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

Keywords

1. Introduction

2. Case presentation

3. Discussion

4. Conclusion

Funding

CRediT authorship contribution statement

Consent for publication

Competing interests

Acknowledgments

References

Abstract

Persian medicine is a branch of complementary and alternative medicine that tries to offer simple and suitable approaches and methods for treating diseases and health protection. Ma’oljobon is known as a kind of whey protein. It is a remedy with various characteristics, such as removing viscous wastes from the body without causing any dryness and moistening, while also providing nutrition. A 7-year-old boy with severe chronic cough refers to Traditional Persian Medicine Clinic due to allergic rhinitis. Formerly he had multiple failed attempts of treatment. The cough resolved with a 12-week period administration of Ma’oljobon. This is the first report evaluating the remedial effect of Ma’oljobon on allergic rhinitis.

1. Introduction

Allergic rhinitis is paroxysms of rhinorrhea, sneezing, and nasal obstruction accompanied by cough and itching (1-3). The prevalence of Allergic rhinitis is increasing in developed countries. In some countries such as the United States, 10-30 percent of the population suffer from this condition (3-7). Unfortunately, misdiagnosis of allergic rhinitis has a heavy economic burden on countries due to the unnecessary prescription of medication, physician visits, and disturbing school performance (8-13). Nowadays, pharmacotherapy and allergen avoidance are choices for managing symptoms of allergic rhinitis. Due to self-treatment with over-the-counter medications, that have significant side effects, the clinicians’ obligation is to ensure that the patient receives essential medication with the lowest side effects (14-16).

Ma’oljobon is derived from cow milk. It is an Arabic word which consists of “Maå” (water) and “jobon” (cheese) (17). It is a pale green-colored liquid, derived down in the course of the cheeseproducing process by adding either rennet or acid (citric acid, lactic acid, acetic acid, etc.) or by adding vinegar or oxymel (syrup of honey and vinegar) to hot milk to separate liquid and coagulated part (17, 18). Ma’oljobon is a kind of whey protein (17-22). Twenty percent of cow protein is whey (23). The major biological components of whey protein are lactoferrin, betalactoglobulin, alfa lactalbumin, glycomacropeptide, immunoglobulin (18, 23). Beta-lactoglobulin and alfa lactalbumin are the principal whey proteins that account for 80% of the total product (24), while other components include lactose, mineral, growth factor, lactoperoxidase, and lysozyme (25, 26). Whey protein is a functional food with several health benefits (23), such as anti-inflammatory and antioxidant activity (27). Also, it has a role in increasing immunity, along with its anti-viral and anti-bacterial activity due to its rich protein and immunoglobulin (28-30). However, there is controversy about the temperament of Ma’oljobon; It is a product with wet and cold temperament in some studies (18, 19, 31), and wet and warm in some other references (32, 33). This is the first report evaluating the remedial effect of Ma’oljobon on allergic rhinitis.

Abstract

Keywords

1. Introduction

2. Methods

3. Results

4. Discussion

acknowledgements

References

Abstract

Introduction
Tamil Nadu administers intravenous iron sucrose for correcting moderate anaemia among pregnant women (Haemoglobin level 7–8.9 g/dl) based on preliminary studies. We did a cross-sectional study to estimate compliance level and that of factors associated with intravenous iron sucrose treatment for moderate anaemia among pregnant women attending health facilities of Kancheepuram health district, Tamil Nadu, India, 2017.

Methods
We needed five pregnant women of 20–30 weeks from 70 clusters (health subcentres) for the assumptions of 64% compliance, 7% absolute precision, 95% Confidence Interval (CI) and a design effect of two. We collected data on knowledge and experience with iron sucrose treatment and reasons for non-compliance. We abstracted haemoglobin levels and administered doses from records. We computed compliance level (%) with 95% CI and estimated adjusted odds ratio (AOR) for non-compliance through logistic regression analysis.

Results
The median age of 350 women was 24 years (Range = 22 to 26). Compliance level to intravenous iron sucrose was 79% (95% CI: 73 to 84). Non-compliance was more likely among women aged 25–35 years (AOR: 2.1, 95% CI: 1.2 to 3.7), primi (AOR: 2.2’ 95% CI: 1.2 to 3.8) and not received treatment information (AOR: 3.1, 95% CI: 1.1 to 8.8). Major reasons for non-compliance were lack of information about treatment, belief that food was better than injections and that injections could harm the baby.

Conclusions
The compliance to intravenous iron sucrose was insufficient. Providing clear information about intravenous iron sucrose to moderately anaemic pregnant women could increase the compliance to intravenous iron sucrose.

1. Introduction

Anemia is the most common nutritional deficiency disorder of pregnancy. The World Health Organization (WHO) estimated global prevalence of anaemia among pregnant women of 15–45 years as 38% in 2011.1 Prevalence of anaemia among pregnant women in South East Asian region (as defined by WHO Regions) is 49%, which is the highest among all the regions in the world.1 In India, the prevalence of anaemia among pregnant women is 54%, which is the highest prevalence in the South East Asian region.1 Prevalence of anaemia among pregnant women in Tamil Nadu is 44%.2

Anaemia during pregnancy will lead to poor maternal and perinatal outcomes. Anaemic pregnant women have a two-fold increase of preterm deliveries, higher incidences of low birth weight, postpartum haemorrhage and puerperal sepsis.3 The babies born to anaemic women have a higher incidence of intensive care unit (NICU) admissions, hyperbilirubinemia, respiratory distress syndrome, neonatal seizures, birth asphyxia and neonatal sepsis.3 According to the ministry of women and child development under Government of India, 20% of maternal deaths in India are due to anaemia and India contributes to half of the global maternal deaths due to anaemia.4

Abstract

Keywords

Introduction

Methods

Results

Discussion

Conclusions

Other information

Declarations

Acknowledgements

References

Article Info

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Abstract

Background
Poor treatment adherence among leprosy patients contribute to relapse, development of antimicrobial resistance, and the eventual plateauing of the prevalence and incidence of leprosy not just in the Philippines, but also worldwide. For this reason, we aimed to identify the patterns and determinants affecting treatment completion and default among multibacillary leprosy patients.

Methods
We conducted a retrospective cohort study involving three large hospitals in Metro Manila, Philippines. Patients who started the World Health Organization – Multiple Drug Therapy for multibacillary leprosy between January 1, 2007 and December 31, 2013 were included in the study. Selected socio-demographic and clinical data were abstracted from the patient treatment records. Survival analysis and proportional hazards regression were used to analyze the data.

Results
Records of 1,034 patients with a total follow-up time of 12,287 person-months were included in the analysis. Most patients were male, younger than 45 years old, had an initial bacterial index between 1 and 4, and were residents of Metro Manila. Less than 20% had their treatment duration extended to more than 12 months. Treatment adherence of the patients was poor with less than 60% completing treatment. Most patients complete their treatment within 12 months, but treatment duration may be extended for up to three years. Patients who default from treatment usually do so a few months after initiating it. After adjusting for other variables, hospital, initial bacterial index, and non-extended treatment duration were associated with treatment completion. These factors, in addition to age, were also found to be associated with treatment default.

Conclusion
This study provides quantitative evidence that there might be marked variations in how doctors in particular hospitals manage their patients, and these findings underscore the need to revisit and re-evaluate clinical practice guidelines to improve treatment outcomes and adherence

1. Introduction

Poor treatment adherence among leprosy patients is associated with relapse and the occurrence of antimicrobial resistance [[1]]. It has also been reported to contribute to the plateauing incidence and prevalence of leprosy in the Philippines [[2]], and worldwide [[3], [4], [5], [6]]. A perceived reason for poor treatment adherence is the long duration of the World Health Organization (WHO) multiple drug therapy (MDT) regimen, lasting a year for multibacillary leprosy patients [[7], [8]], which could even be extended for up to three years [[9], [10]]. In addition to the long duration of treatment, a host of psychosocial, economic, medical and health service, as well as personal factors were found to affect treatment adherence [[11]]. Two earlier reviews reported the following factors to be associated with poor treatment adherence: socio-economic status; educational attainment; gender; alcohol consumption; knowledge about leprosy; stigma associated with the disease; cultural factors; transportation costs; remoteness of residence; financial concerns; adverse effects of MDT; source of MDT; MDT drug shortages; poor relationship between patient and healthcare provider; and occurrence of leprosy reactions [[1], [12]]

Abstract

Background

Methods

Results

Conclusion

Keywords

1. Introduction

2. Methods

2.1. Data analysis

3. Results

4. Discussion

5. Conclusions

Funding

Author contribution

Declaration of Competing Interest

References

Abstract

Background
The number of students enrolled in the colleges of pharmacy in Saudi Arabia is high, and the number of pharmacy graduates expected to join the workforce in the coming years is expected to grow. There are limited number of studies that assess factors influencing pharmacy students’ career choices in Saudi Arabia in the literature. The aim of this study was to assess the factors that influence career goals and to investigate students’ perceptions about their career goals.

Methods
This study was a prospective cross-sectional survey targeting PharmD students in their last year (i.e. interns) in the academic year of 2018 – 2019. A questionnaire containing four parts and total questions of 32 was completed by interns. Data collected and analyzed using Qualtrics. This study was reviewed and approved by the Unit of Biomedical Ethics Research Committee at King Abdulaziz University.

Results
93 were reachable via email and all of them attended the interview and completed the survey (100% response rate). The most important job considerations were: work environment (67.7%), advancement opportunities (55.9%), salary (52.7%), benefits (40.9%), flexible work schedule (34%), and finally geographic region (29%). The top ranked career goal upon graduation were in industry and drug company (35.5%), clinical pharmacy (26.9%), (14%) academics/research and hospital pharmacy setting (inpatient/outpatient) (14%) each, and regulatory and community pharmacy (3.2% and 4.3%, respectively)

Conclusion
This study showed that work environment, advancement opportunities, and salary were the most important job consideration for pharmacy interns. The top ranked career goals were industry and drug company followed by clinical pharmacy. Further studies across Saudi Arabia are needed to confirm our results.

1. Introduction

Pharmacy education in Saudi Arabia (SA) has been receiving a lot of attention from both government and private sectors as the numbers of colleges have leaped from one college of pharmacy in 1999 to 27 colleges in pharmacy in 2018. (Alomran et al., 2018) Furthermore, this growth has been reflected on the quality and outcomes of some of these colleges as they acquire national and international accreditations and rank in the top colleges of pharmacy in the world in various academic rankings of world universities such as the QS ranking, where King Abdulaziz University ranks 50–100 in the field of Pharmacy. (QS Ranking, 2020) Most colleges in Saudi Arabia now offer a Doctor of Pharmacy degree (PharmD), in which students must complete a six-year entry level program including an experiential education period where they apply their knowledge in practical settings for a minimum of one academic year; while others still offer a 5-year Bachelor of Pharmacy degree (Almaghaslah et al., 2019). In 2018, the number of students enrolled at all colleges of pharmacy in SA was estimated to be 14,004 students and by 2022 the number of pharmacy graduates is expected to be 3,118 pharmacists that are ready to join the workforce.

Highlights

Abstract

Abbreviations

Keywords

1. Introduction

2. Mechanisms of action of COVID-19 candidate drugs

3. Potential drug-drug interactions between ASMs and COVID-19 candidate drugs

4. Potential drug interactions between ASMs and antipyretic and anti-inflammatory drugs concomitantly used in COVID-19 patients

5. Conclusion

Data availability statement

References

Abstract

In regard to the global pandemic of COVID-19, it seems that persons with epilepsy (PWE) are not more vulnerable to get infected by SARS-CoV-2, nor are they more susceptible to a critical course of the disease. However, management of acute seizures in patients with COVID-19 as well as management of PWE and COVID-19 needs to consider potential drug-drug interactions between antiseizure drugs and candidate drugs currently assessed as therapeutic options for COVID-19. Repurposing of several licensed and investigational drugs is discussed for therapeutic management of COVID-19. While for none of these approaches, efficacy and tolerability has been confirmed yet in sufficiently powered and controlled clinical studies, testing is ongoing with multiple clinical trials worldwide. Here, we have summarized the possible mechanisms of action of drugs currently considered as potential therapeutic options for COVID-19 management along with possible and confirmed drug-drug interactions that should be considered for a combination of antiseizure drugs and COVID-19 candidate drugs. Our review suggests that potential drug-drug interactions should be taken into account with drugs such as chloroquine/hydroxychloroquine and lopinavir/ritonavir while remdesivir and tocilizumab may be less prone to clinically relevant interactions with ASMs.

1. Introduction

The catastrophic global pandemic of Coronavirus disease 2019 (COVID-19) has put large parts of the world on a transient standstill. COVID-19 was first discovered in December 2019 and the causative agent was a novel subtype of beta-coronaviruses, known as SARS-CoV-2 (Rothan and Byrareddy, 2020). The novel coronavirus is an enveloped non-segmented positive-sense RNA virus (Richman et al., 2016) that was transmitted to humans via zoonotic transmission, similar to its precursors, severe acute respiratory syndrome coronavirus (SARS-CoV) (Ksiazek et al., 2003) and the Middle East respiratory syndrome coronavirus (MERS-CoV) (Zaki et al., 2012). These viruses primarily affect the respiratory system, however, clinical literature also provides evidence for neuroinvasive and neurotropic properties of SARS-CoV-2 (Carod-Artal, 2020; Li et al., 2020b; Najjar et al., 2020). Neurological symptoms reported in patients with COVID-19 include febrile seizures, status epilepticus and complications including encephalopathy, cerebral haemorrhage (Asadi-Pooya, 2020; Asadi-Pooya and Simani, 2020; Carod-Artal, 2020; Yin et al., 2020). These clinical manifestations suggest that people with neurological disorders may be more vulnerable to experience severe symptoms of COVID-19 disease. However, that does not seem to be the case. The International League Against Epilepsy (ILAE) has informed that persons with epilepsy (PWE) are not likely to be more susceptible to get COVID-19 nor are they inclined to suffer through severe manifestations of SARS-CoV-2 infection (ILAE, 2020). Even if PWE are exposed to SARS-CoV-2, it is unlikely that the frequency of seizures increases (ILAE, 2020). Nevertheless, management of COVID-19 in PWE or with acute reactive seizures requires certain precautions and guidelines to avoid worsening of the condition. In particular, potential drug-drug interaction that may occur on concomitant administration of anti-seizure medication (ASM) along with the drugs for treatment of COVID-19 need to be taken into account.

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- Materials and methods

3- Results

4- Discussion

References

Abstract

Drug resistance is a big problem in cancer treatment and one of the most prominent mechanisms underlain is overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, ABCC1 and ABCG2. Inhibition of ABC transporters is an important approach to overcome drug resistance. The inositol-requiring enzyme 1α (IRE1α), an arm of unfolded protein response (UPR), splices XBP1 mRNA to generate an active transcription factor XBP1s. UPR is implicated in drug resistance. However, the underlying mechanism is unclear. We found that the anticancer drugs such as 5-fluorouracil (5-FU) activated the IRE1α-XBP1 pathway to induce the expression of ABCB1, ABCC1 and ABCG2 in colon cancer cells. Inhibition of IRE1α RNase activity with small molecule 4μ8c suppressed the drug-induced expression of these ABC transporters and sensitized 5-FU-resistant colon cancer cells to drug treatment. In vivo xenograft assay indicates that administration of 4μ8C substantially enhanced the efficacy of 5-FU chemotherapy on 5-FU-resistant colon cancer cells. These results suggest that IRE1α-targeting might be a strategy to cope with drug resistance of colon cancer.

Introduction

Cancers have the ability to develop resistance to chemotherapy, and the increasing prevalence of these drug resistant cancers necessitates further research and treatment development. Multidrug resistance is a phenomenon by which, after exposure to a chemotherapeutic agent, cancer cells develop resistance, and simultaneous cross-resistance, to a wide range of functionally and structurally unrelated chemotherapeutic drugs (1, 2). Intrinsic or acquired multidrug resistance is one of the main reasons for chemotherapy failure, leading to the recurrence of malignant tumors and ultimately, patient relapse or death (3). A variety of mechanisms have been attributed to multidrug resistance, such as enhanced drug efflux, increased DNA damage repair, reduced apoptosis, elevated autophagy, and/or altered drug metabolism (4-6). Previous studies have confirmed that multidrug resistance both in cancer cell lines and human tumor tissues is most often associated with the overexpression of the ATP-binding cassette (ABC) transporters (4, 7, 8). These ABC transporters are efflux pumps that transport various structurally unrelated and potentially dangerous substances out of the cells. They hydrolyze ATP for energy and actively pump drug components out of cells, leading to drug resistance. In these transporters, ABCB1 (also known as MDR1 or P-gp), ABCC1 (MRP1) and ABCG2 (BCRP1) play an important role in drug resistance in vivo (4, 7). Developing inhibitors of ABC transporters is an important approach to overcoming drug resistance. Extensive efforts have been made to develop inhibitors targeting ABC transporters, particularly ABCB1. However, no such agents have been developed successfully as was initially hoped.

1- Introduction

2- Experimental section

3- Results and discussion

4- Conclusions

References

Abstract

In this paper, a targeting hyaluronic acid (HA)/mesoporous silica nanoparticle (MSN) based drug delivery system (DDS) with dual-responsiveness was prepared for cancer therapy. To avoid the side reaction between the anti-cancer drug doxorubicin hydrochloride (DOX) and HA, host-guest interaction was applied to fabricate the DDS named DOX@MSN-SS-N=C-HA. The “nanocontainer” MSN was modified with benzene ring via both pH-sensitive benzoic imine bond and redox-sensitive disulfide linkage. When DOX was loaded in the pores of MSN, the channels were then capped by the “gatekeeper” β-CD grafted HA (HA-g-CD) through host-guest interaction between β-CD and benzene. HA endowed the drug carriers with the targeting capability in CD44 over-expressed cancer cells. After cellular uptake, the carriers could rapidly release DOX for cell apoptosis due to both the hydrolysis of benzoic imine bond at low pH and the cleavage of disulfide bond at a high concentration of glutathione (GSH) intracellular. In vitro drug release studies and in vitro cytotoxicity studies were taken to investigate the dual-responsiveness of the carriers. And the CD44-receptor mediated cancer cell targeting capability was investigated as well. In conclusion, the targeted dual-responsive complex DDS fabricated through host-guest interaction has promising potential in cancer therapy.

Introduction

Chemotherapy remains one of the major therapeutic approaches applied to treat cancer in clinic. However, the disadvantages of traditional chemotherapeutic drugs such as unfavorable pharmacokinetics, poor biodistribution and lack of selectivity for target tissues reduce the utilization of the drugs and cause serious side effects [1]. To tackle these problems, anti-cancer drug delivery systems (DDSs) based on nanotechnology have been introduced and developed rapidly in recent decades [1–4]. DDSs such as liposomal daunorubicin (DaunoXome), pegylated liposomal doxorubicin (Doxil), albumin nanoparticle based Nan-paclitaxel (Abraxane) and polymeric micelle paclitaxel (GenexolPM) have already been approved for clinical treatment of cancer [3,4]. These nanosized DDSs can be accumulated in tumor tissues more easily via enhanced permeability and retention (EPR) effect to improve the pharmacokinetics and biodistribution of the drugs, as well as to reduce their side effects [5]. Though the commercial DDSs represented by the liposomal doxorubicin can overcome part of the shortcomings of traditional anticancer drugs, they cannot or only modestly improve patients’ overall survival [3,6–9]. Therefore, more efforts are needed to develop novel advanced DDSs. The properties including controlled drug release based on stimuli- sensitivity [10,11] and ligand-mediated active cancer targeting [12–15] introduced make the newly reported DDSs with better therapeutic effects [1–4]. During the past decade, mesoporous silica nanoparticle (MSN) based DDSs have attracted considerable attention from scientists worldwide [16,17]. MSNs can be simply synthesized with tunable size, shape, pore size and volume [17,18], and are easy surface functionalization [16]. These advantages, as well as the high drug loading capacity and good biocompatibility, ensure that MSNs are excellent choices for designing safe and efficient drug carriers [16–18].