Cocrystallization-like strategy for the codelivery of hydrophobic and hydrophilic drugs in a single carrier material formulation

Codelivery of drugs by drug carriers is a promising strategy against several diseases such as infections and cancer. However, traditional drug carriers are typically characterized by low drug payload, limiting their treatment efficacy. Using nanocrystals of insoluble drug as carriers, a carrier free platform was developed previously to deliver a second insoluble drug for codelivery. To extend the concept, we hypothesized, herein, that the platform allows for codelivery of hydrophobic and hydrophilic drugs using a cocrystalization-like strategy. To obtain proof-of-concept, paclitaxel (PTX), an insoluble chemotherapeutic agent, and dichloroacetic acid (DCA), a water-soluble inhibitor of pyruvate dehydrogenase kinase, were utilized as model drugs. PTX-DCA hybrid nanocrystals (PTX-DCA NCs) were prepared by anti-solvent precipitation and characterized. Their in vitro antitumor activity against cancer cells was evaluated. PTX-DCA NCs prepared from the optimized formulation had a diameter of 160 nm and a rod-shape morphology and possessed encapsulated efficacy of approximately 30% for DCA. The use of the hybrid crystals enabled synergy to kill cancer cells, in particular in PTX-resistant cells in a dose-dependent pattern. In conclusion, by using a cocrystalization-like strategy, a hydrophilic drug can be formulated into a drug’s nanocrystal for codelivery.     

Application of nanotechnology in CAR-T-cell immunotherapy

It is cellular immunotherapy for the tumor that the in vitro modified immunocytes from patients or donors are reinfused into patients to kill tumor cells. Chimeric antigen receptor T cell (CAR-T) therapy, one of the most successful and representative tumor cellular immunotherapies, is now the weapon for cancer after extensive research. Although CAR-T immunotherapy achieves success in treating relapsed/refractory hematological tumors, its drawbacks, including the poor effect in solid tumors, cytokine release syndrome (CRS) or CAR-T-related encephalopathy syndrome (CRES), on-target, off-tumor effect, and high cost, cannot be overlooked. Nanotechnology is advantageous in the construction of CARs, the transfection of T cells, the expansion, delivery, and antitumor effect of CAR-T cells, and the reduction of CAR-T therapy-associated toxicities. Currently, introducing nanotechnology into CAR-T immunotherapy has already been performed in numerous studies with highly promising results. In this review, we summarized the nanotechnologies used in CAR-T immunotherapy and discussed the challenges and directions of CAR-T immunotherapy combined with nanotechnologies in the future.     

A systematic investigation on flavonoids,catechin, β-sitosterol and lignin glycosides from Saraca asoca (ashoka) having anti-cancer & antioxidant properties with no side effect

Saraca asoca is an IUCN red-listed tree species that extensively famous in the Ayurvedic medicine field. Saraca asoca (Roxb.) de Wilde belongs to the family Fabaceae, has been used to treat various gynecological disorders, bacterial infections, worm infestations, haemmorhagic dysentery, uterine pain, skin diseases, cancer, circulatory, cardiovascular disorders, and many others. All parts of the Saraca asoca have medicinal values. Numerous antioxidant compounds like flavonoids, catechin, beta-sitosterol, lignin glycosides are present in the bark, leaf, and flower of Saraca asoca plant, which help to stabilize free radicals molecules that are associated with the development of cancer conditions. Currently in the cancer research study field new and more effective modes of natural therapies are recently being analyzed. Traditional medicines have been used for their preventative role against various diseases in the human population. Plant based therapy for cancer prevention is becoming more demanding due to its various unique properties such as natural chemical composition, less expensiveness, naturally available., easily orally administrable, significant chemo-protective activities, nontoxic to normal cells in the body, less side effects compared to other synthetic chemotherapeutic drugs. The chemotherapeutic drugs will be harmful to both cancer and normal cells. Additionally, some common side effects or health consequences like vomiting, nausea, bleeding, hair fall, alopecia, hyperuricemia, thrombocytopenia, bone marrow depression, mucositis are very common after chemotherapeutic drug treatment in cancer. This review paper summarizes the evidences which agree with the fact that flavonoids and other phenolic compounds in Saraca asoca plant possess significant antioxidant activity and an efficient chemopreventive characteristic against different types of cancer. This paper reviews the anticancer activities of Saraca asoca bark and flower and discusses the potential preventive roles of phenolic and flavonoids compounds, present in bark and flower of Saraca asoca in the cancer treatment process.     

The energy blocker inside the power house: mitochondria targeted delivery of 3-bromopyruvate

A key hallmark of many aggressive cancers is accelerated glucose metabolism. The enzymes that catalyze the first step of glucose metabolism are hexokinases. Elevated levels of hexokinase 2 (HK2) are found in cancer cells, but only in a limited number of normal tissues. Metabolic reprogramming of cancer cells using the energy blocker 3-bromopyruvate (3-BP), which inhibits HK2, has the potential to provide tumor-specific anticancer agents. However, the unique structural and functional characteristics of mitochondria prohibit selective subcellular targeting of 3-BP to modulate the function of this organelle for therapeutic gain. A mitochondria-targeted gold nanoparticle (T-3-BP-AuNP), decorated with 3-BP and delocalized lipophilic triphenylphosphonium cations to target the mitochondrial membrane potential (Δψ _m), was developed for delivery of 3-BP to cancer cell mitochondria by taking advantage of the higher Δψ _m in cancer cells compared to normal cells. In vitro studies demonstrated an enhanced anticancer activity of T-3-BP-AuNPs compared to the non-targeted construct NT-3-BP-AuNP or free 3-BP. The anticancer activity of T-3-BP-AuNPs was further enhanced upon laser irradiation by exciting the surface plasmon resonance band of AuNP and thereby utilizing a combination of 3-BP chemotherapeutic and AuNP photothermal effects. The lower toxicity of T-3-BP-NPs in normal mesenchymal stem cells indicated that these NPs preferentially kill cancer cells. T-3-BP-AuNPs showed an enhanced ability to modulate cancer cell metabolism by inhibiting glycolysis as well as demolishing mitochondrial oxidative phosphorylation. Our findings demonstrate that concerted chemo-photothermal treatment of glycolytic cancer cells with a single NP capable of targeting mitochondria, mediating simultaneous release of a glycolytic inhibitor and photothermal ablation, may have promise as a new anticancer therapy.     

Virus-Like Particle-Encapsulated Doxorubicin Enters and Kills Murine Tumor Cells Differently from Free Doxorubicin

The use of nanoparticles as chemotherapeutic carriers has been suggested as a way to overcome a range of side effects associated with classical cancer treatment such as poor selectivity and tumor resurgence. Obtaining precise control of the size and shape of therapeutic nanoparticles is crucial to optimize the targeting of tumor sites. In this work, it is shown that a previously developed system of polypeptide encapsulating individual DNA molecules, that forms rod-shaped nanoparticles of precisely controlled aspect ratio, can be loaded with the DNA-intercalating chemotherapeutic drug doxorubicin (DOX). It is characterized the size and shape of the DOX loaded-Virus-Like DNA Particles (DOX-VLDP) and shown that in this system the DOX payload does not leak out. Through in vitro cell studies, it is shown that DOX-VLDP is internalized by melanoma tumor cells (B16F10 cells) in a delayed and endocytosis-dependent way culminating in increased cytotoxicity and selectivity to tumor cells in comparison with free DOX. In addition, it is found that DOX-VLDP trigger apoptosis and autophagy pathways in treated cells. Taken together, the data on the DOX-VLDP nanoparticles shows that they kill cancer cells differently from free DOX.     

Sensitization of cancer cells to DNA damaging agents by imidazolines

Apoptosis, or programmed cell death, is a cellular mechanism used to regulate cell number and eliminate damaged or mutated cells. Concomitant with the initiation of the apoptotic cell signal, chemotherapeutic agents also induce anti-apoptotic factors, such as NF-kappaB, which compromise the overall efficacy of chemotherapeutic anticancer treatment. Here we describe an adjuvant therapy in which a small molecule is used to sensitize cancer cells toward apoptosis induced by chemotherapeutics. Our results indicate that the imidazoline 1d modulates the pro-survival NF-kappaB pathway and selectively sensitizes cancer cells toward DNA damaging agents, thus enhancing the overall efficacy of the treatment. Pretreatment of cancer cells with the noncytotoxic imidazoline 1d (10 nM) resulted in a significant increase in apoptosis and anticancer efficacy of the clinically significant DNA damaging agents camptothecin and cisplatin. Noncancerous cells remained unaffected during this regimen.     

Traditional Medicinal Plants as a Source of Inspiration for Osteosarcoma Therapy

Osteosarcoma is one of the most common types of bone cancers among paediatric patients. Despite the advances made in surgery, chemo-, and radiotherapy, the mortality rate of metastatic osteosarcoma remains unchangeably high. The standard drug combination used to treat this bone cancer has remained the same for the last 20 years, and it produces many dangerous side effects. Through history, from ancient to modern times, nature has been a remarkable source of chemical diversity, used to alleviate human disease. The application of modern scientific technology to the study of natural products has identified many specific molecules with anti-cancer properties. This review describes the latest discovered anti-cancer compounds extracted from traditional medicinal plants, with a focus on osteosarcoma research, and on their cellular and molecular mechanisms of action. The presented compounds have proven to kill osteosarcoma cells by interfering with different pathways: apoptosis induction, stimulation of autophagy, generation of reactive oxygen species, etc. This wide variety of cellular targets confer natural products the potential to be used as chemotherapeutic drugs, and also the ability to act as sensitizers in drug combination treatments. The major hindrance for these molecules is low bioavailability. A problem that may be solved by chemical modification or nano-encapsulation.     

A supramolecular co-delivery strategy for combined breast cancer treatment and metastasis prevention

We herein propose a co-delivery approach where small interference RNA(siRNA) and anticancer chemotherapeutic drug are simultaneously loaded into a single delivery carrier for the combined treatment of breast cancer and metastasis prevention.The co-delivery vector is composed of chondroitin sulfate(CS)-coated β-cyclodextrin-polyethylenemine polymer,which is capable of loading paclitaxel(PTX) and siRNA simultaneously to form therapeutic nanocomplexes.The nanocomplex,termed as CPPTX-siCD146-CS,is d...     

Targeting Toxins toward Tumors

Many cancer diseases, e.g., prostate cancer and lung cancer, develop very slowly. Common chemotherapeutics like vincristine, vinblastine and taxol target cancer cells in their proliferating states. In slowly developing cancer diseases only a minor part of the malignant cells will be in a proliferative state, and consequently these drugs will exert a concomitant damage on rapidly proliferating benign tissue as well. A number of toxins possess an ability to kill cells in all states independently of whether they are benign or malignant. Such toxins can only be used as chemotherapeutics if they can be targeted selectively against the tumors. Examples of such toxins are mertansine, calicheamicins and thapsigargins, which all kill cells at low micromolar or nanomolar concentrations. Advanced prodrug concepts enabling targeting of these toxins to cancer tissue comprise antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), lectin-directed enzyme-activated prodrug therapy (LEAPT), and antibody-drug conjugated therapy (ADC), which will be discussed in the present review. The review also includes recent examples of protease-targeting chimera (PROTAC) for knockdown of receptors essential for development of tumors. In addition, targeting of toxins relying on tumor-overexpressed enzymes with unique substrate specificity will be mentioned.     

Crucial role of HMGA1 in the self-renewal and drug resistance of ovarian cancer stem cells

Cancer stem cells are a subpopulation of cancer cells characterized by self-renewal ability, tumorigenesis and drug resistance. The aim of this study was to investigate the role of HMGA1, a chromatin remodeling factor abundantly expressed in many different cancers, in the regulation of cancer stem cells in ovarian cancer. Spheroid-forming cancer stem cells were isolated from A2780, SKOV3 and PA1 ovarian cancer cells by three-dimensional spheroid culture. Elevated expression of HMGA1 was observed in spheroid cells along with increased expression of stemness-related genes, such as SOX2, KLF4, ALDH, ABCB1 and ABCG2. Furthermore, spheroid A2780 cells, compared with adherent cells, showed higher resistance to chemotherapeutic agents such as paclitaxel and doxorubicin. HMGA1 knockdown in spheroid cells reduced the proliferative advantage and spheroid-forming efficiency of the cells and the expression of stemness-related genes. HMGA1 overexpression in adherent A2780 cells increased cancer stem cell properties, including proliferation, spheroid-forming efficiency and the expression of stemness-related genes. In addition, HMGA1 regulated ABCG2 promoter activity through HMGA1-binding sites. Knockdown of HMGA1 in spheroid cells reduced resistance to chemotherapeutic agents, whereas the overexpression of HMGA1 in adherent ovarian cancer cells increased resistance to chemotherapeutic agents in vitro. Furthermore, HMGA1-overexpressing A2780 cells showed a significant survival advantage after chemotherapeutic agent treatment in a xenograft tumorigenicity assay. Together, our results provide novel insights regarding the critical role of HMGA1 in the regulation of the cancer stem cell characteristics of ovarian cancer cells, thus suggesting that HMGA1 may be an important target in the development of therapeutics for ovarian cancer patients.     

The Oxime Ethers with Heterocyclic,Alicyclic and Aromatic Moiety as Potential Anti-Cancer Agents

Chemotherapy is one of the most commonly used methods of cancer disease treatment. Due to the acquisition of drug resistance and the possibility of cancer recurrence, there is an urgent need to search for new molecules that would be more effective in destroying cancer cells. In this study, 1-(benzofuran-2-yl)ethan-1-one oxime and 26 oxime ethers containing heterocyclic, alicyclic or aromatic moiety were screened for their cytotoxicity against HeLa cancer cell line. The most promising derivatives with potential antitumor activity were 2-(cyclohexylideneaminoxy)acetic acid (18) and (E)-acetophenone O-2-morpholinoethyl oxime (22), which reduced the viability of HeLa cells below 20% of control at concentrations of 100–250 μg/mL. Some oxime ethers, namely thiazole and benzothiophene derivatives (24–27), also reduced HeLa cell viability at similar concentrations but with lower efficiency. Further cytotoxicity evaluation confirmed the specific toxicity of (E)-acetophenone O-2-morpholinoethyl oxime (22) against A-549, Caco-2, and HeLa cancer cells, with an EC50 around 7 μg/mL (30 μM). The most potent and specific compound was (E)-1-(benzothiophene-2-yl)ethanone O-4-methoxybenzyl oxime (27), which was selective for Caco-2 (with EC50 116 μg/mL) and HeLa (with EC50 28 μg/mL) cells. Considering the bioavailability parameters, the tested derivatives meet the criteria for good absorption and permeation. The presented results allow us to conclude that oxime ethers deserve more scientific attention and further research on their chemotherapeutic activity.     

Evaluation of Antioxidative Mechanisms In Vitro and Triterpenes Composition of Extracts from Silver Birch (Betula pendula Roth) and Black Birch (Betula obscura Kotula) Barks by FT-IR and HPLC-PDA

Silver birch, Betula pendula Roth, is one of the most common trees in Europe. Due to its content of many biologically active substances, it has long been used in medicine and cosmetics, unlike the rare black birch, Betula obscura Kotula. The aim of the study was therefore to compare the antioxidant properties of extracts from the inner and outer bark layers of both birch trees towards the L929 line treated with acetaldehyde. Based on the lactate dehydrogenase test and the MTT test, 10 and 25% concentrations of extracts were selected for the antioxidant evaluation. All extracts at tested concentrations reduced the production of hydrogen peroxide, superoxide anion radical, and 25% extract decreased malonic aldehyde formation in acetaldehyde-treated cells. The chemical composition of bark extracts was accessed by IR and HPLC-PDA methods and surprisingly, revealed a high content of betulin and lupeol in the inner bark extract of B. obscura. Furthermore, IR analysis revealed differences in the chemical composition of the outer bark between black and silver birch extracts, indicating that black birch may be a valuable source of numerous biologically active substances. Further experiments are required to evaluate their potential against neuroinflammation, cancer, viral infections, as well as their usefulness in cosmetology.     

Alum colloid encapsulated inside β-glucan particles enhance humoral and CTL immune responses of MUC1 vaccine

We have developed a MUC1 antigen-based antitumor vaccine loaded on alum colloid encapsulated insideβ-glucan particles(GP-Al). The constructed vaccine induced strong MUC1 antigen specific Ig G antibody titers and enhanced CD8~+ T cells cytotoxic effect to kill tumor cells. These results indicated that GP-Al can be served as an efficient delivery system and adjuvant for the development of cancer vaccines especially small molecule antigens based cancer vaccines.     

Free Radicals as a Double-Edged Sword: The Cancer Preventive and Therapeutic Roles of Curcumin

Free radicals, generally composed of reactive oxygen species (ROS) and reactive nitrogen species (RNS), are generated in the body by various endogenous and exogenous systems. The overproduction of free radicals is known to cause several chronic diseases including cancer. However, increased production of free radicals by chemotherapeutic drugs is also associated with apoptosis in cancer cells, indicating the dual nature of free radicals. Among various natural compounds, curcumin manifests as an antioxidant in normal cells that helps in the prevention of carcinogenesis. It also acts as a prooxidant in cancer cells and is associated with inducing apoptosis. Curcumin quenches free radicals, induces antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase), and upregulates antioxidative protein markers–Nrf2 and HO-1 that lead to the suppression of cellular oxidative stress. In cancer cells, curcumin aggressively increases ROS that results in DNA damage and subsequently cancer cell death. It also sensitizes drug-resistant cancer cells and increases the anticancer effects of chemotherapeutic drugs. Thus, curcumin shows beneficial effects in prevention, treatment and chemosensitization of cancer cells. In this review, we will discuss the dual role of free radicals as well as the chemopreventive and chemotherapeutic effects of curcumin and its analogues against cancer.     

Inherent Chemotherapeutic Anti-Cancer Effects of Low-Dimensional Nanomaterials

Low-dimensional nanomaterials (LDNs) are receiving increasing attention in cancer therapy owing to their unique properties, especially the large surface area-to-volume ratio. LDNs such as metallic nanoparticles (NPs), hydroxyapatite NPs, graphene derivatives, and black phosphorus (BP) nanosheets have been proposed for drug delivery, photothermal/photodynamic therapies, and multimodal theranostic treatments. The therapeutic effectiveness is mainly based on the physical characteristics of LDNs, but their inherent bioactivity has not been fully capitalized. In this Minireview, recent advances in the anti-cancer effects of various types of LDNs with inherent chemotherapeutic bioactivity are described and the bioactivity mechanisms are discussed on the cellular and molecular levels. BP, one of the newest and exciting members of the LDN family, is highlighted owing to the excellent inherent bioactivity, selectivity, and biocompatibility in cancer therapy. LDNs and related derivatives possess inherent bioactivity and selective chemotherapeutic effects suggesting large potential as nanostructured anti-cancer agents in cancer therapy.     

Distinguishable Targeting of Non-Small Cell Lung Cancer Using Hyaluronan Functionalized Platinum Nanoclusters and Their Inhibition Behaviors of Proliferation,Invasion, Migration

Lung cancer is the leading cause of cancer deaths worldwide and most cancer patients receiving conventional chemotherapy suffer from severe side effects due to the non-selective effects of chemotherapeutic drugs on normal cells. Targeted nanomaterials can obtain excellent accumulation at the tumor site through their active or passive targeting mechanisms, thereby reducing the toxicity of the drugs in various ways. In this study, hyaluronic acid (HA) which could specifically bind to CD44 on the surface of tumor cells, was used to modify amine-caged platinum nanoclusters (Pt NCs-NH₂) to obtain targeting HA-Pt NCs-NH₂. Based on the differential expression of CD44 on the surface of three lung cells (non-small cell lung cancer cell H1299, small cell lung cancer cell H446, and embryonic lung fibroblast HFL1), HA-Pt NCs-NH₂ can differentially enter the three cells and achieve their targeting of non-small cell lung cancer cell (NSCLC) cells. Pt NCs significantly inhibited the proliferation, migration and invasion of NSCLC cells and induced their apoptosis in comparison of classical cisplatin and carboplatin, showing a bright future in early diagnosis and treatment of NSCLC.     

Clinical implications of proliferation activity in T1 or T2 male gastric cancer patients

Proliferation activity has already been established as a prognostic marker or as a marker for anticancer drug sensitivity. In gastric cancer, however, the prognostic significance of proliferation activity is still being debated. Several studies evaluating proliferation activity using Ki-67 have shown controversial results in terms of the relationship between proliferation activity and overall survival (OS) or drug sensitivity in gastric cancer patients. Because cytoskeleton-associated protein 2 (CKAP2) staining has recently been introduced as a marker of proliferation activity, we analyzed 437 gastric cancer tissues through CKAP2 immunohistochemistry, and we evaluated the chromatin CKAP2-positive cell count (CPCC) for proliferation activity. Although the CPCC did not show any significant correlation with OS in the male, female or total number of cases, it did show a significant correlation in the T1 or T2 male patient subgroup, according to log-rank tests (P=0.001) and univariate analysis (P=0.045). Additionally, multivariate analysis with the Cox proportional hazard regression model showed a significant correlation between the CPCC and OS (P=0.039) for the co-variables of age, gender, T stage, N stage, histology, tumor location, tumor size and adjuvant chemotherapy. In male gastric cancer cell lines, faster-growing cancer cells showed higher sensitivity to cisplatin than slow-growing cells. Thus our study indicates that CPCC-measured proliferation activity demonstrates a significantly worse prognosis in T1 or T2 male gastric cancer patients. The CPCC will help to more precisely classify gastric cancer patients and to select excellent candidates for adjuvant chemotherapy, which in turn will facilitate further clinical chemotherapeutic trials.     

AaTs-1: A Tetrapeptide from Androctonus australis Scorpion Venom,Inhibiting U87 Glioblastoma Cells Proliferation by p53 and FPRL-1 Up-Regulations

Glioblastoma is an aggressive cancer, against which medical professionals are still quite helpless, due to its resistance to current treatments. Scorpion toxins have been proposed as a promising alternative for the development of effective targeted glioblastoma therapy and diagnostic. However, the exploitation of the long peptides could present disadvantages. In this work, we identified and synthetized AaTs-1, the first tetrapeptide from Androctonus australis scorpion venom (Aa), which exhibited an antiproliferative effect specifically against human glioblastoma cells. Both the native and synthetic AaTs-1 were endowed with the same inhibiting effect on the proliferation of U87 cells with an IC₅₀ of 0.56 mM. Interestingly, AaTs-1 was about two times more active than the anti-glioblastoma conventional chemotherapeutic drug, temozolomide (TMZ), and enhanced its efficacy on U87 cells. AaTs-1 showed a significant similarity with the synthetic peptide WKYMVm, an agonist of a G-coupled formyl-peptide receptor, FPRL-1, known to be involved in the proliferation of glioma cells. Interestingly, the tetrapeptide triggered the dephosphorylation of ERK, p38, and JNK kinases. It also enhanced the expression of p53 and FPRL-1, likely leading to the inhibition of the store operated calcium entry. Overall, our work uncovered AaTs-1 as a first natural potential FPRL-1 antagonist, which could be proposed as a promising target to develop new generation of innovative molecules used alone or in combination with TMZ to improve glioblastoma treatment response. Its chemical synthesis in non-limiting quantity represents a valuable advantage to design and develop low-cost active analogues to treat glioblastoma cancer.     

N-Heterocyclic Carbene Iron Complexes as Anticancer Agents: In Vitro and In Vivo Biological Studies

Cisplatin and its derivatives are commonly used in chemotherapeutic treatments of cancer, even though they suffer from many toxic side effects. The problems that emerge from the use of these metal compounds led to the search for new complexes capable to overcome the toxic side effects. Here, we report the evaluation of the antiproliferative activity of Fe(II) cyclopentadienyl complexes bearing n-heterocyclic carbene ligands in tumour cells and their in vivo toxicological profile. The in vitro antiproliferative assays demonstrated that complex Fe1 displays the highest cytotoxic activity both in human colorectal carcinoma cells (HCT116) and ovarian carcinoma cells (A2780) with IC₅₀ values in the low micromolar range. The antiproliferative effect of Fe1 was even higher than cisplatin. Interestingly, Fe1 showed low in vivo toxicity, and in vivo analyses of Fe1 and Fe2 compounds using colorectal HCT116 zebrafish xenograft showed that both reduce the proliferation of human HCT116 colorectal cancer cells in vivo.