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Co-delivery of doxorubicin and quercetin by Janus Hollow Silica Nanomotors for overcoming multidrug resistance in breast MCF-7/Adr cells
Abstract
Multidrug resistance (MDR) greatly hinders the efficacy of chemotherapy in a variety of hematological malignancies and solid tumors. Traditionally, Quercetin (Que) based co-delivery drugs strategies show lower water solubility and lack of motion ability for drugs active transfer. In order to overcome this disadvantage, we have developed a Janus nanomotors [email protected](DQ) for targeted combination therapy. The combined strategy could increase the intracellular accumulation of the two drugs (quercetin and doxorubicin) through the high-speed motion of the motor and higher killing rate of Dox on MCF-7/Adr cells by using quercetin. By reversing Dox resistance, [email protected](DQ), could achieve lower RI values (8.1) and higher RF values (6.8) in MCF-7/Adr cells compared to free Dox, which means [email protected] (DQ) is effective against multidrug resistance. This work exhibits a novel nanoplatform, which could not only load chemotherapy drugs efficiently, but could also improve the effect of chemotherapy drugs by overcoming MDR.
... the ZP analysis indicates the presence of negative charges (-) on the surface of Que-Mls NPs, which have the potential to restrict nonspecific interactions with serum proteins. this can contribute to a reduction in systemic toxicity and an improvement in stability [76]. this demonstrates how improved composition affects potential systemic circulation time, cell absorption, and clearance ratio. in Mht study, it was determined that MNPs become magnetized when exposed to a MF in Mht, converting MF energy into heat [20]. in Mls, the thermal energy released as a result of NPs placed in an MF causes the disintegration of the liposomal carrier. ...
... Que cytotoxicity results concluded that the highest cellular viability was observed at a concentration of 5 µg/ml of Que on cancer cells [56]. Zhou et al. [76] found that the decreased ic 50 of the (Dox + Que) group was associated with increased cytotoxicity in McF-7 cells, indicating that the drug carrier can effectively DD to cells and demonstrate high cytotoxicity. DR assays conducted at physiological temperature support this conclusion, showing that even a minor quantity of Que was sufficient to facilitate a cytotoxic effect. ...
... To evaluate the targeting ability, a liposomal drug delivery system was designed for the coadministration of doxorubicin (DOX) and quercetin, which enhanced drug accumulation and demonstrated enhanced cytotoxicity in MCF-7/ADR cells by downregulating P-glycoprotein (P-gp) without affecting adenosine triphosphate (ATP) production. In addition, in vivo antitumor studies showed that the liposomal drug delivery system (DOX/quercetin) inhibited MCF-7/ADR solid tumors and reduced P-gp overexpression without noticeable histological changes in the heart [121]. Shaji et al. used multilamellar vesicles (MLVs) with phosphatidylcholine and cholesterol in a 9:1 ratio to encapsulate quercetin, showing hepatoprotective activity in rats [122]. ...
Quercetin is a flavonoid with a low molecular weight that belongs to the human diet’s phenolic phytochemicals and nonenergy constituents. Quercetin has a potent antioxidant capacity, being able to capture reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive chlorine species (ROC), which act as reducing agents by chelating transition-metal ions. Its structure has five functional hydroxyl groups, which work as electron donors and are responsible for capturing free radicals. In addition to its antioxidant capacity, different pharmacological properties of quercetin have been described, such as carcinostatic properties; antiviral, antihypertensive, and anti-inflammatory properties; the ability to protect low-density lipoprotein (LDL) oxidation, and the ability to inhibit angiogenesis; these are developed in this review.
... To evaluate the targeting ability, a liposomal drug delivery system was designed for co-administration of Doxorubicin (DOX) and Quercetin, which enhanced drug accumulation and demonstrated enhanced cytotoxi-city in MCF-7/ADR cells by down-regulating P-glycoprotein (P-gp) 19 without affecting Adenosine Triphosphate (ATP) produc-tion. In addition, in vivo antitumor studies showed that the liposomal drug delivery system (DOX/quercetin) inhibited MCF-7/ADR solid tumors and reduced P-gp overexpression without noticeable histological changes in the heart [121]. Shaji et al. used Multilamellar Vesicles (MLV) with phosphatidylcholine and cholesterol in a 9:1 ratio to encapsulate Quercetin, showing hepatoprotective activity in rats [122]. ...
Quercetin is a flavonoid with a low molecular weight that belongs to the human diet's phenolic phytochemicals and non-energy constituents. Quercetin has a potent antioxidant capacity, being able to capture Reactive Oxygen Species (ROS), reactive nitro-gen species (RNS), and Reactive Chlorine Species (ROC), which act as reducing agents by chelating transition metal ions. Its structure has five functional hydroxyl groups, which work as electron donors and are responsible for capturing free radicals. In addition to its antioxidant capacity, it was described different pharmacological properties of Quercetin, such as carcinostatic properties, antiviral, antihypertensive, anti-inflammatory, protection of Low-Density Lipoprotein (LDL) oxidation, and inhibi-tion of angiogenesis are developed in this review.
... The negative charge of the formula was due to the hydroxy group, indicating the successful encapsulation of Q by cross-linked MgFe 2 O 4 @Liopsomes (MLs) NPs [84]. The occurrence of negative charges on the Q-MLs NPs surface may minimizing inappropriate binding to serum proteins, so reducing systemic toxicity and increasing stability [85]. Furthermore, according to the results, when Q-MLs, the ZP of surface properties decreased with a negative charge (− 16.8 mV), indicating that more formulation affects the cell absorption, clearing percentage, and potentially long bloodstream duration. ...
... Fig. 5b indicated that, the incorporation of QC affects the physicochemical properties of MLs, which leads to an increase in the negative charge. The existence of negative charges on the surface of QC-MLs NPs may limit nonspecific interactions with serum proteins, so reducing systemic toxicity and increasing stability [53]. Moreover, more formulation influences clearance rate, cell uptake, and promising systemic circulation time. ...
With nanotechnology development, breast cancer has attracted tremendous research interest in treatment development as one of the significant threats to public health. Magnetoliposomes (MLs) offer multiple applications for use in cancer therapy, such as drug delivery (DD) mediated by alternating magnetic fields (AMF). The present study aims to synthesize nickel ferrite (NiFe 2 O 4) magnetic nanoparticles (MNPs) encapsulated within nano-liposomes (NiFe 2 O 4 @Liposome) to form MLs. Herein, Quercetin (QC)-loaded MLs (QC-MLs) nano-composites were applied as hyperthermia (HT), DD system, and chemo-hyperthermia in the presence of AMF. It is the first time to fabricate QC-loading NiFe 2 O 4 @Liposome for biomedical applications. The drug loading (DL) and entrapment efficiency (EE) of free QC, MLs, and QC-MLs were evaluated, QC was efficiently encapsulated into MLs, and the EE and DL were up to 83.5 ± 1.4 % and 7.3 ± 0.1 %, respectively. Furthermore, we applied MHT on QC-MLs and MLs with a specific absorption rate (SAR) of 200 and 205 W/g, respectively, at the same concentration (6 mg/mL). The in-vitro QC release from MLs functionalized magnetite QC-loaded MLs was studied at 62.3 % at pH 5.1 and 44 % at pH 7.4, proving the encapsulated QC pH after 24 h. The MCF-7 cell line was used as an in-vitro model. Cytotoxic studies of novel synthesized QC-MLs, free QC, and MLs were evaluated by MTT assay on the MCF-7 cancer cell.
Janus structure hydrogels (JSHs) are novel materials. Their primary fabrication methods and various applications have been widely reported. JSHs are primarily composed of Janus particles (JNPs) and polysaccharide components. They exhibit two distinct physical or chemical properties, generating intriguing characteristics due to their asymmetric structure. Normally, one side (adhesive interface) is predominantly constituted of polysaccharide components, primarily serving excellent adhesion. On the other side (functional surface), they integrate diverse functionalities, concurrently performing a plethora of synergistic functions. In the biomedical field, JSHs are widely applied in anti-adhesion, drug delivery, wound healing, and other areas. It also exhibits functions in seawater desalination and motion sensing. Thus, JSHs hold broad prospects for applications, and they possess significant research value in nanotechnology, environmental science, healthcare, and other fields. Additionally, this article proposes the challenges and future work facing these fields.
Combination therapy is an emerging strategy to overcome multidrug resistance (MDR) in hepatocellular carcinoma (HCC) chemotherapy treatment. However, the passive diffusion in traditional delivery systems greatly retards the approach and penetration of drugs into hepatocellular carcinoma cells and thus hinders the efficacy of combination therapy. Micro/nanomotors with autonomous locomotion in a tiny scale provide the possibility of tackling this issue. Herein, an active drug delivery micromotor platform delicately designed to load drugs with different physicochemical properties and enhance the drug permeability of cells is demonstrated for HCC chemotherapy treatment. The biocompatible micromotor platform Mg/PLGA/CHI comprised magnesium (Mg) coated with two polymer layers made of poly(lactic-co-glycolic acid) (PLGA) and chitosan (CHI), where the hydrophobic and hydrophilic drugs doxorubicin (Dox) and Curcumin (Cur) were loaded, respectively. The autonomous motion of the micromotors with velocity up to 45 μm s-1 greatly enhanced the diffusion of chemotherapeutic drugs and led to higher extracellular and intracellular drug distribution. Moreover, hydrogen produced during the motion eliminated the excess reactive oxygen species (ROS) in the human hepatocellular carcinoma (HepG2) cells. Compared with inert groups, the absorption of Dox and Cur from the active micromotors was about 2.9 and 1.5 times higher in human hepatocellular carcinoma (HepG2) cells. In addition, the anti-tumor activity also obviously improved at the micromotor concentration of 1 mg mL-1 (cell proliferation was reduced by almost 30%). Overall, this work proposes an approach based on loading different chemotherapy agents on an active delivery system to enhance drug permeability and overcome MDR and provides a potentially effective therapeutic strategy for the treatment of HCC.
Nano/mikromotorlar, enerjiyi harekete dönüştürme kabiliyetine sahip nano veya mikro boyutta makinalardır. Bunlar; kimyasal yakıt ve harici etkenler neticesinde enerjiyi harekete dönüştürme prensibi ile çalışırlar. Bu harici etkenler; manyetik alan, elektrik alan, ultrason ve ışık gibi etkenler olabilir. Farklı tahrik mekanizmalarına sahip nano/mikromotorlar kanser ve bulaşıcı hastalıkların teşhis ve tedavisinde önemli rol oynarlar. Özellikle kanser tedavilerinde en çok tercih edilen yöntem olan kemoterapi ve radyoterapi gibi yöntemlerin insan sağlığı üzerindeki olumsuz etkileri, araştırmacıları nano/mikromotor çalışmalarına yönlendirmiştir. Nano/mikromotorlar; kanserleşmiş hücrenin erken teşhisini mümkün kılması ve geleneksel kanser tedavilerindeki yan etkilerin en aza indirilmesi gibi avantajlara sahiptir. Bu derlemede nano/miktomotorların sınıflandırılması ve sentez yöntemleri ele alınmakla birlikte, nano/mikromotorların kanser teşhis ve tedavisinde kullanımı açıklanmıştır.
This article is the American Cancer Society’s update on female breast cancer statistics in the United States, including population‐based data on incidence, mortality, survival, and mammography screening. Breast cancer incidence rates have risen in most of the past four decades; during the most recent data years (2010–2019), the rate increased by 0.5% annually, largely driven by localized‐stage and hormone receptor‐positive disease. In contrast, breast cancer mortality rates have declined steadily since their peak in 1989, albeit at a slower pace in recent years (1.3% annually from 2011 to 2020) than in the previous decade (1.9% annually from 2002 to 2011). In total, the death rate dropped by 43% during 1989–2020, translating to 460,000 fewer breast cancer deaths during that time. The death rate declined similarly for women of all racial/ethnic groups except American Indians/Alaska Natives, among whom the rates were stable. However, despite a lower incidence rate in Black versus White women (127.8 vs. 133.7 per 100,000), the racial disparity in breast cancer mortality remained unwavering, with the death rate 40% higher in Black women overall (27.6 vs. 19.7 deaths per 100,000 in 2016–2020) and two‐fold higher among adult women younger than 50 years (12.1 vs. 6.5 deaths per 100,000). Black women have the lowest 5‐year relative survival of any racial/ethnic group for every molecular subtype and stage of disease (except stage I), with the largest Black–White gaps in absolute terms for hormone receptor‐positive/human epidermal growth factor receptor 2‐negative disease (88% vs. 96%), hormone receptor‐negative/human epidermal growth factor receptor 2‐positive disease (78% vs. 86%), and stage III disease (64% vs. 77%). Progress against breast cancer mortality could be accelerated by mitigating racial disparities through increased access to high‐quality screening and treatment via nationwide Medicaid expansion and partnerships between community stakeholders, advocacy organizations, and health systems.
Over the past few years, the cancer-related disease has had a high mortality rate and incidence worldwide, despite clinical advances in cancer treatment. The drugs used for cancer therapy, have high side effects in addition to the high cost. Subsequently, to reduce these side effects, many studies have suggested the use of natural bioactive compounds. Among these, which have recently attracted the attention of many researchers, quercetin has such properties. Quercetin, a plant flavonoid found in fresh fruits, vegetables and citrus fruits, has anti-cancer properties by inhibiting tumor proliferation, invasion, and tumor metastasis. Several studies have demonstrated the anti-cancer mechanism of quercetin, and these mechanisms are controlled through several signalling pathways within the cancer cell. Pathways involved in this process include apoptotic, p53, NF-κB, MAPK, JAK/STAT, PI3K/AKT, and Wnt/β-catenin pathways. In addition to regulating these pathways, quercetin controls the activity of oncogenic and tumor suppressor ncRNAs. Therefore, in this comprehensive review, we summarized the regulation of these signalling pathways by quercetin. The modulatory role of quercetin in the expression of various miRNAs has also been discussed. Understanding the basic anti-cancer mechanisms of these herbal compounds can help prevent and manage many types of cancer.
Quercetin is a polyphenolic bioactive compound highly enriched in dietary fruits, vegetables, nuts, and berries. Quercetin and its derivatives like rutin and hyperoside are known for their beneficial effects in various neurological conditions including epilepsy. The clinical studies of quercetin and its derivatives in relation to epilepsy are limited. This review provides the evidence of most recent knowledge of anticonvulsant properties of quercetin and its derivatives on preclinical studies. Additionally, the studies demonstrating antiseizure potential of various plants extracts enriched with quercetin and its derivatives has been included in this review. Herein, we have also discussed neuroprotective effect of these bioactive compound and presented underlying mechanisms responsible for anticonvulsant properties in brief. Finally, limitations of quercetin and its derivatives as antiseizure compounds as well as possible strategies to enhance efficacy have also been discussed.
Multi-drug resistance (MDR) has become the largest obstacle to the success of cancer patients receiving traditional chemotherapeutics or novel targeted drugs. Here, we developed a targeted nanoplatform based on biodegradable boronic acid modified ε-polylysine to co-deliver P-gp siRNA, Bcl-2 siRNA, and doxorubicin for overcoming the challenge. The targeted nanoplatform showed a robust suppressing efficiency for the invasion, proliferation, and colony formation of adriamycin (ADR) resistant breast cancer cell line (MCF-7/ADR) cells in vitro. The ATP responsiveness of the nanoplatform was also proved in the research. In the in vivo antitumor experiment, the targeted nanoplatform showed a significant inhibition of tumor growth with good biocompatibility. The goal of this study is to develop a novel and facile strategy to prepare a highly efficient and safe gene and drug delivery system for MDR breast cancer based on biocompatible ε-polylysine polymers.
Polyphenols are the known group of phytochemicals that essentially consists of phenolic rings. These are the plant product present in varied fruits and vegetables. These secondary metabolites perform a protective function in plants from environmental and biological stress. When consumed as a human diet these are also known to prevent various age-associated diseases. Polyphenols are known to possess antioxidant properties and protect against oxidative stress. The literature survey was carried out using databases such as PubMed, Science direct and Springer. The research articles from last 10–12 years were selected for this review based on its relevancy with the topic. The articles selected was mainly focused on quercetin and its health benefits. The present review highlights the main functions of a flavonoid, quercetin. Quercetin is among the widely occurring polyphenol, found abundantly in nature. It is commonly present in different plant products. Onion is known to have the highest quantity of quercetin. This plant compound is possessed antioxidant properties and is considered to have a protective function against aging. It is known to be present in both free and conjugated forms. Quercetin has anti-oxidative, anti-inflammatory, anti-proliferative, anti-carcinogenic, anti-diabetic, and anti-viral properties. The molecule is lipophilic and can easily cross the BBB (Blood-Brain Barrier) and hence protects from neurodegenerative diseases. Various in vivo and in vitro studies have demonstrated the role of quercetin and here a detailed review of quercetin as a curative agent in neurodegeneration, diabetes, cancer, and inflammation has been carried out. Studies have proved that quercetin plays a crucial role in the prevention of age-related disorders. Quercetin is a potent antioxidant which is currently being used in various pharmaceuticals. Properties of quercetin can be further explored in various other disorders. Nanoformulations and liposomal formulations of quercetin can be made to treat other age associated diseases.
Rationale: Multidrug resistance (MDR) and metastasis of breast cancer remain major hurdles in clinical anticancer therapy. The unsatisfactory outcome is largely due to insufficient cytotoxicity of chemotherapeutic agents and limited immunogenic cell death (ICD). On the other hand, efflux proteins, especially P-glycoprotein (P-gp), can recognize and promote the efflux of drugs from tumor cells.
Methods: In this study, silver nanoparticles (Ag NPs) and peptide- functionalized doxorubicin (PDOX) were used to prepare a theranostic nanocomposite (Ag-TF@PDOX), which induced organelle-mediated immunochemotherapy and drug efflux protein inhibition in drug-resistant breast cancer cells (MCF-7/ADR) via a strategy based on endoplasmic reticulum (ER) stress and cell-nucleus penetration.
Results: The silver nanoparticle-triggered persistent activation of ER stress synergizes with chemotherapy to enhance cytotoxicity and stimulate the ICD effect. It has the potential to enhance chemosensitivity by downregulating of P-gp expression due to the increased production of ATP-consuming chaperones. In addition, the novel peptide (CB5005), which not only penetrates the cell membrane but also has a nuclear localization sequence, is conjugated to DOX to improve both cellular internalization and intranuclear accumulation. Moreover, surface TA-Fe³⁺ engineering endows the nanocomposite with ATP-responsive disassembly and ATP depletion properties to improve biocompatibility and decrease ATP-dependent drug efflux. Ag-TF@PDOX has potential as a dual-mode (PAI/MRI) contrast-enhanced agent for realizing theranostic guidance.
Conclusion: This theranostic nanocomposite greatly restricts the growth of drug-resistant breast tumors and activates a strong immune response as well, providing an opportunity for the development of therapeutics that reverse tumor MDR and metastasis at the subcellular level.
Lacking nano-systems for precisely codelivering the chemotherapeutics paclitaxel (PTX) and the natural P-glycoprotein (P-gp) inhibitor, quercetin (QU), into cancer cells and controlling their intracellular release extremely decreased the anticancer effects in multidrug resistant (MDR) tumors. To overcome this hurdle, we constructed hybrid polymeric nanoparticles (PNPs) which consist of redox-sensitive PTX/polyethyleneimine-tocopherol hydrogen succinate-dithioglycollic acid PNPs and pH-sensitive hyaluronic acid-QU conjugates. The obtained hybrid PNPs can be internalized into drug-resistant breast cancer cells by the hyaluronic acid/CD44-mediated endocytosis pathway and escape from the lysosome through the “proton sponge effect”. Under the trigger of intracellular stimuli, the nanoplatform used the pH/glutathione dual-sensitive disassembly to release QU and PTX. The PTX diffused into microtubules to induce tumor cell apoptosis, while QU promoted PTX retention by down-regulating P-gp expression. Moreover, tocopherol hydrogen succinate and QU disturbed mitochondrial functions by generating excessive reactive oxygen species, decreasing the mitochondrial membrane potential, and releasing cytochrome c into the cytosol which consequently achieved intracellular multilevel chemotherapy amplification in MDR cancers. Importantly, the PNPs substantially suppressed tumors growth with an average volume 2.54-fold lower than that of the control group in the MCF-7/ADR tumor-bearing nude mice model. These presented PNPs would provide a valuable reference for the coadministration of natural compounds and anticarcinogens for satisfactory combination therapy in MDR cancers.
Breast cancer is a dangerous type of cancer in women. Quercetin (QRT), a naturally occurring flavonoid, has wide biological effects including antioxidant, anticarcinogenic, anti-inflammatory, antiallergic, and antiviral activities. The anticancer activity is considered the most valuable effect of QRT against several types of cancer, including prostate, liver, lung, colon, and breast cancer. Scorpion venom peptides (SV) has been found to induce apoptosis and aggravate cancer cells, making it a promising anticancer agent. QRT, SV, and Phospholipon® 90H (PL) were incorporated in a nano-based delivery platform to assess QRT’s cellular uptake and antiproliferative efficacy against a lung cancer cell line derived from human breast cancer cells MCF-7. Several nanovesicles were prepared and optimized, using four-factor Box–Behnken, in an experimental design. The optimized phytosomes showed vesicle size and zeta potential values of 116.9 nm and 31.5 mV, respectively. The IC50 values revealed that MCF-7 cells were significantly more sensitive to the optimized QRT formula than the plain formula and raw QRT. Cell cycle analysis revealed that optimized QRT formula treatment resulted in significant cell cycle arrest at the S phase. The results also indicated that treatment with QRT formula significantly increased caspase-9, Bax, Bcl-2, and p53 mRNA expression, compared with the plain formula and QRT. In terms of the inflammatory markers, the QRT formula significantly reduced the activity of TNF-α and NF-κB, in comparison with the plain formula and QRT only. Overall, the findings from the study proved that a QRT formulation could be a promising therapeutic approach for the treatment of breast cancer.
A Janus cargo has been developed via the combination of magnetic mesoporous silica (MMS) with asymmetric decoration of Pt nanoparticles (PtNPs). Mesoporous morphology of MMS provides plenty of space for loading photosensitizers and targeting agents; the magnetic feature endows the as-formed nanospheres with satisfactory isolation function in removal of low abundant target cells. The excellent catalytic ability of PtNPs can effectively alleviate the hypoxia condition of tumor microenvironment via the decomposition of hydrogen peroxide (H2O2), as well as an O2-drived nanomotor for highly efficient drug release. Using CCRF-CEM as the model target cell, the Janus cargo is demonstrated to possess significantly improved performance in cell capture and photodynamic therapy. Specially, owing to the patchy Pt decoration, the loaded photosensitizers exhibit a more efficient release behavior. More importantly, asymmetric O2-emission from one side of the nanocargo acts as a driving force, which could effectively accelerate the motion ability of cargo in cell media, thus leading to an enhanced therapeutic effect compared with the traditionally symmetric nanocargo. This Janus cargo would offer a new paradigm to design highly efficient drug carrier for gaining an improved photodynamic therapy in hypoxic cancer cells.
Graphic abstract
The fast evolution of medical micro‐ and nanorobots in the endeavor to perform non‐invasive medical operations in living organisms has boosted the use of diverse medical imaging techniques in the last years. Among those techniques, photoacoustic imaging (PAI), considered a functional technique, has shown to be promising for the visualization of micromotors in deep tissue with high spatiotemporal resolution as it possesses the molecular specificity of optical methods and the penetration depth of ultrasound. However, the precise maneuvering and function's control of medical micromotors, in particular in living organisms, require both anatomical and functional imaging feedback. Therefore, herein, the use of high‐frequency ultrasound and PAI is reported to obtain anatomical and molecular information, respectively, of magnetically‐driven micromotors in vitro and under ex vivo tissues. Furthermore, the steerability of the micromotors is demonstrated by the action of an external magnetic field into the uterus and bladder of living mice in real‐time, being able to discriminate the micromotors’ signal from one of the endogenous chromophores by multispectral analysis. Finally, the successful loading and release of a model cargo by the micromotors toward non‐invasive in vivo medical interventions is demonstrated.
Lymphoma is a name for malignant diseases of the lymphatic system including Hodgkin's lymphoma and non-Hodgkin's lymphoma. Although several approaches are used for the treatment of these diseases, some of them are not successful and have serious adverse effects. Therefore, other effective treatment methods might be interesting. Studies have indicated that plant ingredients play a key role in treating several diseases. Some plants have already shown a potential therapeutic effect on many malignant diseases. Quercetin is a flavonoid found in different plants and could be useful in the treatment of different malignant diseases. Quercetin has its antimalignant effects through targeting main survival pathways activated in tumor cells. In vitro/in vivo experimental studies have demonstrated that quercetin possesses a cytotoxic effect on lymphoid cancer cells. Regardless of the optimum results that have been obtained from both in vitro/in vivo studies, few clinical studies have analyzed the antitumor effects of quercetin in lymphoid cancers. Thus, it seems that more clinical studies should introduce quercetin as a therapeutic, alone or in combination with other chemotherapy agents. Here, in this study, we reviewed the anticancer effects of quercetin and highlighted the potential therapeutic effects of quercetin in various types of lymphoma.
Osteosarcoma is a primary bone tumor. Although it is a rare disease in general, it is the most common primary bone tumor among children. Despite the significant advances made in the field of osteosarcoma treatment, the outcomes of this disease are still unfavorable. Besides, there is still no targeted therapy for osteosarcoma that can be used in clinical settings. Quercetin is a member of the phytochemical family which is used for different diseases including cardiovascular diseases, diabetes, and cancer. Its anti-cancer effects are examined in many types of cancer including breast, colon, lung, prostate, and pancreatic cancers and have shown promising results. Herein, the studies dealing with the antitumor roles of quercetin in osteosarcoma are reviewed in this article. We take a look into quercetin’s ability to affect proliferation, apoptosis, invasion, and chemo-resistance of the osteosarcoma cells through regulating protein expression and signaling pathways.
Development of bioinspired nanomachines with an efficient propulsion and cargo-towing has attracted much attention in the last years due to their potential biosensing, diagnostics, and therapeutics applications. In this context, self-propelled synthetic nanomotors are promising carriers for intelligent and controlled release of therapeutic payloads. However, the implementation of this technology in real biomedical applications is still facing several challenges. Herein, we report the design, synthesis, and characterization of innovative multifunctional gated platinum-mesoporous silica nanomotors constituted of a propelling element (platinum nanodendrite face), a drug-loaded nanocontainer (mesoporous silica nanoparticle face), and a disulfide-containing oligo(ethylene glycol) chain (S-S-PEG) as a gating system. These Janus-type nanomotors present an ultrafast self-propelled motion due to the catalytic decomposition of low concentrations of hydrogen peroxide. Likewise, nanomotors exhibit a directional movement, which drives the engines toward biological targets, THP-1 cancer cells, as demonstrated using a microchip device that mimics penetration from capillary to postcapillary vessels. This fast and directional displacement facilitates the rapid cellular internalization and the on-demand specific release of a cytotoxic drug into the cytosol, due to the reduction of the disulfide bonds of the capping ensemble by intracellular glutathione levels. In the microchip device and in the absence of fuel, nanomotors are neither able to move directionally nor reach cancer cells and deliver their cargo, revealing that the fuel is required to get into inaccessible areas and to enhance nanoparticle internalization and drug release. Our proposed nanosystem shows many of the suitable characteristics for ideal biomedical destined nanomotors, such as rapid autonomous motion, versatility, and stimuli-responsive controlled drug release.
SARS-CoV-2 is a betacoronavirus causing severe inflammatory pneumonia, so that excessive inflammation is considered a risk factor for the disease. According to reports, cytokine storm is strongly responsible for death in such patients. Some of the consequences of severe inflammation and cytokine storms include acute respiratory distress syndrome, acute lung injury, and multiple organ dysfunction syndromes. Phylogenetic findings show more similarity of the SARS-CoV-2 virus with bat coronaviruses, and less with SARS-CoV. Quercetin is a carbohydrate-free flavonoid that is the most abundant flavonoid in vegetables and fruits and has been the most studied to determine the biological effects of flavonoids. Inflammasomes are cytosolic multi-protein complexes assembling in response to cytosolic PAMP and DAMPs, whose function is to generate active forms of cytokines IL-1β and IL-18. Activation or inhibition of the NLRP3 inflammasome is affected by regulators such as TXNIP, SIRT1 and NRF2. Quercetin suppresses the NLRP3 inflammasome by affecting these regulators. Quercetin, as an anti-inflammatory, antioxidant, analgesic and inflammatory compound, is probably a potential treatment for severe inflammation and one of the main life-threatening conditions in patients with COVID-19.
The ability of acoustically propelled micro and nanoscale motors to perform diverse tasks while moving in solutions can open up new applications in diverse fields such as medicine, biotechnology, and materials science. However, the current understanding of the underlying propulsion mechanisms of ultrasound‐driven structures is limited for translating their motion and operation to practical applications. Here, the behavior of Janus microparticles displaying acoustically driven propulsion is demonstrated. A new approach to harness the acoustically‐induced vibration and oscillation of a density asymmetric Janus microstructure into translational motion is presented, based on fixing the micromotor orientation with an external magnetic field. Such acoustic propulsion of Janus microparticles is realized through a judicious material selection based primarily on density and asymmetry considerations. Experimental data and theoretical models indicate that the density asymmetry provides an acoustic propulsive force for translational motion. The Janus structure presented here is also able to propel using chemical and magnetic actuations, paving the way for different hybrid nanovehicles. The new approach to harvest acoustic energy leads to a robust motile platform and expands the horizons of ultrasound‐propelled micro/nanomotors, offering new possibilities for their design and applications.
Catalytic light‐powered micromotors have become a major focus in current autonomous self‐propelled micromotors research. The attractiveness of such machines stems from the fact that these motors are “fuel‐free,” with their motion modulated by light irradiation. In order to study how different metals affect the velocities of metal/TiO2 micromachines in the presence of UV irradiation in pure water, Pt/TiO2, Cu/TiO2, Fe/TiO2, Ag/TiO2, and Au/TiO2 Janus micromotors are prepared. The metals have different chemical potentials and catalytic effects toward water splitting reaction, with both the effects expected to alter the photoelectrochemically‐induced reaction and propulsion rates. Analysis of structures, elemental compositions, motion patterns, velocities, and overall performances of different metals (Pt, Au, Ag, Fe, Cu) on TiO2 are observed by scanning electron microscopy, energy dispersive X‐ray spectroscopy, and optical microscopy. Electrochemical Tafel analysis is performed for the different metal/TiO2 structures and it is concluded that the effective velocity is a result of the synergistic effect of chemical potential and catalysis. It is found that the Pt/TiO2 Janus micromotors exhibit the fastest motion compared to the rest of the prepared materials. Furthermore, after exposure to UV light, every fabricated micromotor shows high possibility of forming assembled chains which influence their velocity. Pt, Cu, Fe, Ag, and Au metals incorporated with TiO2 microspheres are used for the fabrication of light‐driven micromotors. These micromotors display different average velocities under UV light determined by their chemical potentials and catalytic properties toward the water splitting reaction.
Background and purpose
In a past study, we developed and optimized a novel cationic PEGylated niosome containing anticancer drugs (doxorubicin or quercetin) and siRNA. This study intended to evaluate the anti-tumor effects of the combination therapy to target both the proteins and genes responsible for the development of gastric cancer. CDC20, known as an oncogene, is a good potential therapeutic candidate for gastric cancer.
Methods
In order to increase the loading capacity of siRNA and achieve appropriate physical properties, we optimized the cationic PEGylated niosome in terms of the amount of the cationic lipids. Drugs (doxorubicin and quercetin) and CDC20siRNA were loaded into the co-delivery system, and physical characteristics, thermosensitive controlled-release, gene silencing efficiency, and apoptosis rate were determined.
Results
The results showed that the designed co-delivery system for the drugs and gene silencer had an appropriate size and a high positive charge for loading siRNA, and also showed a thermosensitive drug release behavior, which successfully silenced the CDC20 expression when compared with the single delivery of siRNA or the drug. Moreover, the co-delivery of drugs and CDC20siRNA exhibited a highly inhibitory property for the cell growth of gastric cancer cells.
Conclusion
It seems that the novel cationic PEGylated niosomes co-loaded with anticancer drug and CDC20siRNA has a promising application for the treatment of gastric cancer.
CdS quantum dots/C60 tubular micromotors with chemical/multi‐light‐controlled propulsion and “on‐the‐fly” acceleration capabilities are described. In situ growth of CdS quantum dots on the outer fullerene layer imparts this layer with light‐responsive properties in connection to inner Pt, Pd or MnO2 layers. This is the first time that visible light is used to drive bubble‐propelled tubular micromotors. The micromotors exhibit a broad absorption range from 320 to 670 nm and can be wirelessly controlled by modulating light intensity and peroxide concentration. The built‐in accelerating optical system allows for the control of the velocity over the entire UV/Vis light spectra by modulating the catalyst surface chemistry. The light‐responsive properties have been also exploited to accelerate the chemical dealloying and propulsion of micromotors containing a Cu/Pd layer. Such dual operated hybrid micromotors hold considerable promise for designing smart micromachines for on‐demand operations, motion‐based sensing, and enhanced cargo transportation.
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Background: The discovery of early diagnosis and prognostic markers for breast cancer can significantly improve survival and reduce mortality. LSM1 is known to be involved in the general process of mRNA degradation in complexes containing LSm subunits, but the molecular and biological functions in breast cancer remain unclear. Methods: In the present study, we investigated the expression profiles, prognostic roles, and genetic alterations of LSM1 in patients with breast cancer through several public databases, containing Oncomine and Gene Expression Profiling Interactive Analysis, Human Protein Atlas, Kaplan–Meier plotter and cBioPortal. Then, we constructed the protein-protein interaction networks of LSM1 proteins and their interactors by using the String database and Cytoscape software. In addition, we performed the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichmente. Finally, we explored the mechanisms underlying LSM1 involvement in BRCA by using gene set enrichment analysis. Results: We found that functional LSM1 inactivation caused by mutations and profound deletions predicted poor prognosis in BRCA patients. LSM1 was highly expressed in both BRCA tissues and cells compared to normal breast tissues/cells. High LSM1 expression is associated with poorer overall survival and disease-free survival. The association between LSM1 and immune infiltration of breast cancer was assessed by TIMER and CIBERSORT algorithms. LSM1 showed a strong correlation with various immune marker sets. Most importantly, pharmacogenetic analysis of BRCA cell lines revealed that LSM1 inactivation was associated with increased sensitivity to refametinib, and trametinib. However, both drugs could mimic the effects of LSM1 inhibition and their drug sensitivity was associated with MEK molecules. Therefore, we investigated the clinical application of LSM1 to provide a basis for sensitive diagnosis, prognosis and targeted treatment of breast cancer. Conclusions: In brief, our finding may contribute to increasing currently limited prognostic biomarkers and treatment options for breast cancer.
Polymeric micelles have acquired quite an interest as an innovative drug delivery system for the diagnosis and treatment of breast cancer, as they endeavour numerous benefits over the conventional drug delivery system, which include enhanced biocompatibility and biodegradability, increased targeting and accumulation of the chemotherapeutics to the cancer site, prolonged circulation time, improved retention of the drug-loaded polymeric micelle within the tumor with reduced off-site effects. The present review offers state of the art in polymeric micelle as a nano-drug delivery system for chemotherapeutics and their efficiency in cancer management. The review article also highlights different types of copolymers employed for the preparation of polymeric micelles along with their physicochemical attributes, types of polymeric micelles, method of preparation, characterization, and their application in the field of cancer diagnostics.
Nanocarriers and nanoparticles in the drug delivery systems increase the drug's effectiveness due to their permeability and retention properties to tumor tissues. Exosomes are small extracellular natural vesicles released from the plasma membrane and they are promise drug delivery vehicles to be used in anti-cancer therapy. The prominent features of exosomes as nanocarriers are biocompatibility, their natural form, high stability, and low toxicity. These features also distinguish the exosome from synthetic nanoparticles. Exosomes were isolated from healthy epithelial breast cells (MCF10 A) using an aqueous two-phase system (ATPS). Isolated exosomes were characterized with NTA (Nanoparticle Tracking Analysis), Zeta sizer, AFM (Atomic Force Microscopy), and flow cytometry. Lapatinib chemotherapeutic drug was loaded into isolated exosomes with the electroporation method. The loaded drug was characterized and measured using high-performance liquid chromatography (HPLC). The cytotoxicity of free lapatinib (Lap), lapatinib encapsulated exosome (LapExo), and empty exosome (Exo) were determined in HER2 positive breast cancer SKBR 3 and healthy breast MCF10 A cells. Lapatinib-loaded exosomes significantly reduced cellular proliferation of SKBR 3 cells at lower doses compared to free Lap treatment. Apoptosis analysis showed that LapExo treatment led to a high apoptotic rate in comparison to free Lap treatment on SKBR 3 cells. Lapatinib targeting mechanisms through the downstream components of HER2 and EGFR signaling pathway were evaluated post Lap and LapExo treatment on breast cancer SKBR-3 and healthy MCF10 A cells. LapExo treatment showed similar effect on mRNA expression and protein levels as Lap treatment. This indicates that exosomal loading and delivery of chemotherapeutic drugs did not interfere the acting mechanism of drug. In the present study, we successfully loaded lapatinib chemotherapeutic drugs in exosomes that derived from non-cancerous epithelial breast cells. The lapatinib-loaded exosomes allowed us to use the lower dose concentration of the drug for breast cancer treatment. They increased the effectiveness of drug compared to lapatinib alone. Overall, this study revealed that using of exosome natural vesicles in drug delivery approaches enable cancer therapy to be more effective and could enhance the therapeutic index of chemotherapeutic drugs.
The therapeutic limitations such as insufficient efficacy, drug resistance, metastasis, and undesirable side effects are frequently caused by the long duration monotherapy based on chemotherapeutic drugs. multiple combinational anticancer strategies such as nucleic acids combined with chemotherapeutic agents, chemotherapeutic combinations, chemotherapy and tumor immunotherapy combinations have been embraced, holding great promise to counter these limitations, while still taking including some potential risks.
Nowadays, an increasing number of research has manifested the anticancer effects of phytochemicals mediated by modulating cancer cellular events directly as well as the tumor microenvironment. Specifically, these natural compounds exhibited suppression of cancer cell proliferation, apoptosis, migration and invasion of cancer cells, P-glycoprotein inhibition, decreasing vascularization and activation of tumor immunosuppression. Due to the low toxicity and multiple modulation pathways of these phytochemicals, the combination of chemotherapeutic agents with natural compounds acts as a novel approach to cancer therapy to increase the efficiency of cancer treatments as well as reduce the adverse consequences. In order to achieve the maximized combination advantages of small-molecule chemotherapeutic drugs and natural compounds, a variety of functional nano-scaled drug delivery systems, such as liposomes, host-guest supramolecules, supramolecules, dendrimers, micelles and inorganic systems have been developed for dual/multiple drug co-delivery. These co-delivery nanomedicines can improve pharmacokinetic behavior, tumor accumulation capacity, and achieve tumor site-targeting delivery.
In that way, the improved antitumor effects through multiple-target therapy and reduced side effects by decreasing dose can be implemented. Here, we present the synergistic anticancer outcomes and the related mechanisms of the combination of phytochemicals with small-molecule anticancer drugs. We also focus on illustrating the design concept, and action mechanisms of nanosystems with co-delivery of drugs to synergistically improve anticancer efficacy. In addition, the challenges and prospects of how these insights can be translated into clinical benefits are discussed.
Breast cancer is one of the most prevalent cancers in women and a leading cause of mortality. As per the GLOBCAN report of 2021, breast cancer has surpassed lung cancer which until recently was the most commonly diagnosed cancer. Despite significant efforts to improve early detection and therapeutic efficacy of breast cancer, the frequent emergence of drug resistance remains the predominant basis for the poor prognosis of cancer patients harboring various malignancies. Long non-coding RNA (lncRNAs) are known to affect a variety of components of genome function, including epigenetics, gene transcription, splicing, translation, as well as many central biological processes like cell cycle progression, cell differentiation, development, and pluripotency. LncRNAs are dysregulated in various malignancies and interact with a multitude of RNAs and proteins to impact drug resistance. LncRNAs regulate chemoresistance in cancer by employing an assortment of molecular mechanisms including multidrug efflux, suppression of apoptosis, DNA damage response, epigenetic alterations, as well as functioning as competitive endogenous RNA. When combined with other regulatory mechanisms, these pathways form a complex orchestration of signaling that ultimately lead to chemoresistance.
The current review delves into the role of lncRNAs in inducing drug resistance to conventional therapeutic anti-cancer drugs used for the treatment of breast cancer. We propose that lncRNAs that provoke drug resistance could be used to develop new targeted and tailored therapeutics providing a novel approach to introduce promising personalized treatment modalities to overcome chemoresistance in breast cancer patients. Hence, lncRNAs that drive anticancer drug resistance can be potentially explored as biomarkers of disease prognosis and may provide unique opportunities to circumvent chemoresistance in breast cancer patients.
Breast cancer incidence has increased in recent decades. In the present study, an optimum formulation of chitosan (CS)-adorned niosome-based nanocarriers for co-delivery of doxorubicin (DOX) and vincristine (VIN) was developed for the treatment of breast cancer to reduce drug doses and overcome multidrug resistance. The three-level Box–Behnken method was utilized to optimize the particles in terms of size, polydispersity index (PDI), entrapment efficacy (EE (%)), and percent of drug release (%). The release rate of two drugs from CS-adorned nanoparticles (DOX+VIN/Nio/CS) in acidic and physiological pH is less than uncoated niosome (DOX+VIN/Nio). In addition, acidic pH increases the release rate of drugs from these formulations. The size, polydispersity index, and entrapment efficacy of nanoparticles were more stable at 4 °C compared to 25 °C. MTT assay showed that the IC50 of DOX+VIN/Nio/CS is the lowest value between all fabricated formulations. We evaluated the cancer metastasis and migration (MMP2, MMP9) and transcriptional targets for the tumor suppressor protein (Bax, Bcl2) that induces cell cycle arrest or apoptosis in response to DNA. Bax gene was highly expressed, while the Bcl2, MMP2, and MMP9 genes decreased in DOX+VIN/Nio/CS compared to control, free forms of DOX, VIN, DOX+VIN, and DOX+VIN/Nio. DOX+VIN/Nio/CS inhibited cell migration and increased apoptosis, cell uptake, and endocytosis in human SKBR3 breast cancer cells compared to DOX, VIN, DOX+VIN. These in vitro data are promising to treat breast cancer with advanced pH-responsive drug release nanoformulations.
Efficient intracellular drugs delivery and accumulation are the key determinant for overcoming tumor multidrug resistance (MDR). To realize this purpose, dual-pH responsive chitosan nanoparticles (DCCA/DOX-NPs) were fabricated to treat MDR tumor in human breast cancer (MCF-7/ADR). The particles were firstly sensitive to tumor extracellular pH 6.5, contributing to the surface charge reversal (−6.32 → 11.45 mV) by the cleavage of β-carboxylic amide, which greatly increased cellular uptake efficiency. DCCA/DOX-NPs further responded to lower intracellular pH 5.0, thereby triggering DOX and cinnamaldehyde (CA) release by the cleavage of Schiff base. Cells assays verified that dual-pH sensitive particles caused higher toxicity in MDR tumor cells. Furthermore, the particles could overcome tumor resistance by decreasing intracellular levels of ATP and PARP-1, eventually receiving stronger antitumor efficiency in vivo (84.94%). Overall, this amphiphilic chitosan nanosystem with various bioactivities could work as an alternative promising for treating MDR tumor.
The present investigation was carried out to engineer N-acetyl-d-glucosamine (NADG) coupled quercetin-loaded (Q) nano-lipid-based carriers (NADG-Q-NLBCs) to target breast cancer. The constructed nano-bioconjugate was characterized by various techniques, and the in vitro drug release profiles were examined using zero and first-order kinetic models. The characterization data confirmed the morphology, size, charge distribution, crystallinity, and chemical interactions among the various moieties of the nano-bioconjugate. Further, the synthesized NADG-Q-NLBCs were applied to target the human breast cancer cells (MCF-7), which interestingly showed a more cytotoxic effect compared to the lone NLBCs and free Quercetin. The flow cytometry study confirmed NADG-Q-NLBCs induced apoptosis in MCF-7 cells in a targeted manner. The percentage of early apoptotic cells was found to be 25% in the case of NADG-Q-NLBCs, which is almost 2.5 times higher than the Q-NLBCs. However, the number of viable cells reached the maximum when treated with NLBCs. The present investigation suggests that the constructed nano-bioconjugate could be a capable carrier of drugs with sustained pharmacokinetics and improved physicochemical properties.
In this study, tubular poly(3,4-ethylene dioxythiophene)-polypyrrole/Ni/ Pt (PEDOT-PPy-COOH/Ni/Pt) micromotors were prepared and modified with L-asparaginase, which is an anti-leukemic drug. Inner Pt layer of the micromotor decomposes H2O2 to produce O2 and allows the motor for self-propulsion, while the Ni segment enables remote control of the motors via a magnetic field. These tiny motors have self-propulsion capability and can be easily controlled by an external magnetic field. By immobilizing asparaginase, these enzyme-carrying motors demonstrated improved activity for the L-asparagine hydrolysis. At the end of the immobilization process, the enzyme showed improved thermal and pH stability, ascending protease resistance, longer storage time, and reusability. Kinetic parameters of free and immobilized asparaginase were also evaluated. It was shown that affinity for asparaginase towards its substrate did not change significantly upon immobilization. Besides Vmax value of immobilized L-asparaginase was found to be higher than that of free enzyme. Stability against protease trypsin was also tested and it was demonstrated that immobilized L-asparaginase was more stable for trypsin than free L-asparaginase. Finally, artificial serum experiments were also constructed to show the possible in vivo usage, and it was realized that L-asparaginase immobilized micromotor exhibited higher activity than free enzyme and control static micromotor experiments.
The ability to in situ tune various motion modes of micromotors is challenging, yet critical for any practical applications of micromotors in complex microenvironments. Here, we designed and synthesized magnetic...
In the present study, the three functions, including enhanced permeability and retention (EPR) effect, deep penetration within tumor, and receptor-mediated endocytosis, were integrated into a single platform in order to improve antitumor efficiency. A novel nanoparticle (dendrigraft [email protected] [email protected] dicarboxylic [email protected]@ hyaluronic acid composite) has been successfully developed and was denoted as DGL-GA-CDA-DOX-HA. The transmission electron microscope (TEM), dynamic light scattering (DLS), polymer dispersity index (PDI), fourier transform infrared spectrometer (FTIR), and zeta potentials were used to characterize the physicochemical properties of the nanoparticles. According to the results of TEM and DLS, the DGL-GA-CDA-DOX-HA nanoparticles could be rapidly degraded with a size shrink from 182.5 nm to 47.7 nm by hyaluronidase (HAase) added in the medium. The loading amount of DOX reached 252.03 ± 36.38 mg/g for DGL-GA-CDA-DOX nanoparticles. When the nanoparticles were in a medium with HAase at pH 5.0, the drug quickly released. However, when the nanoparticles were exposed to a medium without HAase at pH 5.0, or a neutral medium containing HAase, drug release slowed down. The modification of GA on nanoparticles significantly enhanced their affinity and cytotoxicity to hepatocellular carcinoma HepG2 cells. The study showed that the penetrability of DGL-GA-CDA-DOX and DGL-GA-CDA DOX-HA nanoparticles pre-degraded by HAase in vitro multicellular tumor spheroids were always better than that of DGL-GA-CDA-DOX-HA nanoparticles untreated by HAase. The imaging in vivo and ex vivo exhibited that DGL-GA-CDA-DOX-HA nanoparticles could preferentially accumulate in the tumor site. Correspondingly, the DGL-GA-CDA-DOX-HA displayed the preferable antitumor efficiency to other experimental groups in H22 tumor-bearing mice, with a tumor inhibition rate of 71.6%. In short, these results suggested that DGL-GA-CDA-DOX-HA nanoparticles could promote therapeutic effects by modulating particle size and GA receptor-mediated endocytosis.
Developing new strategies to overcome biological barriers and achieve efficient delivery of therapeutic nanoparticles (NPs) is the key to achieve positive therapeutic outcomes in nanomedicine. Herein, a multistage-responsive clustered nanosystem is designed to systematically resolve the multiple tumor biological barriers conflict between the enhanced permeability retention (EPR) effect and spatially uniform penetration of the nanoparticles. The nanosystem with desirable diameter (initial size of ~50 nm), which is favorable for long blood circulation and high propensity of extravasation through tumor vascular interstices, can accumulate effectively around the tumor tissue through the EPR effect. Then, these pH-responsive nanoparticles are conglomerated to form large-sized aggregates (~1000 nm) in the tumor under the acidic microenvironment, and demonstrated great tumor retention. Subsequently, the photothermal treatment disperses the aggregates to be ultrasmall gold nanoclusters (~5 nm), thereby improving their tumor penetration ability, and enhancing the radiotherapeutic effect by radiosensitizer. In 4T1 tumor model, this nanosystem shows great tumor accumulation and penetration, and the tumor growth and the lung/liver metastasis in particle/PTT/RT treated mice is significantly inhibited. As a photoacoustic/fluorescence imaging agent and PT/RT synergistic agent, this pH-/laser-triggered size multistage-responsive nanosystem displayes both great tumor accumulation and penetration abilities, and shows excellent potential in tumor therapy.
The field of micromotors has been growing exponentially with increased emphasis on biomedical applications, with various in vivo demonstrations of targeted drug delivery, biosensing, and gene delivery, among others. In parallel, these micromotors have been recently used for probing the rheological properties of both intra- and extracellular environments. Here, we demonstrate the application of magnetic micromotors for investigation of rheological properties of human blood. While there are several techniques to sense mechanical properties of blood, such as deformability of the red blood cells, this is the first experimental observation of using micromotors for these biophysical investigations. We hope that this will lead to a better understanding of the nature of interactions of micromotors with biological systems and expand the scope of micromotors for probing other related systems, such as interstitial fluids and other complex biological fluids.
Luteolin, kaempferol, apigenin and quercetin are four common flavonol glycoside compounds found in many plants that possess multiple biological activities. The current study focused on their anti-inflammatory and antioxidant activities in vitro by assaying the NO content, phagocytosis, DPPH and ABTS radical scavenging activities and ferric reducing antioxidant power. This study indicated that all four compounds at concentrations of 50, 100 and 200 μM could reduce both the concentration of NO and phagocytosis; their antioxidant activities increased as the concentration increased from 0.5 to 32.0 μg/ml; the IC50 DPPH values were 2.099, 5.318, 1.84, 10.5 and 3.028 μg/ml for luteolin, kaempferol, quercetin, BHT and VC, respectively; the IC50 ABTS values were 0.59, 0.8506, 0.8243, 0.5083, 1.4497 and 2.1563 μg/ml for luteolin, kaempferol, apigenin, quercetin, BHT and VC, respectively; and the FRAP values ranged from 0.0101 to 0.0402 mmol Fe²⁺/μg/ml for the six compounds. Compared with the test results, quercetin is a perfect anti-inflammatory and antioxidant agent that has potential as an adjuvant treatment for inflammatory diseases and oxidative stress. In addition, this research preliminarily revealed that antioxidant activity is directly proportional to the number of phenolic hydroxyl groups, and after comparison of the anti-inflammatory and antioxidant activities, the compounds with enol groups were superior to those without enol groups, which will be further verified in future in vivo experiments.
Multidrug resistance (MDR) of a tumor is the main cause of failure of clinical chemotherapy. Herein, we report a simple, yet versatile, tumor-targeting "calcium ion nanogenerator" (TCaNG) to reverse drug resistance by inducing intracellular Ca2+ bursting. Consequently, the TCaNG could induce Ca2+ bursting in acidic lysosomes of tumor cells and then reverse drug resistance according to the following mechanisms: (i) Ca2+ specifically accumulates in mitochondria, suppressing cellular respiration and relieving tumor hypoxia, thus inhibiting P-glycoprotein biosynthesis by downregulating HIF-1α expression. (ii) Ca2+-bursting-induced respiratory depression blocks intracellular ATP production, which further leads to the P-gp incompetence. As a result, the TCaNG could decrease the IC50 of DOX to MCF-7/ADR cells by approximately 30 times and reduce the proliferation of drug-resistant tumors by approximately 13 times without obvious side effects. This simple, safe, and effective "Ca2+ bursting" strategy holds the potential for clinical application in tumor treatment.
Multidrug resistance (MDR) in tumor has long been considered a major factor in the failure of tumor chemotherapy. P-glycoprotein (P-gp)-mediated drug efflux plays a significant role in the MDR of tumor. Herein, paclitaxel (PTX) and P-gp inhibitor quercetin (QC) co-loaded and chondroitin sulfate (ChS)-coated mesoporous silica nanoparticles (MSNs) ([email protected]) were developed to reverse MDR in breast cancer and improve chemotherapy efficacy. The dual drug-loaded nanoparticles (NPs) showed a nanoscale size of ∼ 227.2 nm and redox-responsive drug release property. In vitro cell experiments showed that NPs exhibited CD44 receptor-mediated active targeting in MCF-7/ADR cells. The dual drug-loaded NPs had lower IC50 value, higher apoptosis rate, obvious G2M phase arrest as well as stronger microtubule destruction in MCF-7/ADR cells compared to PTX-loaded NPs, suggesting that QC addition, significantly, improved the sensitivity of MCF-7/ADR cells to PTX. Further study found that QC-loaded NPs down-regulated the expression of P-gp. Notably, the dual drug-loaded NPs exhibited tumor-targeting ability, prolonged tumor retention time and effective anti-tumor effect without obvious toxicity to normal tissues in vivo. Taken together, our research provides a viable approach to overcome MDR in breast cancer.
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Background: Breast cancer in the most common malignancy among women in Haiti and is mostly diagnosed at an advanced stage. While it is well known that molecular subtype is a prognostic factor, it needs to be investigated among Haitian patients with breast cancer. This study aimed to evaluate the impact of molecular classification of breast cancer on the survival of patients managed in Haiti’s largest cancer clinic. Methods: A retrospective study was conducted on the breast cancer patients of Innovating Health International (IHI) in Port-au-Prince, Haiti from January 2014 to December 2018. Chart review included all patients with breast cancer and tested for molecular classification. Data on variables such as date of admission, age, TNM staging, molecular classification, outcome and date of death were collected for the analysis. Mortality rate and median overall survival (OS) were estimated as of December 31 st , 2019 and stratified according to molecular subtypes. Results: Among the 948 breast cancer cases diagnosed for the study period, 234 (24.7%) of them had a complete molecular classification. The mean age was 51.5 years [range: 23-94]. 55.1% of the patients were ER-positive, among them 33.7% ER+/PR+/HER2-, 15.4% ER+/PR-/HER2-, 2.1% ER+/PR-/HER2+ and 3.8% ER+/PR+/HER+ (triple positive). There were overall 25.6% of luminal A and 29.5% of luminal B cases. 44.9% were ER-negative, among them 14.1% ER-/PR-/HER2+ (HER2-enriched) and 29.1% ER-/PR-/HER2- (triple-negative). 92.2% of the patients had advanced breast cancer (stages IIB to IV). 29.5% had metastatic breast cancer, 22.8% for luminal A cases, 27.0% for luminal B, 36.7% for HER2-enriched and 32.8% for TNBC. Overall mortality rate was 42.3%, respectively 33.3% for luminal A cases, 37.7% for luminal B, 42.4% for HER2-enriched cases and 55.9% for TNBC. Median OS was not yet reached for luminal A, luminal B and HER2-enriched breast cancer, with a respective mean survival of 52.4 months, 51.3 months and 51.6 months. However, OS was 30.6 months for triple-positive breast cancer and 23.7 months for TNBC. Conclusions: Patients with luminal A breast cancer were less likely to have metastatic disease and thus had lower mortality rate and better overall survival. This was likely due to its less aggressive biology and the availability of hormone therapy. Poor availability and inaccessibility of HER2-targeted drugs were the main cause of the higher mortality rate among HER2-enriched patients. TNBC remains the most aggressive subtype.
Gas therapy has emerged as a forceful strategy for augmenting the effects of chemotherapeutic drugs against cancer cells. However, it remains extremely challenging to effectively deliver gas into tissues of interest and unravel its underlying mechanisms. Herein, we designed a near-infrared (NIR) light-switchable nitric oxide (NO) delivery nanosystem for high-efficacy multi-drug resistance (MDR) reversal in cancer therapy based on a yolk-shell upconverting [email protected] silica ([email protected]). The internal hol-low cavity and flower-like mesoporous shell of [email protected] not only enabled a significantly high encapsulation capacity for NO precursor (BNN6) and doxorubicin (DOX), but also allowed the enhanced cellular uptake, resulting in NIR-triggered NO generation and low pH-triggered DOX release in cancer cells. Mechanistically, intracellular NO can down-regulate the drug efflux-related P-glycoprotein and ATP-binding cassette transporters, thereby increasing DOX accumulation in the cell nuclei. Such combination ther-apy of NO and DOX induced the apoptosis of MDR cells and completely inhibited the growth of MDR tumors in vivo. We further elucidated the therapy mechanism via proteomic profiling, showcasing the down-regulation of ubiquitin-proteasome pathway and nuclear factor kappa-B signaling pathway in the NO-treated MDR cells. Therefore, our findings develop a promising nanoscale gas/drug delivery paradigm for fighting MDR tumors and providing molecular insights into cancer therapy.
The therapeutic efficacy of chemotherapy in many types of hematological malignancies and solid tumors is dramatically hindered by multidrug resistance (MDR). This work presents a combination strategy of pretreatment of MDA-MB-231/MDR1 cells with quercetin (QU) followed by doxorubicin (DOX) to overcome MDR, which can be delivered by mixed micelles composed of the reduction-sensitive hyaluronic acid-based conjugate and D-α-tocopheryl polyethylene glycol 1000 succinate. The combination strategy can enhance the cytotoxicity of DOX on MDA-MB-231/MDR1 cells by increasing intracellular DOX accumulation and facilitating DOX-induced apoptosis. The probable MDR-reversal mechanisms are that the pretreatment cells with QU-loaded mixed micelles downregulate P-glycoprotein expression to decrease DOX efflux as well as initiate mitochondria-dependent apoptotic pathways to accelerate DOX-induced apoptosis. In addition, this combination strategy not only can potentiate in vivo tumor-targeting efficiency but also can enhance the anti-tumor effect in MDA-MB-231/MDR1-bearing nude mice without toxicity or side effects. This research suggests that the co-administration of natural compounds and chemotherapeutic drugs could be an effective strategy to overcome tumor MDR which deserves further exploration.
Chemotherapy faces challenges, including poor aqueous solubility of the drugs, and cardiotoxicity. Micellar drug delivery systems (DDS) are used to encapsulate anticancer drugs for better therapeutic effects, however, with poor loading content. Herein, we synthesized a micellar DDS using -benzyloxy substituted poly(ε-caprolactone) as the hydrophobic block, and co-loaded anticancer doxorubicin (Dox) and antioxidant quercetin (Que). -Substituted oligo(ethylene) glycol (OEG) poly(ε-caprolactone)s were used as hydrophilic blocks to make the polymers thermoresponsive. Variation of the OEG chain allowed the tunability of the lower critical solution temperature. Moreover, drug loading and release were studied. Thermodynamic stability, size, and morphology were determined by fluorescence measurements, dynamic light scattering, and transmission electron microscopy. Combination loading demonstrated improved loading of Dox and Que. Biological studies were performed using HepG2 human liver cancer and H9c2 rat heart cells. The use of biodegradable, biocompatible and thermoresponsive polymers along with the co-loading approach is a good strategy in developing DDSs.
A nanocarrier system of methoxypolyethylene glycol amine (mPEG-NH2) functionalized polydopamine (PDA) coated hollow mesoporous silica nanoparticles (HMSNs-PDA-PEG) was developed with pH-responsive, which combined doxorubicin hydrochloride (DOX) and quercetin (QUR) to reverse multidrug resistance (MDR) and improved anticancer effects on taxol (TAX) and DOX double resistant human colorectal cancer cell line HCT-8 (HCT-8/TAX cells). Well-dispersed nanoparticles (HMSNs-PDA-PEG) were prepared with a dimension of around 170 nm. The surface morphology and chemical properties of HMSNs-PDA-PEG were also successfully characterized by transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), thermal gravimetric analysis (TGA), X-ray diffraction (XRD), Brunauer-Emmett-Teller (BET) method, Fourier transform infrared spectroscopy (FT-IR) and dynamic light scattering (DLS). Drug release experiments results indicated that DOX and QUR (QD) loaded nanoparticles (HMSNs-PDA-PEG@QD) had similar release kinetic profiles of each drug, which all exhibited highly sensitive to pH value due to the surface PDA coating. Additionally, the HCT-8 cells or HCT-8/TAX cells were employed to assess the cellular uptake and cytotoxicity of various drug-free or drug-loaded HMSNs samples. Meanwhile, a series of biological evaluations demonstrated that the HMSNs-PDA-PEG@QD exhibited remarkable ability to overcome MDR compared with free DOX and HMSNs-PDA-PEG@DOX. Taken together, these results revealed that HMSNs-PDA-PEG@QD was suitable as a prospective and efficient drug delivery nanosystem for overcoming multidrug resistance.
Skin aging might happen due to extrinsic and intrinsic factors that usually can induce the increase of free radicals and generate oxidative stress, which lead to skin alterations. Thus, there is a search for antioxidant substances that can control these effects. Quercetin (QT) is a flavonoid with antioxidant potential however presents poor percutaneous permeation, low stability and phototoxicity. Therefore, the encapsulation in nanoparticles is an interesting strategy to overcome these challenges. Nanostructured lipid carriers (NLC) is a promising type of vehicle that can improve drug penetration on skin and enhance the entrapment efficiency as well as improve the drug stability. These nanoparticles can be produced using natural lipids with biological properties resulting in a carrier with biological activities. The aim of this study was to produce NLC to load QT enhancing its permeation and obtaining an effective and safe topical formulation. The NLC were characterized regarding their size, zeta potential, entrapment efficiency, thermal behavior, morphology and evaluation of the biological properties using in vitro methods to analyze the antioxidant activity, skin permeation, antiallergic potential, cytotoxicity and phototoxicity potential on monolayer (HaCaT cells and 3T3 NRU PT) and on reconstructed human skin model (H3D-PT). The average size of QT-NLC was 130 nm with low polydispersity index (PdI) (~0.260), and negative zeta potential (around of −13 mV). Through the thermal behavior analysis, the nanoparticle exhibited a low recrystallization index (13.03%), which is important to obtain high entrapment efficiency (97.42%) and avoid drug expulsion during the storage time. The nanoparticles showed a homogeneous morphology and were very stable regarding to size and PdI over to 120 days. On terms of biological properties QT-NLC presented antioxidant activity, enhanced penetration of quercetin in the skin and showed an antiallergic potential. Furthermore, in the reconstructed human skin model that consider viable epidermis bioavailability due to the presence of stratum corneum, it was observed that the topical formulation of QT-NLC presented no phototoxic potential. Therefore, the developed nanostructure is a vehicle with potential for topical administration of quercetin.
There is mounting interest in synthetic microswimmers (“micromotors”) as microrobots as well as a model system for the study of active matters, and spatial navigation is critical for their success. Current navigational technologies mostly rely on magnetic steering or guiding with physical boundaries, yet limitations with these strategies are plenty. Inspired by an earlier work with magnetic domains on a garnet film as predefined tracks, we present an interdigitated microelectrodes (IDE) system where, upon the application of AC electric fields, metallodielectric (e.g. SiO2-Ti) Janus particles are hydrodynamically confined and electrokinetically propelled in one dimension along the electrode center lines with tunable speeds. In addition, co-moving micromotors moved in single files, while those moving in opposite directions primarily reoriented and moved past each other. At high particle densities, turbulence-like aggregates formed as many-body interactions became complicated. Furthermore, a micromotor made U-turns when approaching an electrode closure, while it gradually slowed down at the electrode opening and was collected in large piles. Labyrinth patterns made of serpentine chains of Janus particles emerged by modifying the electrode configuration. Most of these observations can be qualitatively understood by a combination of electroosmotic flows pointing inward to the electrodes, and asymmetric electrical polarization of the Janus particles under an AC electric field. Emerging from these observations is a strategy that not only powers and confines micromotors on pre-fabricated tracks in a contactless, on-demand manner, but is also capable of concentrating active particles at predefined locations. These features could prove useful for designing tunable tracks that steer synthetic microrobots, as well as to enable the study of single file diffusion, active turbulence and other collective behaviors of active matters.
Quercetin, a natural polyphenol with strong antioxidant activity, was loaded in Eudragit-coated liposomes conceived for intestinal delivery. Eudragit was used to form a protective shell on the surface of liposomes to resist gastric environment and allow the delivery of quercetin to the intestine. The physico-chemical properties of the liposomes were assessed by light scattering and cryogenic transmission electron microscopy. Small, spherical, uni- and bilamellar liposomes were produced, with the presence of multilamellar structures in Eudragit-coated liposomes. The Eudragit coating increased the physical stability of the vesicular system in fluids mimicking the gastrointestinal environment. Further, the incorporation of quercetin in the vesicular system did not affect its intrinsic antioxidant activity, as DPPH radical was almost completely inhibited, and the vesicles were also capable of ensuring optimal protection against oxidative stress in human intestinal cells by reducing reactive oxygen species (ROS)production. The proposed approach based on quercetin vesicular formulations may be of value in the treatment of pathological conditions associated with intestinal oxidative stress.
Photothermal therapy (PTT) based on photothermal effect of the gold nanostructures, has been widely applied as a noninvasive therapy approach in cancer treatment. However, bare Au nanoparticles are not stable enough during the irradiation process, and cannot harvest sufficient energy to kill tumor cells. To improve this, we have fabricated a stable bioagent by loading gold nanorods (AuNRs) into multicompartment mesoporous silica nanoparticles (MMSNs) for the photothermal therapy. The procedure is that when AuNRs entrapped in MMSNs are irradiated by a laser in the near-infrared region of 808 nm, the hyperthermia produced by the assembled composites is strong enough to damage tumor tissues directly. Both experiments in vitro and in vivo demonstrate that the nanocomposites are perfect candidates as PTT agents for the cancer treatment with a high efficiency. Furthermore, it is found that the nanocomposites have good photostability and consistent temperature fluctuation over 11 on/off cycles with irradiation which the pure AuNRs will not have.
Asymmetric dual-function of Janus micro/nanoparticles that have different surface modifications, structures or material properties, are extremely promising as building blocks in constructing micro-/nanomotors. However, current synthesis strategies are usually lack of controlling the coverages of Janus micro/nanoparticles, which hinders in-depth researches of their effects on the performance of Janus nanomotors. This study demonstrates a versatile approach for fabrication of Janus dendritic porous silica nanomotors with precisely modulated coverages from 0 to 100% by controlling the embedded depth of aminopropyl-modified dendritic porous silica nanoparticles (DPSNs-NH2) with positive charges and subsequently adsorbing the oppositely charged Pt nanoparticles. The diffusion coefficients of DPSNs-NH2 with different coverages of Pt NPs are systematically investigated. The propulsion can be enhanced by the improvement of catalytic activity of DPSNs, and half-coated DPSNs-NH2 exhibit highest propulsion among DPSNs-NH2 with other coverages. More importantly, compared with solid silica nanospheres, the initial increase of the coverage of DPSNs-NH2 makes more enhancements to the motion performance，which can be used to optimize the relations between the propulsion velocity and loading efficiency of bovine serum albumin. This work paves the way to fabricate tunable multifunctional Janus micro/nanomotors for future advanced devices.