data extraction and quality valuation of articles were performed by two reviewers. 51 articles were the results of the search and based on the inclusions and exclusions criteria, 7 articles were included in the final review. As a conclusion of these studies demonstrated that although no serious research has been done on this subject at the time of writing this article, similar studies on the related viruses showed notable results. So immunotherapy for this virus can also be a suitable option.

Background

2019-nCoV a large enveloped virus with a positive sense, singlestranded RNA genome, is the third known coronavirus after SARS-CoV and MERS-CoV that was first identified in late December 2019 and causes severe respiratory illness and pneumonia-like infection in humans [1,2]. WHO has declared the pandemic outbreak of novel coronavirus (2019-nCoV) as a global health emergency. Immunotherapy is an efficient therapeutic option intervention against viral infections. Most immunotherapy attempts have been successful to fight against similar COVID-19 viruses such as SARS-CoV and MERS-CoV. The main methods in this regard include several vaccines and monoclonal antibody candidates. Furthermore, according to existing evidence in fighting against viral infections such as Ebola, influenza, SARS, and MERS plasma exchange can likely reduce the viral load and disease mortality [3,4]. In both SARS-CoV and SARS-CoV-2 viruses entry into the host cells is mediated by interaction of the receptor-binding domain (RBD) in S protein on virus outer-membrane and angiotensin-converting enzyme 2 (ACE2) on cell. So, these proteins can be the major potential targets for immunotherapy [1,5]. The increasing knowledge of MERS-CoV and SARS-CoV immunotherapies in recent years might increase the opportunities to design effective same therapeutics for novel coronavirus [3].

Head and neck cancer (HNC), which includes epithelial malignancies of the upper aerodigestive tract (oral cavity, oropharynx, pharynx, hypopharynx, larynx, and thyroid), are slowly but consistently increasing, while the overall survival rate remains unsatisfactory. Because of the multifunctional anatomical intricacies of the head and neck, disease progression and therapy-related side effects often severely affect the patient’s appearance and self-image, as well as their ability to breathe, speak, and swallow. Patients with HNC require a multidisciplinary approach involving surgery, radiation therapy, and chemotherapeutics. Chemotherapy is an important part of the comprehensive treatment of tumors, especially advanced HNC, but drug resistance is the main cause of poor clinical efficacy. The most important determinant of this phenomenon is still largely unknown. Recent studies have shown that non-coding RNAs have a crucial role in HNC drug resistance. In addition, they can serve as biomarkers in the diagnosis, treatment, and prognosis of HNCs. In this review, we summarize the relationship between non-coding RNAs and drug resistance of HNC, and discuss their potential clinical application in overcoming HNC chemoresistance.

Background

Head and neck cancer (HNC) is a major global health problem. More than 890,000 new cases of HNC and approximately 450,000 HNC-related deaths occur every year [1,2]. The majority of cases are HN squamous cell carcinoma (HNSCC) [3], involving the stratified epithelium of the oral cavity, pharynx, and larynx, with an overall 5-year survival rate of only 40%–50% [3]. Most HNC is closely related to tobacco and alcohol use [1–3]. Patients with HNC might have symptoms including hoarseness, dysphagia, pain, neck mass, and ulcers, which require a multidisciplinary approach involving surgery, radiation therapy, and chemotherapy [4]. Although the treatment is effective for early and locally advanced disease, the prognosis of recurrent and metastatic disease remains poor [5]. Clinically, more than 65% of patients are diagnosed with advanced disease because of the lack of early diagnosis [6]. However, both radiotherapy and surgery reduce patients’ quality of life at this stage [2]. Radiotherapy usually produces obvious side effects, while surgery can significantly affect the normal physiological structure and function of patients [2,7]. Additionally, targeted therapy for HNC has been incorporated into clinical treatment guidelines, but its clinical response and long-term effect are limited, and high costs are associated with this treatment [8]. In recent years, chemical treatment of advanced HNC has been increasingly recognized [9]. In early phase II clinical trials in patients with advanced HNSCC, significant single-agent response rates were up to 30% [5,10].

Coronaviruses are a large group of viruses known to cause illnesses that vary between the common cold and more severe diseases to include severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). A novel coronavirus was identified in December 2019 in Wuhan city, Hubei province, China. This virus represents a new strain that has not been previously identified in humans. The virus is now known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the resulting disease is called coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) declared the novel coronavirus outbreak a global pandemic in March 2020. Despite rigorous global containment and quarantine efforts, the incidence of COVID19 continues to rise, with more than 1,948,617 laboratory-confirmed cases and over 121,846 deaths worldwide. Currently, no specific medication is recommended to treat COVID-19 patients. However, governments and pharmaceutical companies are struggling to quickly find an effective drug to defeat the coronavirus. In the current review, we summarize the existing state of knowledge about COVID-19, available medications, and treatment options. Favilavir is an antiviral drug that is approved in Japan for common influenza treatment and is now approved to treat symptoms of COVID-19 in China. Moreover, Chloroquine and hydroxychloroquine, drugs used to treat malaria and arthritis, respectively, were recommended by the National Health Commission of the People’s Republic of China for treatment of COVID-19. Presently, chloroquine and hydroxychloroquine are under investigation by the US Food and Drug Administration (FDA) as a treatment for COVID-19. The first COVID-19 vaccine is not expected to be ready for clinical trials before the end of the year.

Introduction

In the second week of December 2019, unknown viral infection was identified in a small local fish and wild animal market in Wuhan city, Hubei province in China (Lu et al., 2020). Since this time, the virus has rapidly spread across mainland China, and now has reached other countries (Li et al., 2020a; Chen et al., 2020a). In the early stages of this virus spread, several cases of pneumonia of unknown etiology were reported. Patients have been diagnosed with severe acute respiratory infection symptoms and others with rapidly developing acute respiratory distress syndrome, acute respiratory failure and other serious complications leading to death (Nijuan et al., 2013). The Chinese Center for Disease Control and Prevention (CCDC) identified this infection as a novel coronavirus infection on Jan 7, 2020 and on Feb 11, 2020, the WHO announced a new name for the epidemic disease as 2019-new coronavirus disease (2019-nCoV and now known as COVID19) (Organization, W.H., 2020). Additionally, the International Committee on Taxonomy of Viruses named 2019-nCoV as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has become a major global health concern and the WHO declared the coronavirus outbreak a global pandemic on March 2020 (Whitworth, 2020). As of April 14, 2020, COVID-19 has affected more than 1,948,617 patients in 210 countries and territories around the world and two international conveyances and left around 121,846 deaths worldwide.

Encapsulation of drugs in nano- and microparticles has been known as a promising approach for efficient drug delivery. It has been well established that adjusting the physiochemical properties of these carriers concerning the specific condition of each disease will improve therapeutic efficacy. The role of particle characteristics including composition, size, surface chemistry, density, elasticity on successful drug delivery has been well recognized. In the last few decades, particle shape arose as an important property playing a profound role in drug delivery efficiency. Particle shape plays its role by affecting physiological interactions including opsonization, internalization, margination, circulation half-life, etc. Delivery of a drug carrier to its target site is a desirable goal in drug delivery, and we were wondering whether engineering the particle geometry would bring us closer to this goal. This article has aimed to review researches studying the impact of particle shape on its interactions with the physiological environment and to focus on the role of particle shape in targeted drug delivery to various sites including liver, spleen, lung, brain, and also tumor sites of different tissues.

Introduction

In biomedical applications, nano- and microparticles have been proved to be useful for the early detection, bioimaging, vaccination, and therapy of various diseases [1]. They can prolong the half-life of therapeutic drugs and bioimaging contrast agents and enhance uptake by target host cells [2]. Drug delivery vehicles like liposomes, polymeric micro and nanoparticles, micelles, carbon nanotubes, microbubbles, virus-like particles, dendrimers, and quantum dots have been introduced so far [3]– [7]. These particles have several advantages, such as the possibility of tailoring their properties to improve the efficiency of available therapies, protecting the drug from degradation, providing a controlled and prolonged drug release, and offering active or passive targeting to the tumor site [8]. It should be considered that after the administration of particles, they face a complex environment that exposes them to plentiful interactions, including interactions with serum proteins, different cell types, fluid dynamics, and various biological barriers. All above-mentioned interactions can lead to some challenges such as difficulties in crossing biological barriers, rapid particle elimination from the blood circulation by the reticuloendothelial system (RES), early release of the drug, and aggregation after interaction with serum components, quick removal from the bloodstream, and a low target efficiency [9]. These challenges converge researchers’ concentration on evaluating the effects of particle characteristics on drug delivery efficiency [10]. The role of particle size is well described previously and has a large impact on particle fate in vivo. The size of carrier profoundly affects its behavior in the biological environment.

The novel coronavirus infection that initially found at the end of 2019 has attracted great attention. So far, the number of infectious cases has increased globally to more than 100 thousand and the outbreak has been defined as a pandemic situation, but there are still no “specific drug” available. Relevant reports have pointed out the novel coronavirus has 80% homology with SARS. In the difficulty where new synthesized drug cannot be applied immediately to patients, “conventional drug in new use” becomes a feasible solution. The first medication experience of the recovered patients in the US has led remdesivir to be the “specific drug”. China has also taken immediate action to put remdesivir into clinical trials with the purpose of applying it into clinical therapeutics for Corona Virus Disease 2019 (COVID-19). We started from the structure, immunogenicity, and pathogenesis of coronavirus infections of the novel coronavirus. Further, we analyzed the pharmacological actions and previous trials of remdesivir to identify the feasibility of conducting experiments on COVID-19.

Introduction

The novel coronavirus 2019 (2019-nCoV), officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a newlyemerged human infectious coronavirus. Since December 2019, it has spread rapidly in China in a short period of time. As of March 17, 2020, there have been 81116 confirmed cases and 3231 deaths. It has also outbreak in other countries, such as Korea, Japan, Italy, Singapore, and Iran, with a total of 85296 cases confirmed. Due to it is a newlyemerged virus, researchers have taken quick actions to isolate the virus and perform gene sequencing, making identifying treatments possible. Even so, it takes time to develop new drugs and vaccines, as well as to explore biotherapeutics, thus it is unlikely to be applied to patients with urgent need. Therefore, “conventional drug in new use” becomes a viable solution. The SARS-CoV-2 is 80% homologous with the acute respiratory syndrome-associated coronavirus (SARS-CoV), which also broke out in China in 2002, and some enzymes are even more than 90% homologous [1]. Consequently, we are expecting to find drugs for the treatment of COVID-19 from the experience of SARS-CoV and Middle East Respiratory Syndrome (MERS-CoV). Some drugs, such as ribavirin, interferon, lopinavir, and corticosteroids, have been used in patients with SARS or MERS [2], within the selection range of “conventional drug in new use”. Through clinical treatment of the COVID-19, it has been found that neuraminidase inhibitors (oseltamivir, peramivir, zanamivir), ganciclovir, acyclovir, ribavirin are ineffectual and not recommended for clinical application [3].