Delivery Of Chemotherapeutic Agents Research Articles

Naringin-Dextrin Nanocomposite Abates Diethylnitrosamine/Acetylaminofluorene-Induced Lung Carcinogenesis by Modulating Oxidative Stress, Inflammation, Apoptosis, and Cell Proliferation.

Nanotechnology has proven advantageous in numerous scientific applications, one being to enhance the delivery of chemotherapeutic agents. This present study aims to evaluate the mechanisms underlying the chemopreventive action of naringin-dextrin nanocomposites (Nar-Dx-NCs) against diethylnitrosamine (DEN)/2-acetylaminofluorene (2AAF)-induced lung carcinogenesis in male Wistar rats. DEN was administered intraperitoneally (i.p.) (150 mg/kg/week) for two weeks, followed by the oral administration of 2AAF (20 mg/kg) four times a week for three weeks. Rats receiving DEN/2AAF were concurrently treated with naringin or Nar-Dx-NCs orally at a dose of 10 mg/kg every other day for 24 weeks. Naringin and Nar-Dx-NCs treatments prevented the formation of tumorigenic cells within the alveoli of rats exposed to DEN/2AAF. These findings were associated with a significant decrease in lipid peroxidation, upregulation of antioxidant enzyme (glutathione peroxidase and superoxide dismutase) activity, and enhanced glutathione and nuclear factor erythroid 2-related factor 2 expression in the lungs. Naringin and Nar-Dx-NCs exerted anti-inflammatory actions manifested by a decrease in lung protein expression of tumor necrosis factor-α and interleukin-1β and mRNA expression of interleukin-6, interferon-γ, nuclear factor-κB, and inducible nitric oxide synthase, with a concurrent increase in interleukin-10 expression. The anti-inflammatory effect of Nar-Dx-NCs was more potent than naringin. Regarding the effect on apoptosis, both naringin and Nar-Dx-NCs significantly reduced Bcl-2 and increased Bax and P53 expressions. Moreover, naringin or Nar-Dx-NCs induced a significant decrease in the expression of the proliferator marker, Ki-67, and the effect of Nar-Dx-NCs was more marked. In conclusion, Nar-Dx-NCs improved naringin's preventive action against DEN/2AAF-induced lung cancer and exerted anticarcinogenic effects by suppressing oxidative stress and inflammation and improving apoptotic signal induction and propagation.

Waterborne polyurethane magnetic nanomicelles with magnetically governed functions for breast cancer therapy

Drug delivery strategies aim to maximize a drug's therapeutic efficiency by increasing the drug's concentration at the target site while minimizing delivery to off-target tissues. There is a great deal of interest in using magnetic nanoparticles in combination with applied magnetic fields to selectively control drug accumulation and release in target tissue while minimizing effects on other tissues. In this study, a magnetic targeted drug delivery system based on waterborne polyurethane nanomicelles was prepared by encapsulating hydrophobic doxorubicin (DOX, model drug) and hydrophobic oleic acid-superparamagnetic nanoparticles (SPION-OA) into the hydrophobic core of waterborne polyurethane micelles (CPUM) using the solvent evaporation method. The prepared drug-loaded magnetomicelles (CPUM-DOX-SPION) had a spherical shape with an average diameter of 158 nm. The magnetomicelles showed superparamagnetic properties with excellent magnetic resonance imaging (MRI) contrast effects and T2 relaxation in vitro. In the absence and presence of a magnetic field, the cytocompatibility and cellular uptake of the samples were assessed by MTT assay and flow cytometry, respectively, and the cells were imaged with a confocal microscope. Application of the magnetic field increased cellular cytotoxicity and cellular uptake in association with improved DOX delivery. In addition, the in vivo study of tumor volume showed that tumor growth of the mice group treated with CPUM-DOX-SPION in the presence of an external magnetic field was significantly retarded, with no apparent loss of body weight, compared with the same magnetomicelles in the absence of the magnetic field and with free DOX at the same dose. Moreover, the in vivo MRI experiment indicated the potential of these magnetomicelles as a probe in MRI diagnosis for tumor targeting, and the results showed that magnetically guided delivery of CPUM-SPION magnetomicelles into tumors could significantly improve the targeting efficacy. All the results suggest that the prepared novel magnetomicelles will be promising theranostic systems for effective magnetically guided delivery of chemotherapeutic agents and image-guided personalized medicine.

The safety and utility of low-intensity pulsed ultrasound for effective blood–brain barrier penetration in the treatment of glioblastoma: a scoping review protocol

Abstract Glioblastoma (GBM) is one of the most aggressive central nervous system tumours with suboptimal treatment options and associated poor prognosis. A major impediment to systemic treatment is the limitation of drug delivery to the tumour by the blood-brain barrier (BBB). Several novel techniques to permeate the BBB have been described, however of significant promise is the disruption of the blood brain barrier with low-intensity pulsed ultrasound (LIPU) to facilitate the delivery of varying therapeutic agents. This emerging technique has been demonstrated in clinical studies to enhance delivery of chemotherapeutic agents to the tumour. This study protocol seeks to guide the comprehensive review of literature concerning the safety and utility of LIPU for effective BBB penetration in the treatment of GBM. This protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews (PRISMA ScR) guideline 2020. The search strategy was performed on four databases: PubMed, EMBASE, SCOPUS, and Cochrane Central Register of Controlled Trials. All observational and human randomised controlled studies describing the use of LIPU in the treatment of GBM will be included. Excluded studies include non-human randomized control trials, abstract only articles, letters to the editor, conference proceedings. Our outcomes include frequency of LIPU used, duration of intervention, clinical outcomes, complications, and challenges associated with the use of LIPU. This study aims to assess the safety and feasibility of this technique in the management of the GBM and proscribe its use if found effective to improve the outcomes in these patients.

Functionalized and Nonfunctionalized Nanosystems for Mitochondrial Drug Delivery with Metallic Nanoparticles.

Background: The application of metallic nanoparticles as a novel therapeutic tool has significant potential to facilitate the treatment and diagnosis of mitochondria-based disorders. Recently, subcellular mitochondria have been trialed to cure pathologies that depend on their dysfunction. Nanoparticles made from metals and their oxides (including gold, iron, silver, platinum, zinc oxide, and titanium dioxide) have unique modi operandi that can competently rectify mitochondrial disorders. Materials: This review presents insight into the recent research reports on exposure to a myriad of metallic nanoparticles that can alter the dynamic ultrastructure of mitochondria (via altering metabolic homeostasis), as well as pause ATP production, and trigger oxidative stress. The facts and figures have been compiled from more than a hundred PubMed, Web of Science, and Scopus indexed articles that describe the essential functions of mitochondria for the management of human diseases. Result: Nanoengineered metals and their oxide nanoparticles are targeted at the mitochondrial architecture that partakes in the management of a myriad of health issues, including different cancers. These nanosystems not only act as antioxidants but are also fabricated for the delivery of chemotherapeutic agents. However, the biocompatibility, safety, and efficacy of using metal nanoparticles is contested among researchers, which will be discussed further in this review.

Lipid-based nanoparticle-mediated combination therapy for breast cancer management: a comprehensive review.

Breast cancer due to the unpredictable and complex etiopathology combined with the non-availability of any effective drug treatment has become the major root of concern for oncologists globally. The number of women affected by the said disease state is increasing at an alarming rate attributed to environmental and lifestyle changes indicating at the exploration of a novel treatment strategy that can eradicate this aggressive disease. So far, it is treated by promising nanomedicine monotherapy; however, according to the numerous studies conducted, the inadequacy of these nano monotherapies in terms of elevated toxicity and resistance has been reported. This review, therefore, puts forth a new multimodal strategic approach to lipid-based nanoparticle-mediated combination drug delivery in breast cancer, emphasizing the recent advancements. A basic overview about the combination therapy and its index is firstly given. Then, the various nano-based combinations of chemotherapeutics involving the combination delivery of synthetic and herbal agents are discussed along with their examples. Further, the recent exploration of chemotherapeutics co-delivery with small interfering RNA (siRNA) agents has also been explained herein. Finally, a section providing a brief description of the delivery of chemotherapeutic agents with monoclonal antibodies (mAbs) has been presented. From this review, we aim to provide the researchers with deep insight into the novel and much more effective combinational lipid-based nanoparticle-mediated nanomedicines tailored specifically for breast cancer treatment resulting in synergism, enhanced antitumor efficacy, and low toxic effects, subsequently overcoming the hurdles associated with conventional chemotherapy.

SLN Mediate Active Delivery of Gefitinib into A549 Cell Line: Optimization, Biosafety and Cytotoxicity Studies

Background: Conventional administration of chemotherapeutic agents associated with low drug distribution to cancer cells with multiple systemic toxicities. Thus, enhancing the active delivery of chemotherapeutic agents to cancer cells increases drug distribution and internalization to targeted cells with minimal systemic toxicities. Objective and Aim: The current study was designed to prepare and optimize solid lipid nanoparti-cles (SLN) containing stearic acid (SA) that mediate active delivery and uptake of gefitinib (GEF) to cancer cells. Methods: The stability of the prepared Plain-SLN formulations was characterized for 90 days. The most stable formulations were loaded with GEF (GEF-SLN) and subjected to pharmaceutical char-acterization. In-vitro dissolution of GEF-SLN formulations was studied using the dialysis method. Biosafety in the terms of hemocompatibility was investigated using fresh blood samples. Addition-ally, the cytotoxicity of GEF-SLN was examined against the lung cancer cell line (A549). Results: The obtained results showed that the prepared formulations fall in the nanosize range from 114 to 411 nm with a negative zeta-potential value from -17 to -27 mV. The particle size of Plain-SLN formulations was increased when the GEF is incorporated during preparation. Besides, the crystallinity of SA was disordered following the incorporation of GEF. In addition, GEF entrapment efficiency into SLN was 88% with a sustained-release profile of about 75% in 24 h. Additionally, the present results revealed that using surfactants with high drug solubility negatively impacts the stability of SLN formulation. Furthermore, hemocompatibility results revealed that all SLN formu-lations showed insignificant hemolysis (1- 4%) at all concentrations. Moreover, cytotoxicity exami-nations revealed that SLN enhanced the antiprofilated activity of GEF compared to free GEF. Conclusion: These data concluded that SLN is a hopeful approach to enhancing the selective depo-sition of GEF into cancer cells and reducing the lymphatic metastasis of lung cancer.

Design and application of prodrug fluorescent probes for the detection of ovarian cancer cells and release of anticancer drug

Ovarian cancer is a gynecologic malignancy with high mortality. The main reason is that it is detected at an advanced stage due to a lack of early diagnosis and treatment. Therefore, it is of great interest to develop a chemical tool that can visualize ovarian cancer cells in real-time and eliminate them. Unfortunately, probes that can simultaneously monitor both modes of action for the diagnosis and treatment of ovarian cancer have not been developed. Here, we designed a novel prodrug fluorescent probe (YW-OAc) that not only visually tracks cancer cells but also enables the on-demand delivery of chemotherapeutic agents. By β-Gal-mediated glycosidic bond hydrolysis, the fluorescent signal changed from blue to green (signal 1), enabling visual tracking of ovarian cancer cells. Subsequently, the identified cancer cells were subjected to precise light irradiation to induce anticancer drug release accompanied by a fluorescence transition from green to blue (signal 2), enabling real-time information on drug release. Thus, the prodrug fluorescent probe YW-OAc provides comprehensive two-step monitoring during cancer cell recognition and clearance. Notably, YW-OAc exhibited high affinity (Km = 3.74 μM), high selectivity, and low detection limit for β-Gal (0.0035 U/mL). We also demonstrated that YW-OAc can visually trace endogenous β-Gal in different cells and exhibit high phototoxicity in ovarian cancer cells. We hope that the prodrug fluorescent probe YW-OAc, can be used as an effective tool for biomedical diagnosis and treatment.

A comparative study between two methods of delivery of chemotherapeutic agent in patients with bone and soft tissue sarcoma of lower extremity

BackgroundWe aimed to compare the effects of peripherally inserted central catheters (PICC) and implantable venous access devices (TIVADs) in terms of complications and shoulder function in patients with malignant bone and soft tissue tumors of the lower extremities.MethodsWe analyzed 65 cases of TIVADs (chest wall) and 65 cases of PICC at the orthopedic department of the Fourth Hospital of Hebei Medical University between June 2019 and December 2021, which were diagnosed with malignant bone tumors or soft tissue tumors of the lower extremities (tumors had to be relatively sensitive to chemotherapy), received regular chemotherapy, with ≥ 14 cycles (42 weeks). The two groups were compared in terms of catheter indwelling time, catheter-related complications, Constant-Murley shoulder function score, and displacement of the position of the catheter end on the catheterization side.ResultsCompared to the PICC group, at six months after catheterization, the TIVADs group reported better outcomes for catheter indwelling time, catheter-related complications, and Constant-Murley score for the catheterization-side shoulder joint (p < 0.05). The TIVADs group also reported less displacement of the catheter end position after 180° abduction of the catheterization-side shoulder joint (p < 0.05).ConclusionsCompared with PICC, TIVADs can prolong catheter indwelling time, reduce catheter-related complications, and maintain shoulder joint function, which makes it an ideal venous-access approach when providing chemotherapy to patients with malignant bone and soft tissue tumors of the lower extremities.

Design and Synthesis of Biodegradable Polymeric Nanoparticles for Targeted Delivery of Chemotherapeutics in Triple-Negative Breast Cancer

Type three breast cancer (TNBC) is a highly aggressive form of breast cancer that lacks targeted therapies, leading to poor prognosis and limited therapeutic options The development of biodegradable polymeric nanoparticles (NPs) provides find a promising strategy for targeted delivery of chemotherapeutic drugs to reduce systemic toxicity , enhancing therapeutic efficacy This review focuses on the design and synthesis of biodegradable polymeric nanoparticles for targeted delivery of chemotherapeutic agents in TNBC. Polymeric nanoparticles were synthesized from biocompatible and biodegradable materials, ensuring safe degradation and excretion from the body. Nanoparticles are engineered to encapsulate and release therapeutics in a controlled manner, specifically targeting TNBC cells. Surface modification of nanoparticles with targeting ligands is used to enhance selective binding of TNBC cell receptors, improve drug delivery efficiency, and reduce off-target effects Dynamic light scattering (DLS), scanning to evaluate physicochemical properties, morphology, and drug release profiles a synthesized nanoparticles Microscopic examination (SEM). ), characterization methods including drug excretion testing were used. In vitro and in vivo studies demonstrated increased cellular uptake, targeted drug delivery, and significant cytotoxicity of nanoparticles against TNBC cells, with decreased toxicity to possessing cells healthy The findings suggest that biodegradable polymeric nanoparticles have great potential as targeted therapeutic platforms for TNBC provide. Further optimization and clinical studies are needed to translate this approach into viable treatments for patients with TNBC.

Gene Reprogramming Armed Macrophage Membrane-Camouflaged Nanoplatform Enhances Bionic Targeted Drug Delivery to Solid Tumor for Synergistic Therapy.

Efficient drug delivery to solid tumors remains a challenge. HER2-positive (HER2+) tumors are an aggressive cancer subtype with a resistance to therapy, high risk of relapse, and poor prognosis. Although nanomedicine technology shows obvious advantages in tumor treatment, its potential clinical translation is still impeded by the unsatisfactory delivery and therapeutic efficacy. In this study, a gene reprogramming macrophage membrane-encapsulated drug-loading nanoplatform was developed for HER2+ cancer therapy based on the co-assembly of poly (lactic-co-glycolic acid) (PLGA) nanoparticles and engineered modified macrophage membranes. In this nanoplatform, near-infrared (NIR) fluorescent dye ICG or chemotherapeutic drug doxorubicin (DOX) was loaded into the PLGA cores, and an anti-HER2 affibody was stably expressed on the membrane of macrophages. In comparison to the nanoparticles with conventional macrophage membrane coating, the ICG/DOX@AMNP nanoparticles armed with anti-HER2 affibody showed excellent HER2-targeting ability both in vitro and in vivo. Small animal imaging studies confirmed the improved pharmacokinetics of drug delivery and specific distribution of the ICG/DOX@AMNPs in HER2+ tumors. Mechanistically, compared with DOX@NPs or DOX@MNPs nanoparticles, DOX@AMNPs exhibited synergistic inhibition of HER2+ cancer cells or mice tumor growth by inducing apoptosis and blocking the PI3K/AKT signaling pathway. Altogether, this study proposes a promising biomimetic nanoplatform for the efficient targeted delivery of chemotherapeutic agents to HER2+ tumors, demonstrating its great potential for solid tumor therapy.

Chemotherapy-Sensitized In Situ Vaccination for Malignant Osteosarcoma Enabled by Bioinspired Calcium Phosphonate Nanoagents.

How to effectively treat malignant osteosarcoma remains clinically challenging. Programmed delivery of chemotherapeutic agents and immunostimulants may offer a universal strategy for killing osteosarcoma cells while simultaneously eliciting in situ antitumor immunity. However, targeted chemoimmunotherapy lacks a reliable delivery system. To address this issue, we herein developed a bioinspired calcium phosphonate nanoagent that was synthesized by chemical reactions between Ca2+ and phosphonate residue from zoledronic acid using bovine serum albumin as a scaffold. In addition, methotrexate combination with a phosphorothioate CpG immunomodulator was also loaded for pH-responsive delivery to enable synergistic chemoimmunotherapy of osteosarcoma. The calcium phosphonate nanoagents were found to effectively accumulate in osteosarcoma for nearly 1 week, which is favorable for exerting the vaccination effects in situ by maturing dendritic cells and priming CD8+ T cells to suppress the osteosarcoma progression and pulmonary metastasis through controlled release of the three loaded agents in the acidic tumor microenvironment. The current study may thus offer a reliable delivery platform for achieving targeted chemotherapy-induced in situ antitumor immunity.

Preparation of Magnetic Iron Oxide Incorporated Mesoporous Silica Hybrid Composites for pH and Temperature-Sensitive Drug Delivery

In clinical applications for cancer treatment, chemotherapy coupled with thermotherapy is highly considered. The development of multifunctional nanocomposite materials is an appealing strategy for use in various applications including biomedical applications. We present the preparation of dopamine-modified mesoporous silica material, in which magnetic iron oxide nanoparticles (FeNP) were grown onto the outer surface via the complexation of iron (Fe(III) and Fe(II)) ions with the dopamine groups modified on the silica hybrid and subsequent chemical reduction approaches. The prepared magnetic iron oxide incorporated with mesoporous silica hybrid composite nanoparticles (FeNP@MSHC NPs) had a large surface area (346 m2/g), pore size (3.2 nm), and pore volume (0.048 cm3/g). The formation of FeNP on the outer surface of the FeNP@MSHC NPs results in superparamagnetic characteristics. Furthermore, the prepared FeNP@MSHC NPs have a high drug (Dox) loading capacity (~62%) as well as pH- and temperature-responsive drug release efficiency. In addition, the MTT assay result shows the biocompatibility of the prepared FeNP@MSHC NPs. As a result, the FeNP@MSHC NPs could be utilized in cancer treatment for pH and temperature-sensitive delivery of chemotherapeutic agents to the target sites.

Engineered bacteria combined with doxorubicin nanoparticles suppress angiogenesis and metastasis in murine melanoma models.

Methods capable of distributing antitumour therapeutics uniformly throughout an entire tumour and that can suppress metastasis at the same time, would be of great significance in improving cancer treatment. Bacteria-mediated synergistic therapies have been explored for better specificity, temporal and spatial controllability, as well for providing regulation of the immune microenvironment, in order to provide improved cancer treatment. To achieve this goal, here we developed an engineered bacteria delivery system (GDOX@HSEc) using synthetic biology and interfacial chemistry technologies. The engineered bacteria were concurrently modified to express heparin sulfatase 1 (HSulf-1) inside (HSEc), to attach doxorubicin-loaded glycogen nanoparticles (GDOX NPs) on their surface. Here we demonstrate that HSEc can actively target and colonise tumour sites resulting in HSulf-1 overexpression, thereby suppressing angiogenesis and metastasis. Simultaneously, the GDOX NPs were able to penetrate into tumour cells, leading to intracellular DNA damage. Our results confirmed that a combination of biotherapy and chemotherapy using GDOX@HSEc resulted in significant melanoma suppression in murine models, with reduced side effects. This study provides a powerful platform for the simultaneous delivery of biomacromolecules and chemotherapeutic drugs to tumours, representing an innovative strategy potentially more effective in treating solid tumours. STATEMENT OF SIGNIFICANCE: An original engineered bacteria-based system (GDOX@HSEc) was developed using synthetic biology and interfacial chemistry technologies to concurrently produce naturally occurring heparin sulfatase 1 (HSulf-1) inside and anchor doxorubicin-loaded glycogen nanoparticles on the surface. GDOX@HSEc allowed for combined local delivery of chemotherapeutic agents along with the enzymes and immunostimulatory bacterial adjuvants, which resulted in a synergistic action in the inhibition of tumour growth and metastasis. The study provides a potential therapeutic approach that allows therapeutic agents to be distributed in a spatiotemporally controllable manner in tumours for combinatorial enhanced therapy.

Hybrid Quantum Dot as Promising Tools for Theranostic Application in Cancer

Cancer is one of the leading causes of death worldwide. In the last few decades, cancer treatment has come a long way, but multidrug resistance (MDR) in cancer still has low survival rates. It means that much research is required for an accurate diagnosis and effective therapy. The new era of cancer research could include theranostic approaches and targeted delivery of chemotherapeutic agents utilizing the nanoparticulate system. Recently, there has been much interest gained among researchers for carbon-based and graphene-based quantum dots due to their higher biocompatibility and ease of biofunctionalization compared to conventional heavy metal quantum dots. Moreover, these quantum dots have various interesting utilities, including bioimaging, biosensing, quantum dots-mediated drug delivery, and their role in photodynamic therapy (PDT) and photothermal therapy (PTT). The current review highlighted the utility of hybrid quantum dots as a theranostic system in different cancers and discussed the various bio-molecules conjugated hybrid quantum dots investigated for diagnostic/therapeutic applications in cancer. The influence of conjugation of different biomolecules, such as folic acid, PEG, etc., with hybrid quantum dots on their biopharmaceutical attributes (such as aqueous solubility, tumor penetrability, stability of loaded therapeutics in the tumor microenvironment), delivery of drugs specifically to tumor tissues, and its therapeutic outcome in different cancer has also been discussed.

Complications of Transcatheter Arterial Chemoembolization for Treatment of Primary Liver Cancer

AbstractTranscatheter arterial chemoembolization (TACE) is the standard practice in treating both primary and metastatic liver neoplasms. TACE is a practical, minimally invasive procedure involving the delivery of chemotherapeutic agents into the artery supplying a tumor while simultaneously embolizing its blood supply. This approach can be used for curative and palliative intent across multiple cancer types. Historically, TACE has been instrumental in the treatment algorithms for hepatocellular carcinoma, allowing patients with unresectable disease to be downstaged and to slow disease progression, affording opportunities for transplantation and increased survival. Although benefits of TACE include lower morbidity and mortality versus systemic chemotherapy and surgical approaches, the procedure has risks and complications. Interventional radiologists and physicians involved in the care of these patients should be aware of the associated complications including avoidance and treatment strategies.

Folic acid functionalized carbon nanotubes as pH controlled carriers of fluorouracil: Molecular dynamics simulations

This study deals with molecular dynamics simulations of the folic acid (FA) functionalized carbon nanotube (CNT) as a pH-responsive carrier of fluorouracil (5-FU) drug. We chose FA as a targeting agent, as the folate receptor is considerably upregulated by a broad spectrum of cancer cells. Thus, it may facilitate the targeted delivery of chemotherapeutic agents. The results showed that the FA does not affect the loading capacity of CNT at neutral pH so both CNT and CNTFA can load 51 drug molecules. Unmodified CNT behaves in the same manner at different pH conditions, and so cannot be used as a pH-selective nanocarrier. However, the maximum loading capacity of CNTFA is decreased to 45 by decreasing the environmental pH. The molecular mechanics Poisson-Boltzmann surface area analysis showed that the hydrophobic and π-π stacking interactions are the main forces behind the complex stability. The least value of △Gbind belongs to the CNTFA:5-FU at low pH, which is favorable for drug release from a thermochemical viewpoint. The lowest and highest values of diffusion coefficients are those of CNTFA:5-FU at neutral and low pH, respectively. This means that CNTFA holds the drug molecules tightly at physiological pH, but releases them at low pH environments. Also, the reduction of the number of hydrogen bonds between CNTFA and 5-FU molecules as well as a decrease in height of the radial distribution function profile at low pH propose the CNTFA as a pH-sensitive nanocarrier for 5-FU. The simulation results show the important effect of the FA on the controlled release of 5-FU from CNT, which is suitable for targeted drug delivery applications.

Prediction of Drug Synergism between Peptides and Antineoplastic Drugs Paclitaxel, 5-Fluorouracil, and Doxorubicin Using In Silico Approaches.

Chemotherapy is the main treatment for most early-stage cancers; nevertheless, its efficacy is usually limited by drug resistance, toxicity, and tumor heterogeneity. Cell-penetrating peptides (CPPs) are small peptide sequences that can be used to increase the delivery rate of chemotherapeutic drugs to the tumor site, therefore contributing to overcoming these problems and enhancing the efficacy of chemotherapy. The drug combination is another promising strategy to overcome the aforementioned problems since the combined drugs can synergize through interconnected biological processes and target different pathways simultaneously. Here, we hypothesized that different peptides (P1-P4) could be used to enhance the delivery of chemotherapeutic agents into three different cancer cells (HT-29, MCF-7, and PC-3). In silico studies were performed to simulate the pharmacokinetic (PK) parameters of each peptide and antineoplastic agent to help predict synergistic interactions in vitro. These simulations predicted peptides P2-P4 to have higher bioavailability and lower Tmax, as well as the chemotherapeutic agent 5-fluorouracil (5-FU) to have enhanced permeability properties over other antineoplastic agents, with P3 having prominent accumulation in the colon. In vitro studies were then performed to evaluate the combination of each peptide with the chemotherapeutic agents as well as to assess the nature of drug interactions through the quantification of the Combination Index (CI). Our findings in MCF-7 and PC-3 cancer cells demonstrated that the combination of these peptides with paclitaxel (PTX) and doxorubicin (DOXO), respectively, is not advantageous over a single treatment with the chemotherapeutic agent. In the case of HT-29 colorectal cancer cells, the combination of P2-P4 with 5-FU resulted in synergistic cytotoxic effects, as predicted by the in silico simulations. Taken together, these findings demonstrate that these CPP6-conjugates can be used as adjuvant agents to increase the delivery of 5-FU into HT-29 colorectal cancer cells. Moreover, these results support the use of in silico approaches for the prediction of the interaction between drugs in combination therapy for cancer.

Metallic and polymeric green nanoplatforms in oncology.

Chemotherapy, the cornerstone of cancer treatment, although invaluable, is plagued with unbearable and occasionally life-threatening side effects due to its inability to discriminate between tumorous and healthy cells. Anticancer nanomedicines have gained prominence due to their site-specific delivery of chemotherapeutic agents. In comparison to traditional chemical and physical procedures, which add to the chemical burden of an already ailing body, biosynthesis of nanomaterials by plants and microorganisms has evolved as safer 'green' nano-manufacturing technology. While nanomedicines from plant extracts have been exhaustively researched, the use of microbes as potential nano factories for the production of metal nanoparticles has recently piqued interest. Many bacteria develop defence mechanisms to detoxify hazardous metal ions, which results in formation of nano scaled metals that can be used for numerous therapeutic applications. The intrinsic variability of microbiological systems, however, poses its own set of challenges, necessitating more stringent standardization protocols in order to create nanomaterials with reproducible attributes. In this paper, we review the emerging trends in the green biosynthesis of nanomaterials and their potential applicability in cancer therapeutics. We probe the microbial biosynthetic mechanistic pathways and the efforts taken to control the physicochemical characteristics of nanoparticles. The applications of metallic nanoparticles obtained from microbes as well as polymeric systems obtained from bacteria, fungi and seaweed in oncology are described in detail. The development of these nanomaterials as next-generation green anticancer drugs may result in a revolution in cancer therapeutics.

ACT-20 PHASE 1/2, PROSPECTIVE, INTERNATIONAL MULTI-CENTER STUDY TO ESTABLISH THE SAFETY AND FEASIBILITY OF BLOOD-BRAIN-BARRIER DISRUPTION COMBINED WITH CARBOPLATIN FOR RECURRENT GLIOBLASTOMA; FIRST CLINICAL EXPERIENCE IN JAPAN

Abstract The prognosis for glioblastoma is still very poor despite intensive treatment by surgery, radiation, and chemotherapy. One of the reasons for poor prognosis of glioblastoma is blood-brain-barrier (BBB), which limits the delivery of chemotherapeutic agents to the brain. Focused ultrasound (FUS) therapy is approved for essential tremor and Parkinson disease in Japan and preclinical studies suggest low-intensity focused ultrasound (LIFU) administered with microbubbles (MB) can disrupt BBB and can improve the delivery of chemotherapeutic agents. Thus, currently, focused ultrasound therapy has gained attention in neuro-oncology and a number of clinical trials using FUS for the treatment of glioblastoma are underway. Our institutions (Osaka University Hospital and Saito Yukoukai Hospital) are the first in Japan to join the international multicenter study to examine the safety and feasibility of BBB disruption by FUS and MB combined with intravenous carboplatin for the treatment of recurrent glioblastoma. We are planning to enroll one recurrent glioblastoma patient for this study soon. BBB disruption strategies using FUS and MB for the treatment of neuro-oncological disease has potentials to improve the outcome of patients and many clinical trials will be performed in future.

Synthesis and characterization of a novel, pH-responsive sustained release nanocarrier using polyethylene glycol, graphene oxide, and natural silk fibroin protein by a green nano emulsification method to enhance cancer treatment

In this study, for the first time, by employing a simple and efficient double nano-emulsification method and using sweet almond oil as the organic phase, polyethylene glycol (PEG)/graphene oxide (GO)/silk fibroin (SF) hydrogel-nanocomposite was synthesized. The aim of the research was to fabricate a biocompatible targeted pH-sensitive sustained release carrier, improve the drug loading capacity and enhance the anticancer effect of doxorubicin (DOX) drug. The obtained values for the entrapment (%EE) and loading efficacy (%LE) were 87.75 ± 0.7 % and 46 ± 1 %, respectively, and these high values were due to the use of GO with a large specific surface area and the electrostatic interaction between the drug and SF. The Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analyses confirmed the presence of all the components in the nanocomposite and the suitable interaction between them. Based on the results of dynamic light scattering analysis (DLS) and zeta potential analysis, the mean size of the carrier particles and its surface charge were 293.7 nm and −102.9 mV, respectively. The high negative charge was caused by the presence of hydroxyl groups in GO and SF and it caused proper stability of the nanocomposite. The spherical core-shell structure with its homogeneous surface was also observed in the field emission scanning electron microscopy (FE-SEM) image. The cumulative release percentage of the nanocarrier reached 95.75 after 96 h and it is higher in the acidic environment at all times. The results of fitting the release data to the kinetic models suggested that the mechanism of release was dissolution-controlled anomalous at pH 7.4 and diffusion-controlled anomalous at pH 5.4. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and flow cytometry showed an increase in toxicity on MCF-7 cells and improved apoptotic cell death compared to the free drug. Consequently, the findings of this research introduced and confirmed PEG/GO/SF nanocomposite as an attractive novel drug delivery system for pH-sensitive and sustained delivery of chemotherapeutic agents in biomedicine.