Mitochondria-Targeting Polyprodrugs to Overcome the Drug Resistance of Cancer Cells by Self-Amplified Oxidation-Triggered Drug Release.

The multi-drug resistance (MDR) of cancers is one of the main barriers for the success of diverse chemotherapeutic methods and is responsible for most cancer deaths. Developing efficient approaches to overcome MDR is still highly desirable for efficient chemotherapy of cancers. The delivery of targeted anticancer drugs that can interact with mitochondrial DNA is recognized as an effective strategy to reverse the MDR of cancers due to the relatively weak DNA-repairing capability in the mitochondria. Herein, we report on a polyprodrug that can sequentially target cancer cells and mitochondria using folic acid (FA) and tetraphenylphosphonium (TPP) targeting moieties, respectively. They were conjugated to the terminal groups of the amphiphilic block copolymer prodrugs composed of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) and copolymerized monomers containing cinnamaldehyde (CNM) and doxorubicin (DOX). After self-assembly into micelles with the suitable size (∼30 nm), which were termed as TF@CNM + DOX, and upon intravenous administration, the micelles can accumulate in tumor tissues. After FA-mediated endocytosis, the endosomal acidity (∼pH 5) can trigger the release of CNM from TF@CNM + DOX micelles, followed by enhanced accumulation into the mitochondria via the TPP target. This promotes the overproduction of reactive oxygen species (ROS), which can subsequently enhance the intracellular oxidative stress and trigger ROS-responsive release of DOX into the mitochondria. TF@CNM + DOX shows great potential to inhibit the growth of DOX-resistant MCF-7 ADR tumors without observable side effects. Therefore, the tumor and mitochondria dual-targeting polyprodrug design represents an ideal strategy to treat MDR tumors through improvement of the intracellular oxidative level and ROS-responsive drug release.

Hemin enhances radiosensitivity of lung cancer cells through ferroptosis.

The principle underlying radiotherapy is to kill cancer cells while minimizing the harmful effects on non-cancer cells, which has still remained as a major challenge. In relation, ferroptosis has recently been proposed as a novel mechanism of radiation-induced cell death. In this study, we investigated and demonstrated the role of Hemin as an iron overloading agent in the generation of reactive oxygen species (ROS) induced by ionizing radiation in lung cancer and non-cancer cells. It was found that the presence of Hemin in irradiated lung cancer cells enhanced the productivity of initial ROS, resulting in lipid peroxidation and subsequent ferroptosis. We observed that application of Hemin as a co-treatment increased the activity of GPx4 degradation in both cancer and normal lung cells. Furthermore, Hemin protected normal lung cells against radiation-induced cell death, in that it suppressed ROS after radiation, and boosted the production of bilirubin which was a lipophilic ROS antioxidant. In addition, we demonstrated significant FTH1 expression in normal lung cells when compared to lung cancer cells, which prevented iron from playing a role in increasing IR-induced cell death. Our findings demonstrated that Hemin had a dual function in enhancing the radiosensitivity of ferroptosis in lung cancer cells while promoting cell survival in normal lung cells.

Evaluation of grit and its associated factors among undergraduate pharmacy students from 14 Asian and Middle Eastern countries amid the COVID-19 pandemic.

Introduction: Grit is proposed as an essential trait for academic achievement. Thus, evaluating its current status and the associated factors could aid academic support planning. Objective: The present study aimed to assess grit level and its related factors among undergraduate pharmacy students from 14 countries amid the COVID-19 pandemic. Methods: A cross-sectional survey-based study was conducted among pharmacy students from 14 countries in Asia and the Middle East. A 31-item questionnaire was developed, validated, and pilot-tested, including the validated short scale for grit assessment. The data was collected between 1 February and 15 April 2022. Descriptive and inferential statistics were employed as appropriate. Results: A total of 2665 responses were received, mainly from females (68.7 %), living in urban areas (69.2 %) and studying at private universities (59.1 %). The average grit score on a scale of 5 was 3.15 ± 0.54. The responses revealed higher favourable responses to items on the perseverance of efforts (34.9 % to 54 %) compared to items on the consistency of interests (26.5 % to 31.1 %). Students who did not exercise (AOR: 0.47, 95 %CI: 0.33-0.67) or exercised irregularly (AOR: 0.64, 95 %CI: 0.45-0.90) were less likely to have higher grit scores than those who exercised regularly. Additionally, students who did not receive COVID-19 vaccination (AOR: 0.50, 95 %CI: 0.36-0.71) or received only one dose (AOR: 0.67, 95 %CI: 0.46-0.99) were less likely to have higher grit scores than those who received their booster vaccination. Interestingly, students who chose the pharmacy program as their only available or reasonable choice (AOR: 0.33, 95 %CI: 0.17-0.62) and students from public universities (AOR: 0.82, 95 %CI: 0.68-0.98) were less likely to have higher grit scores. On the other hand, students who did not face educational challenges with online learning (AOR: 1.19, 95 %CI: 1.003-1.416) and students with excellent (AOR: 2.28, 95 %CI: 1.57-3.31) and very good (AOR: 2.16, 95 %CI: 1.53-3.04) academic performance were more likely to have higher grit scores. Conclusion: The findings revealed moderate grit levels. Higher grit levels were thought to be associated with several personal, lifestyle and academic factors. Further interventions to support students' grit attributes are required, particularly concerning the consistency of interests.

Glutathione and Reactive Oxygen Species Dual-Responsive Block Copolymer Prodrugs for Boosting Tumor Site-Specific Drug Release and Enhanced Antitumor Efficacy.

A remarkable hallmark of cancer cells is the heterogeneous coexistence of overproduced intracellular glutathione (GSH) and a high level of reactive oxygen species (ROS) compared with those in normal cells, which have been frequently used as the stimuli to trigger drug release from the nanocarriers. Most of the stimuli-responsive delivery vehicles have been designed to respond to only one redox stimulus (e.g., GSH or ROS). Herein, we develop a GSH and ROS dual-responsive amphiphilic diblock copolymer prodrug (BCP) (GR-BCP) consisting of poly(ethylene glycol) (PEG)- and camptothecin (CPT)-conjugated poly(methacrylate) in the side chains via thioether bonds. In comparison, GSH or ROS single-responsive BCPs (G-BCPs or R-BCPs) were prepared, where CPT drugs were linked by disulfide or thioketal bonds, respectively. The three BCPs can form well-defined spherical micellar nanoparticles in an aqueous solution with a diameter of ∼50 nm. Compared with G-BCP and R-BCP, GR-BCP realized the highest cytotoxicity against HeLa cells with the half-inhibitory concentration (IC50) of 6.3 µM, which is much lower than 17.8 µM for G-BCP and 28.9 µM for R-BCP. Moreover, for in vivo antitumor performance, G-BCP, R-BCP, and GR-BCP showed similar efficiencies in blood circulation and tumor accumulation after intravenous injection. However, GR-BCP realized the most efficient tumor suppression with few side effects. Our findings demonstrate that intracellular GSH and ROS dual-responsive BCPs show a more efficient responsive drug release inside tumor cells for boosting the antitumor efficacy as compared with GSH or ROS single-responsive BCPs, which provides novel strategies for designing redox-responsive BCPs.

Assessment of Academic Resilience and Its Associated Factors Among Pharmacy Students in Twelve Countries.

OBJECTIVE: Academic resilience, a critical determinant of academic achievement, is affected by various factors. There is a paucity of large-scale international assessments of academic resilience among pharmacy students. Therefore, this study aimed to assess academic resilience among pharmacy students in 12 countries and to evaluate factors associated with their academic resilience levels. METHODS: A cross-sectional online survey-based study was conducted among randomly selected pharmacy students in 12 countries: Egypt, Türkiye, Indonesia, Pakistan, Bangladesh, Iraq, Jordan, Nigeria, Malaysia, Saudi Arabia, Sudan, and the United Arab Emirates. After pilot testing, the validated 30-item academic resilience scale (ARS) was used for the assessment. The data were collected between November 1, 2022 and April 15, 2023. Descriptive and inferential statistics were performed, as appropriate. RESULTS: A total of 3950 were received from the 12 participating countries. The mean age was 21.68 ± 2.62 years. About two-thirds of the responses were from female participants and those studying for Bachelor of Pharmacy degrees. Overall, the findings show moderate academic resilience, which varied across countries. The median (IQR) of the total ARS-30 was 114 (103-124). Females exhibited lower negative affective and emotional response subscale levels than males. There were significant cross-country variations in the ARS-30 and all subscales. The highest overall levels were reported for Sudan, Pakistan, and Nigeria and the lowest were reported for Indonesia and Türkiye. Students in private universities tended to have higher overall ARS levels than public university students. Higher academic performance was significantly associated with ARS levels, whereas those with excellent performance exhibited the highest ARS levels. Students with exercise routines had higher ARS levels than those without exercise routines. Finally, students who were engaged in extracurricular activities had higher ARS levels than those who did not participate in these activities. CONCLUSION: The study offers insights into the factors affecting academic resilience in pharmacy students across several countries. The findings could guide interventions and support activities to improve resilience and academic outcomes.

Assessment of Knowledge, Perception, Experience and Phobia toward Corticosteroids Use among the General Public in the Era of COVID-19: A Multinational Study.

BACKGROUND: Corticosteroids play a significant role in managing the vast majority of inflammatory and immunologic conditions. To date, population-based studies on knowledge and attitudes concerning corticosteroids are scarce. This study aims to comprehensively assess knowledge, perception, experience and phobia toward corticosteroid use among the general population in the era of COVID-19. METHODS: A cross-sectional self-administrated questionnaire was used to collect the data from 6 countries. Knowledge and corticophobia scores, descriptive statistics and logistic regression were computed. RESULTS: A total of 2354 participants were enrolled in this study; the majority were females (61.6%) with an average age of 30. Around 61.9% had been infected previously with COVID-19, and about one-third of the participants had experience with corticosteroid use. The mean knowledge score was relatively satisfactory (8.7 ± 4.5 out of 14), and Corticophobia ranked a high score in all countries. Age, female gender, and history of COVID-19 were positively correlated with developing corticophobia. CONCLUSION: Our study highlights that the general knowledge about steroids was satisfactory. However, the phobia toward its use upon indication is high. Therefore, enhancing awareness and providing essential counseling regarding the rational use of corticosteroids may reduce corticophobia.

Determinants of parental seasonal influenza vaccine hesitancy in the Eastern Mediterranean region: A cross-sectional study.

Background: Seasonal influenza vaccine can reduce the risk of influenza-associated hospitalizations and deaths among children. Given that parents are the primary decision makers, this study examined the parental attitude toward childhood influenza vaccine and identified determinants of vaccine hesitancy (VH) in the Eastern Mediterranean region (EMR). Methods: A cross-sectional study was conducted using an anonymous online survey in 14 EMR countries. Parents of children aged 6 months to 18 years were included. The Parent Attitude about Childhood Vaccines (PACV) was used to assess VH. Chi square test and independent t-test were used to test for association of qualitative and quantitative variables, respectively. A structural equations model (SEM) was used to identify direct and indirect determinants of parental VH. Results: Almost half of the parents were hesitant about vaccinating their children against influenza (50.8%). Parental VH was significantly higher among older mothers (37.06 ± 8.8 years, p = 0.006), rural residents (53.6%, p < 0.001), high-income countries residents (50.6%, p < 0.001), and mothers with higher educational levels (52.1%, p < 0.001). Parents of school-aged children (5-9 years) (55.6%, p < 0.001), children free from any comorbidities (52.5%, p < 0.001), children who did not receive routine vaccination at all (51.5%, p = 0.03), children who were not vaccinated against COVID-19 (54.3%, p < 0.001), in addition to parents who were not vaccinated against influenza (57.1%, p < 0.001) were significantly associated with increased likelihood of VH. Parents who were depending on healthcare provider as a source of information regarding vaccines were less likely to report VH (47.9%, p < 0.001), meanwhile those who used social media as their source of health information showed a significantly higher VH (57.2%, p < 0.001). The SEM suggested that mother's age, residence, country income level, child gender, total number of children and source of information regarding vaccines had a direct effect on VH. Meanwhile, parents vaccinated against influenza, children completely or partially vaccinated with routine vaccines and children vaccinated against Coronavirus disease 2019 (COVID-19) had an indirect effect on VH. Conclusion: A high proportion of included parents were hesitant to vaccinate their children against seasonal influenza. This attitude is due to many modifiable and non-modifiable factors that can be targeted to improve vaccination coverage.

Workplace violence against healthcare workers during the COVID-19 pandemic in Sudan: A cross-sectional study.

Background: Workplace violence (WPV) against healthcare workers (HCWs) is a growing global issue. During the coronavirus diseases-2019 (COVID-19) pandemic, violent attacks on HCWs have been documented worldwide. This study aimed to investigate the magnitude and pattern of WPV among HCWs in Sudan during the COVID-19 pandemic. Methods: A web-based cross-sectional study of WPV was conducted among registered medical and health workers (pharmacists, physicians, dentists, nurses, laboratory technicians, and administrative and paramedical staff) during the COVID-19 pandemic in Sudan. Data were collected from August to December 2021 using a self-administered questionnaire distributed through social media platforms. Results: A total of 792 HCWs returned the online questionnaire. The mean age was 33.5 ± 8.6 years, where more than half were females (54.9%) and working during the day shift (58.8%). During the COVID-19 pandemic, three out of every four participants (78.3%) reported experiencing violence, with 65.8 % experiencing it more than three times. The common types of violence experienced were verbal (91.6%), physical (50.0%), and sexual abuse (11.0%). The emergency department reported the highest number of violent incidents (46.9%). Half of these violent events were not reported (50.3%), primarily due to a lack of a reporting system. The demographic factors that were significantly associated with exposure to violence were participants' occupation (p < 0.001), age (p = 0.001), marital status (p = 0.002), and years of working experience (p = 0.020). Conclusion: WPV was rampant among the HCWs in Sudan during the COVID-19 pandemic. The current findings are presented to draw the attention of policy leaders and stakeholders in Sudan to this alarming problem prompting the pressing need for policy and system interventions.

COVID-19 Vaccine Booster Dose Acceptance: Systematic Review and Meta-Analysis.

The World Health Organization (WHO) recommended coronavirus disease 2019 (COVID-19) booster dose vaccination after completing the primary vaccination series for individuals ≥18 years and most-at-risk populations. This study aimed to estimate the pooled proportion of COVID-19 vaccine booster dose uptake and intention to get the booster dose among general populations and healthcare workers (HCWs). We searched PsycINFO, Scopus, EBSCO, MEDLINE Central/PubMed, ProQuest, SciELO, SAGE, Web of Science, Google Scholar, and ScienceDirect according to PRISMA guidelines. From a total of 1079 screened records, 50 studies were extracted. Meta-analysis was conducted using 48 high-quality studies according to the Newcastle-Ottawa Scale quality assessment tool. Using the 48 included studies, the pooled proportion of COVID-19 vaccine booster dose acceptance among 198,831 subjects was 81% (95% confidence interval (CI): 75-85%, I2 = 100%). The actual uptake of the booster dose in eight studies involving 12,995 subjects was 31% (95% CI: 19-46%, I2 = 100%), while the intention to have the booster dose of the vaccine was 79% (95% CI: 72-85%, I2 = 100%). The acceptance of the booster dose of COVID-19 vaccines among HCWs was 66% (95% CI: 58-74%), I2 = 99%). Meta-regression revealed that previous COVID-19 infection was associated with a lower intention to have the booster dose. Conversely, previous COVID-19 infection was associated with a significantly higher level of booster dose actual uptake. The pooled booster dose acceptance in the WHO region of the Americas, which did not include any actual vaccination, was 77% (95% CI: 66-85%, I2 = 100%). The pooled acceptance of the booster dose in the Western Pacific was 89% (95% CI: 84-92%, I2 = 100), followed by the European region: 86% (95% CI: 81-90%, I2 = 99%), the Eastern Mediterranean region: 59% (95% CI: 46-71%, I2 = 99%), and the Southeast Asian region: 52% (95% CI: 43-61%, I2 = 95). Having chronic disease and trust in the vaccine effectiveness were the significant predictors of booster dose COVID-19 vaccine acceptance. The global acceptance rate of COVID-19 booster vaccine is high, but the rates vary by region. To achieve herd immunity for the disease, a high level of vaccination acceptance is required. Intensive vaccination campaigns and programs are still needed around the world to raise public awareness regarding the importance of accepting COVID-19 vaccines needed for proper control of the pandemic.

Acceptance of COVID-19 Vaccine Booster Doses Using the Health Belief Model: A Cross-Sectional Study in Low-Middle- and High-Income Countries of the East Mediterranean Region.

Coronavirus disease (COVID-19) booster doses decrease infection transmission and disease severity. This study aimed to assess the acceptance of COVID-19 vaccine booster doses in low, middle, and high-income countries of the East Mediterranean Region (EMR) and its determinants using the health belief model (HBM). In addition, we aimed to identify the causes of booster dose rejection and the main source of information about vaccination. Using the snowball and convince sampling technique, a bilingual, self-administered, anonymous questionnaire was used to collect the data from 14 EMR countries through different social media platforms. Logistic regression analysis was used to estimate the key determinants that predict vaccination acceptance among respondents. Overall, 2327 participants responded to the questionnaire. In total, 1468 received compulsory doses of vaccination. Of them, 739 (50.3%) received booster doses and 387 (26.4%) were willing to get the COVID-19 vaccine booster doses. Vaccine booster dose acceptance rates in low, middle, and high-income countries were 73.4%, 67.9%, and 83.0%, respectively (p < 0.001). Participants who reported reliance on information about the COVID-19 vaccination from the Ministry of Health websites were more willing to accept booster doses (79.3% vs. 66.6%, p < 0.001). The leading causes behind booster dose rejection were the beliefs that booster doses have no benefit (48.35%) and have severe side effects (25.6%). Determinants of booster dose acceptance were age (odds ratio (OR) = 1.02, 95% confidence interval (CI): 1.01-1.03, p = 0.002), information provided by the Ministry of Health (OR = 3.40, 95% CI: 1.79-6.49, p = 0.015), perceived susceptibility to COVID-19 infection (OR = 1.88, 95% CI: 1.21-2.93, p = 0.005), perceived severity of COVID-19 (OR = 2.08, 95% CI: 137-3.16, p = 0.001), and perceived risk of side effects (OR = 0.25, 95% CI: 0.19-0.34, p < 0.001). Booster dose acceptance in EMR is relatively high. Interventions based on HBM may provide useful directions for policymakers to enhance the population's acceptance of booster vaccination.

Assessment of mental wellbeing of undergraduate pharmacy students from 14 countries: The role of gender, lifestyle, health-related, and academic-related factors.

Background: Pharmacy students will assume future roles as frontline healthcare providers. Therefore, evaluating their current state of mental wellbeing and its associated factors is essential for better planning students' support initiatives. This study aimed to assess mental wellbeing and its associated factors among undergraduate pharmacy students from 14 countries during the pandemic. Methods: A cross-sectional study was conducted among undergraduate pharmacy students in 14 countries in Asia and the Middle East. The validated Warwick-Edinburgh Mental Wellbeing Scale (the 14-item WEMWBS) was adopted to assess mental wellbeing. Data collection was performed online between February and April 2022. Descriptive and inferential statistics were used as appropriate. Results: A total of 2,665 responses were received, mainly from females (68.7%) with a higher presence of private universities (59.1%). About 34.9% had low mental wellbeing levels, while 57 and 8.1% had medium, and high levels, respectively. Binary logistic regression showed that males (AOR: 1.34; CI 95%: 1.11-1.61; p < 0.01) and students with no chronic illnesses (AOR: 2.01; CI 95%: 1.45-2.80; p < 0.001) were more likely to have higher mental wellbeing. Also, participants who did not engage in any exercise (AOR: 0.71; CI 95%: 0.52-0.98; p = 0.04) and those in public universities (AOR: 0.82; CI 95%: 0.69-0.97; p = 0.02) were less likely to have higher mental wellbeing. Additionally, students who had interest/passion for pharmacy (AOR: 1.69; CI 95%: 1.07-2.68; p = 0.02), and those who known pharmacists inspired (AOR: 1.81; CI 95%: 1.06-3.12; p = 0.03), were more likely to have higher mental wellbeing compared with those who had no specific reason for their choice to study pharmacy. The participants with excellent (AOR: 1.87; CI 95%: 1.29-2.70; p = 0.001) or very good self-reported academic performance (AOR: 1.57; CI 95%: 1.12-2.22; p = 0.01) were more likely to have higher mental wellbeing compared to those with fair academic performance. Conclusion: More than a third of the participants had low mental wellbeing. Various demographic, lifestyle, medical and academic factors appeared to affect students' mental wellbeing. Careful consideration of these factors and their integration into the pharmacy schools' plans for student support services and academic advising would be essential to improve students' mental wellbeing.

Hypoxia-responsive block copolymer polyprodrugs for complementary photodynamic-chemotherapy.

The inherent hypoxic microenvironment of solid tumors has an important influence on tumor growth, distant metastasis, and invasiveness. The heterogeneous distribution of hypoxic regions inside tumors limits the therapeutic efficacy of O2-assisted therapeutic strategy (e.g. photodynamic therapy (PDT)). On the other hand, the hypoxia-activable prodrugs cannot work effectively in the regions with enough O2 concentration. To address the issues, we prepare a block copolymer polyprodrug consisting of polyethylene glycol (PEG) and copolymerized segments of nitroimidazole-linked camptothecin (CPT) methacrylate and 5,10,15,20-tetraphenylporphyrin (TPP)-containing methacrylate monomers for complementary photodynamic-chemotherapy. The polyprodrug can self-assemble into polymeric micelles in aqueous solution with suitable size and high stability. After intravenous injection, the polyprodrug micelles show tumor accumulation. Followed by light irradiation (650 nm) at tumor sites, TPP moieties induce singlet oxygen (1O2) production in the oxygen-rich area to exert PDT and cause transformation of the oxygen-rich areas into hypoxia. Simultaneously, in the hypoxic areas, the hypoxia-responsive polyprodrugs can be activated to release free CPT due to the cleavage of nitroimidazole linkages. The polyprodrug micelles with the segments for PDT and hypoxia-activable CPT efficiently suppress the growth of HeLa tumors. The well-defined polyprodrug amphiphiles offer an effective strategy to overcome the disadvantages of single treatment of PDT or hypoxia-responsive prodrugs for complementary photodynamic-chemotherapy of cancers.

Cisplatin resistance reversal in lung cancer by tumor acidity-activable vesicular nanoreactors via tumor oxidative stress amplification.

Drug resistance of cisplatin significantly limits its therapeutic efficacy in clinical applications against different cancers. Herein, we develop a novel strategy to overcome cisplatin drug resistance through sensitizing cisplatin-resistant human lung cancer cells (A549R) under amplified oxidative stress using a vesicular nanoreactor for simultaneous cisplatin delivery and H2O2 generation. We engineer the nanoreactor by the self-assembly of the amphiphilic diblock copolymers to co-deliver glucose oxidase (GOD) and cisplatin (Cis) (Cis/GOD@Bz-V). Cis/GOD@Bz-V was rationally designed to stay impermeable during blood circulation while mild acidity (pH 6.5-6.8) can activate its molecular-weight selective membrane permeability and release cisplatin locally. Diffusion of small molecules such as oxygen and glucose across the membranes can induce the in situ generation of superfluous H2O2 to promote cellular oxidative stress and sensitize A549R cells via activation of pro-apoptotic pathways. Cis/GOD@Bz-V nanoreactors could effectively kill A549R at pH 6.8 in the presence of glucose by the combination of H2O2 generation and cisplatin release. Growth of A549R xenograft tumors can be inhibited efficiently without the obvious toxic side effects via the systemic administration of Cis/GOD@Bz-V. Accordingly, the tumor acidity-activable cisplatin-loaded nanoreactors show great potential to enhance the therapeutic efficacy against cisplatin-resistant cancers.

Tumor-dilated polymersome nanofactories for enhanced enzyme prodrug chemo-immunotherapy.

Combination chemo-immunotherapy of cancers has attracted great attention due to its significant synergistic antitumor effect. The response rates and therapeutic efficacy of immunotherapy can be enhanced significantly after proper combination with chemotherapy. However, chemo-immunotherapy is frequently limited by severe immune-related adverse events and systemic side toxicity. In this report, efficient nanofactory-directed enzyme prodrug chemo-immunotherapy is demonstrated based on enzyme-loaded tumor-dilatable polymersomes with optimized membrane cross-linking density. Upon intravenous injection of the nanofactories, they can passively accumulate at the tumor site. The tumor pH-responsive nanofactories can swell from ~100 nm to ~200 nm under the trigger of tumor acidity, leading to prolonged retention of up to one week inside tumor tissues. Simultaneously, the membrane permeability of the nanofactories has improved significantly, which allows hydrophilic small molecules to pass across the membranes while keeping the enzymes in the inner cavities. Subsequently, the non-toxic prodrug mixtures of chemo-immunotherapy are administrated three times within 6 days, which are in situ activated by the nanofactories selectively at tumor sites. Activated chemotherapeutic drugs kill cancer cells and generate tumor-associated antigens to promote the maturation of dendritic cells. Activated indoleamine 2, 3-dioxygenase 1 inhibitors reverse the immunosuppressive tumor microenvironment. Finally, primary tumors can be effectively suppressed while causing minimal systemic toxicity. The distant tumors that are established after treatment can also be inhibited completely via activation of antitumor immunity in mice. Thus, the tumor-dilatable polymersome nanofactories with long-term intratumoral retention offer a promising paradigm for enhanced enzyme prodrug chemo-immunotherapy.

Therapeutic Polymersome Nanoreactors with Tumor-Specific Activable Cascade Reactions for Cooperative Cancer Therapy.

Therapeutic nanoreactors are of increasing interest in precise cancer therapy, which have been explored to in situ produce therapeutic compounds from inert prodrugs or intrinsic molecules at the target sites. However, engineering a nanoreactor with tumor activable cascade reactions for efficient cooperative cancer therapy remains a great challenge. Herein, we demonstrate a polymersome nanoreactor with tumor acidity-responsive membrane permeability to activate cascade reactions for orchestrated cooperative cancer treatment. The nanoreactors are constructed from responsive polyprodrug polymersomes incorporating ultrasmall iron oxide nanoparticles and glucose oxidase in the membranes and inner aqueous cavities, respectively. The cascade reactions including glucose consumption to generate H2O2, accelerated iron ion release, Fenton reaction between H2O2 and iron ion to produce hydroxyl radicals (•OH), and •OH-triggered rapid release of parent drugs can be specifically activated by the tumor acidity-responsive membrane permeability. During this process, the orchestrated cooperative cancer therapy including starving therapy, chemodynamic therapy, and chemotherapy is realized for high-efficiency tumor suppression by the in situ consumed and produced compounds. The nanoreactor design with tumor-activable cascade reactions represents an insightful paradigm for precise cooperative cancer therapy.

Reduction-Responsive Polymer Prodrug Micelles with Enhanced Endosomal Escape Capability for Efficient Intracellular Translocation and Drug Release.

High-efficiency endosomal escape of drug delivery nanocarriers for glutathione-based reduction-responsive drug release in cytoplasm can significantly enhance the therapeutic efficacy of the loaded therapeutic drugs. In this report, we develop the polymer prodrug micelles self-assembled from the amphiphilic block copolymer prodrug, PEG-b-P(CPTM-co-ImOAMA), consisting of poly(ethylene glycol) (PEG) and copolymerized segments of disulfide bond-linked camptothecin methacrylate monomer (CPTM) and 1-(1H-imidazole-4-yl)-2-(octylamino)-2-oxoethyl methacrylate (ImOAMA). After cellular internalization through endocytosis, PEG-b-P(CPTM-co-ImOAMA) micelles are trapped in endosomes inside the tumor cells. The endosomal pH can trigger the protonation of the imidazole moieties of PImOAMA segments, which may facilitate endosome escape through the proton sponge effect and the improved interactions between protonated imidazole groups, hydrophobic octyl moieties, and endosomal membranes. Moreover, the high concentration of glutathione in the cytoplasm of cancer cells can trigger the release of active camptothecin (CPT) through cleavage of the disulfide linkers from PCPTM. The in vitro results showed that PEG-b-P(CPTM-co-ImOAMA) micelles could be effectively internalized into cells followed by endosomal escape, which contributed to the significantly improved cancer cell-killing efficacy. Moreover, in vivo studies confirmed that the PEG-b-P(CPTM-co-ImOAMA) micelles realized efficient tumor growth inhibition without obvious side toxicity. Therefore, the proposed reduction-responsive polymeric prodrug micelles with high endosomal escape capability could provide a brilliant potential in a drug delivery platform to achieve enhanced antitumor efficacy.

ROS-Responsive Polymeric Nanocarriers with Photoinduced Exposure of Cell-Penetrating Moieties for Specific Intracellular Drug Delivery.

In situ modulation of the surface properties on the micellar drug delivery nanocarriers offers an efficient method to improve the drug delivery efficiency into cells while maintaining stealth and stability during blood circulation. Light has been demonstrated to be a temporally and spatially controllable tool to improve cellular internalization of nanoparticles. Herein, we develop reactive oxygen species (ROS)-responsive mixed polymeric micelles with photoinduced exposure of cell-penetrating moieties via photodynamic ROS production, which can facilitate cellular internalization of paclitaxel (PTX) and chlorin e6 (Ce6)-coloaded micelles for the synergistic effect of photodynamic and chemotherapy. The thioketal-bond-linked block polymers poly(ε-caprolactone)-TL-poly(N,N-dimethylacrylamide) (PCL-TL-PDMA) with a long PDMA block are used to self-assemble into mixed micelles with PCL-b-poly(2-guanidinoethyl methacrylate) (PCL-PGEMA) consisting of a short PGEMA block, which are further used to coencapsulate PTX and Ce6. After intravenous injection, prolonged blood circulation of the micelles guarantees high tumor accumulation. Upon irradiation by 660 nm light, ROS production of the micelles by Ce6 induces cleavage of PDMA to expose PGEMA shells for significantly improved cellular internalization. The combination of photodynamic therapy and chemotherapy inside the tumor cells achieves improved antitumor efficacy. The design of ROS-responsive mixed polymeric nanocarriers represents a novel and efficient approach to realize both long blood circulation and high-efficiency cellular internalization for combined photodynamic and chemotherapy under light irradiation.