Recent strategies to overcome breast cancer resistance.

Breast cancer is potentially a lethal disease and a leading cause of death in women. Chemotherapy and radiotherapy are the most frequently used treatment options. Drug resistance in advanced breast cancer limits the therapeutic output of treatment. The leading cause of resistance in breast cancer is endocrine and hormonal imbalance, particularly in triple negative and HER2 positive breast cancers. The efflux of drugs due to p-gp's activity is another leading cause of resistance. Breast cancer resistant protein also contributes significantly. Strategies used to combat resistance include the use of nanoparticles to target drug delivery by co-delivery of chemotherapeutic drugs and genes (siRNA and miRNA) that help to down-regulate genes causing resistance. The siRNA is specific and effectively silences p-gp and other proteins causing resistance. The use of chemosensitizers is also effective in overcoming resistance. Chemo-sensitizers sensitize cancer cells to the effects of chemotherapeutic drugs. Novel anti-neoplastic agents such as antibody-drug conjugates and mesenchymal stem cells are also effective tools used to improve the therapeutic response in breast cancer. Similarly, combination of photo/thermal ablation with chemotherapy can act to overcome breast cancer resistance. In this review, we focus on the mechanism of breast cancer resistance and the nanoparticle-based strategies used to combat resistance in breast cancer.

Evaluation of mAb 2C5-modified dendrimer-based micelles for the co-delivery of siRNA and chemotherapeutic drug in xenograft mice model.

Combination therapy with small interfering RNA (siRNA) and chemotherapeutic drug is proven to be effective in downregulating cancer resistance proteins, such as P-glycoprotein (P-gp). These proteins are involved in multidrug resistance (MDR) of tumors. A targeted formulation capable of delivering siRNA and chemotherapeutic drug will not only downregulate P-gp but also increase the concentration of the chemotherapeutic drug at the site of tumor thereby increasing the therapeutic effect and lowering the systemic exposure. In this study, monoclonal antibody 2C5-modified dendrimer-based micelles were used to co-deliver siRNA and doxorubicin (DOX) to the tumor site in both male and female xenograft mouse model. The nucleosome-specific 2C5 antibody recognizes the cancer cells via the cell-surface bound nucleosomes. The ability of ability of the 2C5-modified formulation to affect the metastasis of highly aggressive triple negative breast cancer cell migration in (MDA-MB-231) was assessed by a wound healing. Further, the therapeutic efficacy of the formulation was assessed by measuring the tumor volume progression in which the 2C5-modified nanoparticle group had a similar tumor volume to the free drug group at the end of the study, although a 50% increase in DOX concentrations in blood was observed after the last dose of nanoparticle. The free drug group on the other hand showed body weight reduction as well as the visible irritation around the injection spot. The treatment group with 2C5-modified micelles has shown to be safe at the current dose of DOX and siRNA. Furthermore, the siRNA mediated P-gp downregualtion was studied using western blotting assay. We observed a 29% reduction of P-gp levels in both males and females with respect to the control (BHG). We also conclude that the dose of DOX and siRNA should be further optimized to have a better efficacy in a metastatic tumor model, which will be the subject of our future studies.

Role and Therapeutic Targeting Strategies of Neutrophil Extracellular Traps in Inflammation.

Neutrophil extracellular traps (NETs) are large DNA reticular structures secreted by neutrophils and decorated with histones and antimicrobial proteins. As a key mechanism for neutrophils to resist microbial invasion, NETs play an important role in the killing of microorganisms (bacteria, fungi, and viruses). Although NETs are mostly known for mediating microbial killing, increasing evidence suggests that excessive NETs induced by stimulation of physical and chemical components, microorganisms, and pathological factors can exacerbate inflammation and organ damage. This review summarizes the induction and role of NETs in inflammation and focuses on the strategies of inhibiting NETosis and the mechanisms involved in pathogen evasion of NETs. Furthermore, herbal medicine inhibitors and nanodelivery strategies improve the efficiency of inhibition of excessive levels of NETs.

Recent Advances with Precision Medicine Treatment for Breast Cancer including Triple-Negative Sub-Type.

Breast cancer is a heterogeneous disease with different molecular subtypes. Breast cancer is the second leading cause of mortality in woman due to rapid metastasis and disease recurrence. Precision medicine remains an essential source to lower the off-target toxicities of chemotherapeutic agents and maximize the patient benefits. This is a crucial approach for a more effective treatment and prevention of disease. Precision-medicine methods are based on the selection of suitable biomarkers to envision the effectiveness of targeted therapy in a specific group of patients. Several druggable mutations have been identified in breast cancer patients. Current improvements in omics technologies have focused on more precise strategies for precision therapy. The development of next-generation sequencing technologies has raised hopes for precision-medicine treatment strategies in breast cancer (BC) and triple-negative breast cancer (TNBC). Targeted therapies utilizing immune checkpoint inhibitors (ICIs), epidermal growth factor receptor inhibitor (EGFRi), poly(ADP-ribose) polymerase inhibitor (PARPi), antibody-drug conjugates (ADCs), oncolytic viruses (OVs), glucose transporter-1 inhibitor (GLUT1i), and targeting signaling pathways are potential treatment approaches for BC and TNBC. This review emphasizes the recent progress made with the precision-medicine therapy of metastatic breast cancer and TNBC.

Mechanisms of Resistance and Current Treatment Options for Glioblastoma Multiforme (GBM).

Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer that is difficult to treat due to its resistance to both radiation and chemotherapy. This resistance is largely due to the unique biology of GBM cells, which can evade the effects of conventional treatments through mechanisms such as increased resistance to cell death and rapid regeneration of cancerous cells. Additionally, the blood-brain barrier makes it difficult for chemotherapy drugs to reach GBM cells, leading to reduced effectiveness. Despite these challenges, there are several treatment options available for GBM. The standard of care for newly diagnosed GBM patients involves surgical resection followed by concurrent chemoradiotherapy and adjuvant chemotherapy. Emerging treatments include immunotherapy, such as checkpoint inhibitors, and targeted therapies, such as bevacizumab, that attempt to attack specific vulnerabilities in GBM cells. Another promising approach is the use of tumor-treating fields, a type of electric field therapy that has been shown to slow the growth of GBM cells. Clinical trials are ongoing to evaluate the safety and efficacy of these and other innovative treatments for GBM, intending to improve with outcomes for patients.

Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis.

The innovative development of nanomedicine has promised effective treatment options compared to the standard therapeutics for cancer therapy. However, the efficiency of EPR-targeted nanodrugs is not always pleasing as it is strongly prejudiced by the heterogeneity of the enhanced permeability and retention effect (EPR). Targeting the dynamics of the EPR effect and improvement of the therapeutic effects of nanotherapeutics by using EPR enhancers is a vital approach to developing cancer therapy. Inadequate data on the efficacy of EPR in humans hampers the clinical translation of cancer drugs. Molecular targeting, physical amendment, or physiological renovation of the tumor microenvironment (TME) are crucial approaches for improving the EPR effect. Advanced imaging technologies for the visualization of EPR-induced nanomedicine distribution in tumors, and the use of better animal models, are necessary to enhance the EPR effect. This review discusses strategies to enhance EPR effect-based drug delivery approaches for cancer therapy and imaging technologies for the diagnosis of EPR effects. The effort of studying the EPR effect is beneficial, as some of the advanced nanomedicine-based EPR-enhancing approaches are currently undergoing clinical trials, which may be helpful to improve EPR-induced drug delivery and translation to clinics.

Role of circular RNA and its delivery strategies to cancer - An overview.

With the passage of years and the progress of research on ribonucleic acids, the range of forms in which these molecules have been observed grows. One of them, discovered relatively recently, is circular RNA - covalently closed circles (circRNA). In recent years, there has been a huge increase in the interest of researchers in this group of molecules. It entailed a significant increase in the state of knowledge about them, which in turn caused a dramatic change in their perception. Rather than seeing circular RNAs as curiosities that represent a minor information noise in a cell or a result of RNA misprocessing, they came to be regarded as a common, essential, and potentially extremely useful group of molecules. Nevertheless, the current state of the art of circRNA is full of white cards. A lot of valuable information has been obtained from high-throughput methods to study whole transcriptomes, but many issues related to circular RNAs still need to be clarified. Presumably, each answer obtained will raise several new questions. However, circRNAs have a wealth of potential applications, including therapeutic applications.

Co-Encapsulation of Drugs for Topical Application-A Review.

Achieving the best possible outcome for the therapy is the main goal of a medicine. Therefore, nanocarriers and co-delivery strategies were invented to meet this need, as they can benefit many diseases. This approach was applied specifically for cancer treatment, with some success. However, these strategies may benefit many other clinical issues. Skin is the largest and most exposed organ of the human body, with physiological and psychological properties. Due to its exposition and importance, it is not difficult to understand how many skin diseases may impact on patients' lives, representing an important burden for society. Thus, this review aims to summarize the state of the art in research concerning nanocarriers and co-delivery strategies for topical agents' applications targeting skin diseases. The challenge for the medicine of the future is to deliver the drug with spatial and temporal control. Therefore, the co-encapsulation of drugs and the appropriate form of administration for them are so important and remain as unmet needs.

Antibody-modified DNase I micelles specifically recognize the neutrophil extracellular traps (NETs) and promote their degradation.

Neutrophil extracellular traps (NETs) are structures consisting of decondensed chromatin with associated proteins, including histones and antimicrobial peptides, released from activated neutrophils. They are believed to be one of the body's first lines of defense against infectious agents. Despite their beneficial effect on the immune response process, some studies indicate that their excessive formation and the associated accumulation of extracellular DNA (eDNA) together with other polyelectrolytes (F-actin) plays an important role in the pathogenesis of many diseases. Thus NETs formation and removal are clinically significant. The monoclonal antibody 2C5 has strong specificity for intact nucleohistones (NS) and targets NS in NETs as we previously confirmed. Creation of a nano preparation that can specifically recognize and destroy NETs represents the aim for treatment many diseases. 2C5 antibody functionalized micelles coated with DNase I were created to achieve this aim.

Evaluation of mAb 2C5-modified dendrimer-based micelles for the co-delivery of siRNA and chemotherapeutic drug in xenograft mice model.

A combination therapy with small interfering RNA (siRNA) and chemotherapeutic drug is proven to be effective in downregulating the cancer resistance proteins, such as P-glycoprotein (P-gp). These proteins are involved in multidrug resistance (MDR) of tumors. MDR lowers the efficacy of chemotherapy and even renders it ineffective. A possible strategy to counteract the resistance is by downregulating the resistance proteins using siRNA. A targeted formulation capable of delivering siRNA and chemotherapeutic drug will not only downregulate P-gp but also increase the concentration of the chemotherapeutic drug at the site of tumor thereby increasing the therapeutic effect and lowering the systemic exposure. In this study, monoclonal antibody 2C5-modified dendrimer-based micelles were used to co-deliver siRNA and doxorubicin (DOX) to the tumor site in both male and female xenograft mice model. The nucleosome-specific 2C5 antibody recognizes the cancer cells via the cell-surface bound nucleosomes. The ability of the 2C5-modified formulation in affecting the metastasis of highly aggressive triple negative breast cancer (MDA-MB-231) was assessed via wound healing assay where the 2C5-modified formulation halved the rate at which the cells were migrating. Further, the therapeutic efficacy of the formulation was assessed by measuring the tumor volume progression where the 2C5-modified nanoparticle group had a similar tumor volume to the free drug group at the end of the study, although a 50% increase in DOX concentrations in blood was observed after the last dose of nanoparticle. Despite a higher DOX concentration and residence time we did not observe any systemic toxicities in the nanoparticle groups. The free drug group on the other hand showed body weight reduction as well as the visible irritation around the injection spot. The treatment group with 2C5-modified micelles has shown to be safe at the current dose of DOX and siRNA.The ability of 2C5 antibody-functionalized nanoparticles in delivering cargo to the tumor site in vivo was evaluated for DOX using ex vivo imaging and siRNA by western blot study to evaluate the levels of P-gp. Furthermore, the siRNA mediated P-gp downregualtion was studied using western blotting assay. We observed a 29% reduction of P-gp levels in both males and females with respect to the control (BHG). We also conclude that the dose of DOX and siRNA should be further optimized to have a better efficacy in a metastatic tumor model, which will be the subject of our future studies.

Co-Delivery of siRNA and Chemotherapeutic Drug Using 2C5 Antibody-Targeted Dendrimer-Based Mixed Micelles for Multidrug Resistant Cancers.

Multidrug resistance (MDR) observed in tumors significantly hinders the efficacy of chemotherapy. Downregulation of efflux proteins, such as P-glycoprotein (P-gp), using small interfering RNA (siRNA) can be an effective way to minimize the resistance in tumors. In this study, monoclonal antibody 2C5 (mAb 2C5)-PEG7k-DOPE conjugates were post-inserted into the mixed dendrimer micelles containing generation 4 (G4) polyamidoamine (PAMAM)-PEG2k-DOPE and PEG5k-DOPE. The inherent amphiphilic nature of DOPE conjugates causes the copolymers to self-assemble to form a micelle, which can encapsulate hydrophobic chemotherapeutic drugs in its core. The siRNA electrostatically binds to the cationic charges on the G4 PAMAM dendrimer. The tumor-specific mAb 2C5 on the surface of these nano-preparations resulted in improved tumor targeting. This active targeting to tumors can cause increase in the drug and siRNA accumulation at the tumor site, and thereby minimizing the off-target effects. The micelles were shown to have higher cellular association and effectiveness in vitro. The immunomicelle preparation was also tested for cytotoxicity in breast (MDA-MB-231) and ovarian (SKOV-3TR) MDR cancer cell lines.

Liposomal Co-delivery of PD-L1 siRNA/Anemoside B4 for Enhanced Combinational Immunotherapeutic Effect.

Combination therapy has gained a lot of attention thanks to its superior activity against cancer. In the present study, we report a cRGD-targeted liposomal preparation for co-delivery of programmed cell death ligand 1 (PD-L1) small interfering RNA (siRNA) and anemoside B4 (AB4)─AB4/siP-c-L─and evaluate its anticancer efficiency in mouse models of LLC and 4T1 tumors. AB4/siP-c-L showed a particle size of (180.7 ± 7.3) nm and a ζ-potential of (32.8 ± 1.5) mV, with high drug encapsulation, pH-sensitive release properties, and good stability in serum. AB4/siP-c-L demonstrated prolonged blood circulation and increased tumor accumulation. Elevated cellular uptake was dependent on the targeting ligand cRGD. This combination induced significant tumor inhibition in LLC xenograft tumor-bearing mice by downregulating PD-L1 protein expression and modulating the immunosuppressive microenvironment. Liposomes favored the antitumor T-cell response with long-term memory, without obvious toxicity. A similar tumor growth inhibition was also demonstrated in the 4T1 tumor model. In summary, our results indicate that cRGD-modified and AB4- and PD-L1 siRNA-coloaded liposomes have potential as an antitumor preparation, and this approach may lay a foundation for the development of a new targeted drug delivery system.

Nano Silver-Induced Toxicity and Associated Mechanisms.

Nano silver is one of the most widely used engineering nanomaterials with antimicrobial activity against bacteria, fungi, and viruses. However, the widespread application of nano silver preparations in daily life raises concerns about public health. Although several review articles have described the toxicity of nano silver to specific major organs, an updated comprehensive review that clearly and systematically outlines the harmful effects of nano silver is lacking. This review begins with the routes of exposure to nano silver and its distribution in vivo. The toxic reactions are then discussed on three levels, from the organ to the cellular and subcellular levels. This review also provides new insights on adjusting the toxicity of nano silver by changing their size and surface functionalization and their combination with other materials to form a composite formulation. Finally, future development, challenges, and research directions are discussed.

Lipid-Based Drug Delivery Systems in Regenerative Medicine.

The most important goal of regenerative medicine is to repair, restore, and regenerate tissues and organs that have been damaged as a result of an injury, congenital defect or disease, as well as reversing the aging process of the body by utilizing its natural healing potential. Regenerative medicine utilizes products of cell therapy, as well as biomedical or tissue engineering, and is a huge field for development. In regenerative medicine, stem cells and growth factor are mainly used; thus, innovative drug delivery technologies are being studied for improved delivery. Drug delivery systems offer the protection of therapeutic proteins and peptides against proteolytic degradation where controlled delivery is achievable. Similarly, the delivery systems in combination with stem cells offer improvement of cell survival, differentiation, and engraftment. The present review summarizes the significance of biomaterials in tissue engineering and the importance of colloidal drug delivery systems in providing cells with a local environment that enables them to proliferate and differentiate efficiently, resulting in successful tissue regeneration.

Recent Advances in Tumor Targeting via EPR Effect for Cancer Treatment.

Cancer causes the second-highest rate of death world-wide. A major shortcoming inherent in most of anticancer drugs is their lack of tumor selectivity. Nanodrugs for cancer therapy administered intravenously escape renal clearance, are unable to penetrate through tight endothelial junctions of normal blood vessels and remain at a high level in plasma. Over time, the concentration of nanodrugs builds up in tumors due to the EPR effect, reaching several times higher than that of plasma due to the lack of lymphatic drainage. This review will address in detail the progress and prospects of tumor-targeting via EPR effect for cancer therapy.

Developments in Treatment Methodologies Using Dendrimers for Infectious Diseases.

Dendrimers comprise a specific group of macromolecules, which combine structural properties of both single molecules and long expanded polymers. The three-dimensional form of dendrimers and the extensive possibilities for use of additional substrates for their construction creates a multivalent potential and a wide possibility for medical, diagnostic and environmental purposes. Depending on their composition and structure, dendrimers have been of interest in many fields of science, ranging from chemistry, biotechnology to biochemical applications. These compounds have found wide application from the production of catalysts for their use as antibacterial, antifungal and antiviral agents. Of particular interest are peptide dendrimers as a medium for transport of therapeutic substances: synthetic vaccines against parasites, bacteria and viruses, contrast agents used in MRI, antibodies and genetic material. This review focuses on the description of the current classes of dendrimers, the methodology for their synthesis and briefly drawbacks of their properties and their use as potential therapies against infectious diseases.

Self-Assembled Dual-Targeted Epirubicin-Hybrid Polydopamine Nanoparticles for Combined Chemo-Photothermal Therapy of Triple-Negative Breast Cancer.

PURPOSE: Folic acid and cyclic arginylglycylaspartic acid peptides were introduced to the surface of negatively charged lipid-coated hybrid polydopamine-cysteine cores for the delivery of epirubicin (EPI) (E/PCF-NPs). The combined chemo-photothermal therapy using E/PCF-NPs for triple-negative breast cancer was evaluated. MATERIALS AND METHODS: The temperature elevation and thermal toxicity of nanoparticles were studied. The morphology and properties of E/PCF-NPs were characterized by transmission electron microscopy, scanning electron microscopy, and atomic force microscopy. Physicochemical properties, including particle size, zeta potential, drug loading, entrapment efficiency (EE%), stability and in vitro release, were determined. The cell viability, reactive oxygen species (ROS) levels, ratios of oxidized nicotinamide adenine dinucleotide to its reduced form (NAD+/NADH), apoptosis assays, and cellular uptake of E/PCF-NPs were determined on 4T1 cells. Pharmacokinetic studies and tissue distributions were performed and detected by an ultra-high performance liquid chromatography/mass spectrometry system. The antitumor effects of E/PCF-NPs under near-infrared (NIR) laser irradiation were also evaluated. RESULTS: The sphere-like morphology of E/PCF-NPs showed a high EE%, uniform size of 106.7 nm, remarkable stability, and highly improved cytotoxicity under NIR laser, when compared to that of photothermal treatment alone. In vitro release of EPI from E/PCF-NPs was pH sensitive, and a greater response was achieved under NIR laser irradiation. Compared to chemotherapy or photothermal treatment alone, the combined treatment in vitro significantly inhibited the survival rate of 4T1 cells to 17.7%, induced ROS generation, and reduced NAD+/NADH significantly. Treatment with E/PCF-NPs under irradiation induced 4T1 cell apoptosis in approximately 93.6% cells. In vitro cellular uptake of E/PCF-NPs was time-dependent. The long-circulating and higher tumor accumulation of E/PCF-NPs resulted in complete ablation of breast tumor tissue through the enhanced photothermal effect by NIR laser irradiation-mediated cell apoptosis. CONCLUSION: E/PCF-NPs show enhanced anti-cancer effects due to synergistic effects of chemotherapy with photothermal therapy and may be potential therapeutic agents for cancer treatment.

Recent advancements in liposome technology.

The liposomes have continued to be well-recognized as an important nano-sized drug delivery system with attractive properties, such a characteristic bilayer structure assembling the cellular membrane, easy-to-prepare and high bio-compatibility. Extensive effort has been devoted to the development of liposome-based drug delivery systems during the past few decades. Many drug candidates have been encapsulated in liposomes and investigated for reduced toxicity and extended duration of therapeutic effect. The liposomal encapsulation of hydrophilic and hydrophobic small molecule therapeutics as well as other large molecule biologics have been established among different academic and industrial research groups. To date, there has been an increasing number of FDA-approved liposomal-based therapeutics together with more and more undergoing clinical trials, which involve a wide range of applications in anticancer, antibacterial, and antiviral therapies. In order to meet the continuing demand for new drugs in clinics, more recent advancements have been investigated for optimizing liposomal-based drug delivery system with more reproducible preparation technique and a broadened application to novel modalities, including nucleic acid therapies, CRISPR/Cas9 therapies and immunotherapies. This review focuses on the recent liposome' preparation techniques, the excipients of liposomal formulations used in various novel studies and the routes of administration used to deliver liposomes to targeted areas of disease. It aims to update the research in liposomal delivery and highlights future nanotechnological approaches.