Antitumor Studies Research Articles

Synthesis of Amino Acid Schiff Base Nickel (II) Complexes as Potential Anticancer Drugs In Vitro.

Three hexacoordinated octahedral nickel (II) complexes, [Ni (Trp-sal) (phen) (CH3OH)] (1), [Ni (Trp-o-van) (phen) (CH3OH)]•2CH3OH (2), and [Ni (Trp-naph) (phen) (CH3OH)] (3) (where Trp-sal = Schiff base derived from tryptophan and salicylaldehyde, Trp-o-van = Schiff base derived from tryptophan and o-vanillin, Trp-naph = Schiff base derived from tryptophan and 2-hydroxy-1-naphthaldehyde, phen = 1, 10-phenanthroline), have been synthesized and characterized as potential anticancer agents. Details of structural study of these complexes using single-crystal X-ray crystallography showed that distorted octahedral environment around nickel (II) ion has been satisfied by three nitrogen atoms and three oxygen atoms. All these complexes displayed moderate cytotoxicity toward esophageal cancer cell line Eca-109 with the IC50 values of 23.95 ± 2.54 μM for 1, 18.14 ± 2.39 μM for 2, and 21.89 ± 3.19 μM for 3. Antitumor mechanism studies showed that complex 2 can increase the autophagy, reactive oxygen species (ROS) levels, and decrease the mitochondrial membrane potential remarkably in a dose-dependent manner in the Eca-109 cells. Complex 2 can cause cell cycle arrest in the G2/M phase. Additionally, complex 2 can regulate the Bcl-2 family and autophagy-related proteins.

A Profile of the Biological Activity of Functionalized Benzimidazolium Ionic Liquids

Now-a-days, the pharmaceutical industries were facing many challenges that impose the need to develop innovative and effective therapies. Hence, the investigation of effective therapies for cancer is an actual goal of every pharmaceutical industries. Recently, Ionic Liquids (ILs) have been considered as potential target in scientific community because of their unique performance in various fields. Moreover, numerous combinations made between the cation and the anion, which can be tuned the physicochemical and biological properties of ILs. Especially, these ionic liquids play a vital role for designing new drugs and producing potent bioactivity. Herein we synthesized a series of benzimidazolium based ionic liquids with different functional groups and their structure was confirmed by FT-IR, 1H NMR, 13C NMR as well as High resolution Mass spectroscopy technique antimicrobial activity of ILs were screened by five bacterial and fungal strains which was measured in terms of zone of inhibition. All the compounds were found to be effective against all bacterial species and fungi Candida albicans. Moreover, the total antioxidant capacity of ILs has been evaluated by Phosphomolybdenum method. The report indicates that kojic acid functionalized ILs exhibited significant antioxidant activity. In addition, antitumor activity of these compounds has been analyzed using human ovarian cancer cell line SK-OV-3, human prostate cancer cell line DU-145 and human leukemia cancer cell line K-562. The data obtained from antitumour studies showed that an excellent activity of ester functionalized ionic liquid confirms that can be used as an anticancer agent. However, ester functionalized and kojic acid functionalized ILs possess biologically active against the tested strains.

Synthesis, Crystal Structures, and Antimicrobial and Antitumor Studies of Two Zinc(II) Complexes with Pyridine Thiazole Derivatives.

Two pyridine thiazole derivatives, namely, 4-(pyridin-2-yl)-2-(2-(pyridin-2-ylmethylene)hydrazinyl)thiazole (L1) and 4-(pyridin-3-yl)-2-(2-(pyridin-4-ylmethylene)hydrazinyl)thiazole (L2), were afforded by a cyclization reaction between α-haloketone and thioamide, and their Zn(II) complexes were prepared by the reaction of ligands and corresponding metal salts, respectively, and characterized by X-ray diffraction and elemental analysis. Both crystals were obtained by ether diffusion and crystallized in a monoclinic system. The in vitro antimicrobial activity of the Zn(II) complexes and ligands was screened using the microplate reader method, and in vitro antitumor activities of the complexes were evaluated by MTT, with a view to developing new improved bioactive materials with novel properties. The biological activity studies of the compounds showed that the metal complexes were more active than the free ligands, and some compounds had absolute specificity for certain bacteria or cancer cell lines.

Metalloproteinases Suppression Driven by the Curcumin Analog DM-1 Modulates Invasion in BRAF-Resistant Melanomas.

Melanoma is the most aggressive skin cancer, and BRAF (V600E) is the most frequent mutation that led to the development of BRAF inhibitors (BRAFi). However, patients treated with BRAFi usually present recidivism after 6-9 months. Curcumin is a turmeric substance, and it has been deeply investigated due to its anti-inflammatory and antitumoral effects. Still, the low bioavailability and biodisponibility encouraged the investigation of different analogs. DM-1 is a curcumin analog and has shown an antitumoral impact in previous studies. Evaluated DM-1 stability and cytotoxic effects for BRAFi-sensitive and resistant melanomas, as well as the role in the metalloproteinases modulation. DM-1 showed growth inhibitory potential for melanoma cells, demonstrated by reduction of colony formation, migration and endothelial tube formation, and cell cycle arrest. Subtoxic doses were able to downregulate important Metalloproteinases (MMPs) related to invasiveness, such as MMP-1, -2 and -9. Negative modulations of TIMP-2 and MMP-14 reduced MMP-2 and -9 activity; however, the reverse effect is seen when increased TIMP-2 and MMP-14 resulted in raised MMP-2. These findings provide essential details into the functional role of DM-1 in melanomas, encouraging further studies in the development of combinatorial treatments for melanomas.

The Antitumor Effects of Britanin on Hepatocellular Carcinoma Cells and its Real-Time Evaluation by In Vivo Bioluminescence Imaging.

Hepatocellular carcinoma is cancer with many new cases and the highest mortality rate. Chemotherapy is the most commonly used method for the clinical treatment of hepatocellular carcinoma. Natural products have become clinically important chemotherapeutic drugs due to their great potential for pharmacological development. Many sesquiterpene lactone compounds have been proven to have antitumor effects on hepatocellular carcinoma. Britanin is a sesquiterpene lactone compound that can be considered for the treatment of hepatocellular carcinoma. The present study aimed to investigate the antitumor effect of britanin. BEL 7402 and HepG2 cells were used to study the cytotoxicity and antitumor effects of britanin. Preliminary studies on the nuclear factor kappa B pathway were conducted by western blot analysis. A BEL 7402-luc subcutaneous tumor model was established for the in vivo antitumor studies of britanin. In vivo bioluminescence imaging was conducted to monitor changes in tumor size. The results of the cytotoxicity analysis showed that the IC50 values for britanin in BEL 7402 and HepG2 cells were 2.702μM and 6.006μM, respectively. The results of the colony formation demonstrated that the number of cells in a colony was reduced significantly after britanin treatment. And the results of transwell migration assays showed that the migration ability of tumor cells was significantly weakened after treatment with britanin. Tumor size measurements and staining results showed that tumor size was inhibited after britanin treatment. The western blot analysis results showed the inhibition of p65 protein expression and reduced the ratio of Bcl-2/Bax after treatment. A series of in vitro and in vivo experiments demonstrated that britanin had good antitumor effects and provided an option for hepatocellular carcinoma treatment.

Preparation of RGD4C fused anti-TNFα nanobody and inhibitory activity on triple-negative breast cancer in vivo

AimsTriple-negative breast cancer (TNBC) is not sensitive to current endocrine treatments, so new treatment strategies need to be explored. Based on previous antitumour studies on anti-TNFα nanobody, we designed a novel fusion nanobody to enhance antitumour activity of the anti-TNFα nanobody in TNBC. Main methodsThe RGD4C contains RGD sequence, which is the smallest recognition unit binding to the αvβ3 receptor on tumour cell membranes and involved in tumour cell adhesion, proliferation, and metastasis. RGD4C was fused to anti-TNFα nanobody to investigate the antitumour activity in vitro and in vivo. Key findingsThe antitumour effects of fusion nanobody V-L-R-H could effectively bind to αvβ3 and inhibit cell migration and proliferation of MDA-MB-231, which had satisfying purification efficiency and approving antigen or receptor binding activity. V-L-R-H could inhibit the TNFα-mediated PI3K/AKT/NF-κB signal pathway and integrin αvβ3 correlative FAK focal adhesion signal pathway. Mouse xenograft tumour experiments showed that the V-L-R-H could inhibit tumour proliferation and metastasis; reduce the TNFα, HIFα, Ki67, and CD31 concentrations in tumour; and inhibit the process of epithelial-mesenchymal transition. SignificanceThe fusion nanobody enhanced antitumour activity of the anti-TNFα nanobody on TNBC. It provided a reference for the design of dual functional fusion proteins and development of tumour treatment strategies of antagonistic TNFα and αvβ3, and a new therapeutic strategy and research direction for the treatment of TNBC.

Abstract LB-104: Quantification of the preclinical and clinical relationship between pRAD50 and efficacy after treatment with the ATR inhibitor ceralasertib (AZD6738)

Abstract Ceralasertib is a potent and selective ATP competitive inhibitor of ataxia telangiectasia and Rad3 related (ATR) in clinical development as monotherapy and in combination with olaparib (Lynparza) and durvalumab (Imfinzi) in patients with advanced solid tumors. Paired pre- and on-treatment tumour samples from seven patients during ceralasertib monotherapy in Phase 1 studies (NCT02223923, NCT02264678), all ATM expressing, showed increases in pRAD50 on treatment. This study aimed to robustly understand the relationship between ceralasertib pharmacokinetics, pRAD50 (pSer635) induction by immunohistochemistry and anti-tumor efficacy, in mouse xenografted models; to enable interpretation of paired clinical tumour samples. First, in vivo data were generated in a range of xenografted models (HBCx9 [TNBC, Xentech], HCC1806 [BC], OCI-Ly19 [DLBCL] and OE21 [HNSCC]) and NSCLC and HNSCC PDX models at Champions). Mouse ceralasertib doses (6.25 - 25mg/kg BID and 50mg/kg QD) reflected the observed free drug exposure achieved at clinical doses. In pharmacodynamic studies, animals were dosed continuously for 5 days, with PKPD endpoints being assessed on the 5th day. In anti-tumor studies, animals were randomized and treated for at least 28 days continuously. Increases in pRAD50 on treatment, versus control, were both dose and time dependent. There was a wide range of baseline pRAD50 expression (H-Scores ranging from 2 to 48) but the fold increase was consistent; a 3-fold increase being seen at the highest dose. Similarly, the anti-tumor activity was dose dependent with a range of sensitivities being observed across the models; the OCI-Ly19 model was most sensitive with %TGI ranging 43% to 104%. Mathematical modelling confirmed a consistent PKPD relationship for the fold increase of pRAD50. The effect was not saturated at the tested drug exposures and the slope relating drug in plasma to fold pRAD50 increases was estimated to be 0.75 uM-1. Modelling also demonstrated a relationship between pRAD50 and the observed anti-tumor activity, across all models. Of note, the fold induction required for efficacy increased with the baseline pRAD50 The hypothesis for this observation is that the baseline pRAD50 H-score is a functional measure of DDR signaling and so low pRAD50 may be indicative of impaired signaling and thus sensitivity to inhibition of DDR signaling. The results demonstrate the utility of generating PKPD-Efficacy relationships across a range of patient relevant xenografts and PDXs. Here, a marker of ATR inhibitor pharmacology, pRAD50, has been related to anti-tumor activity increasing our understanding of predictive markers of drug sensitivity. Clinical translation of these findings is being tested in a Phase I study, where patients provide paired tumour biopsies pre-treatment and following ceralasertib monotherapy dosing (NCT02264678). Citation Format: James William Thomas Yates, Zena Wilson, Gemma N. Jones, Kevin Harrington, Matthew Krebs, Magnus Dillon, Andrew J. Pierce, Emma Dean, Alan Lau. Quantification of the preclinical and clinical relationship between pRAD50 and efficacy after treatment with the ATR inhibitor ceralasertib (AZD6738) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-104.

Abstract 1741: Single protein encapsulation as a drug delivery platform for developing efficacious anticancer therapeutics

Abstract Small molecule anticancer drugs are potent and effective agents against a variety of malignancies. However, severe side effects are often associated with their application due to systemic toxicities caused by their indiscriminate infiltration into normal tissues, organs, and cells. Using natural human serum albumin (HSA) as the carrier, Sunstate Biosciences LLC has recently invented the SPE platform for anticancer drug formulation. The SPE technology employs only FDA-approved components to form HAS-encapsulated product SPE-DRUG. Unlike HSA nanoparticles that usually contain a number of HSA molecules through chemical conjugation/crosslinking or aggregation, the SPE-DRUG has a single HSA molecule that encloses a variable number of DRUG molecules via noncovalent interactions, and importantly it retains the molecular size of HSA. Both the DRUG/HSA ratio and the binding strength can be tuned precisely to allow controlled release of the DDRUG during circulation. The SPE platform is versatile and can be applied to the formulation of a variety of single- and multiple-anticancer drugs. We have successfully prepared the following formulated drugs: SPEDOX, SPEEPI, SPEDAU, SPEMIT, SPEIDA, SPEVIC, SPEVIB, SPEVIL, and SPEDOC. All SPE-DRUGS are highly water soluble to form clear and stable solutions. Their size distribution profiles determined by DLS are almost identical to that of HSA, suggesting no disruption of the structure and properties of native HSA. Pharmacokinetic properties of SPEDOX were evaluated. Mouse heart tissues harvested at 2/24 h were analyzed. Antitumor efficacy using a breast cancer model (MDA-MB-231) were also evaluated at various doses. Key findings include 1) ~ 47 fold increase in AUC, 2) ~ 4-8 fold decrease in free DOX in the mouse heart tissue, and 3) fivefold increase in MTD and substantial enhancement of tumor efficacy (34/88% TGI for DOX/SPEDOX). Drug release studies in pH 7.4 PBS and pH 5.2 acetate buffer revealed that SPEDOX, SPEEPI, SPEDAU, SPEMIT, SPEDA, SPEVIC, SPEBIB, SPEVIL released their drug molecules twice as fast in acetate buffer than in PBS. The enhanced drug release in acidic media provides a possible mechanism for targeting tumors due to their acidic environment, thereby leading to increased antitumor efficacy. Separate antitumor efficacy studies with SPEMIT also showed enhanced antitumor efficacy against MDA-MB-231 (16/56% TGI for MIT/SPEMIT). In conclusion, Sunstate Biosciences' novel SPE drug formulation and delivery platform can significantly enhances the pharmacokinetics and antitumor efficacy and, at the same time, reduces the side effect of the drug, leading to increased therapeutic indexes. SPE-DRUGS have the potential to revolutionize cancer treatment regimens and save lives of difficult-to-treat cancer patients. Citation Format: C. J. Yu. Single protein encapsulation as a drug delivery platform for developing efficacious anticancer therapeutics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1741.

Tailored core‒shell dual metal–organic frameworks as a versatile nanomotor for effective synergistic antitumor therapy

Malignant tumor has become an urgent threat to global public healthcare. Because of the heterogeneity of tumor, single therapy presents great limitations while synergistic therapy is arousing much attention, which shows desperate need of intelligent carrier for co-delivery. A core‒shell dual metal–organic frameworks (MOFs) system was delicately designed in this study, which not only possessed the unique properties of both materials, but also provided two individual specific functional zones for co-drug delivery. Photosensitizer indocyanine green (ICG) and chemotherapeutic agent doxorubicin (DOX) were stepwisely encapsulated into the nanopores of MIL-88 core and ZIF-8 shell to construct a synergistic photothermal/photodynamic/chemotherapy nanoplatform. Except for efficient drug delivery, the MIL-88 could be functioned as a nanomotor to convert the excessive hydrogen peroxide at tumor microenvironment into adequate oxygen for photodynamic therapy. The DOX release from MIL-88-ICG@ZIF-8-DOX nanoparticles was triggered at tumor acidic microenvironment and further accelerated by near-infrared (NIR) light irradiation. The in vivo antitumor study showed superior synergistic antitumor effect by concentrating the nanoparticles into dissolving microneedles as compared to intravenous and intratumoral injection of nanoparticles, with a significantly higher inhibition rate. It is anticipated that the multi-model synergistic system based on dual-MOFs was promising for further biomedical application.

Abstract 2212: An antibody drug conjugate targeting activated matriptase, exhibits synergistic cytotoxicity with a PARP inhibitor, olaparib in triple negative breast cancer

Abstract Matriptase, is a serine protease type II transmembrane protein. Matriptase forms a cognate pair with its Kunitz type endogenous inhibitor HAI-1 and is commonly deregulated and ubiquitously expressed in a variety of human carcinomas and in particular, breast cancer. This enzyme activity is regulated by binding to its endogenous inhibitors (HAI-1 or 2). Previously, we reported the synthesis and anti-tumor studies of a novel antibody drug conjugate (ADC) targeting activated matriptase of tumor cells (Oncotarget, 2018,9(40):25983). The activated matriptase-specific monoclonal antibody (M69) was conjugated with a potent anti-mitotic toxin, monomethyl auristatin-E (MMAE) via a lysosomal protease (cathepsin B) -cleavable dipeptide linker. The ADC was found to be potent and selective against multiple activated matriptase-positive epithelial carcinoma cell lines including triple negative breast cancer (TNBC), as well as alone and in combination with bortezomib in Mantle cell lymphoma (Frontiers in Oncology, 2019,9:258). In-vivo studies showed that the ADC has potent anti-tumor effects alone or in combination with cisplatin or carboplatin against TNBC xenografts and a primary human TNBC (PDX), respectively. The chimeric ADC (mouse-human chimera) also evoked an immune response against TNBC xenografts in humanized mouse models. Here, we report the sensitivity of TNBC tumors with and without a BRCA mutation to ADC alone or in combination with a PARP inhibitor, Olaparib. We analyzed the mutational status of BRCA1, BRAC2, p53 and activated matriptase expression of four TNBC cell lines (MDA-MB-468, MDA-MB-231, HCC1806 and MDA-MB-436). All of the cell lines had p53 mutations. The MDA-MB-468 cell line with a mutation in BRCA 2, and expression of activated matriptase was the most sensitive cell line to both olaparib and the chimeric MMAE ADC, and the combination of them resulted in marked synergistic cell kill. The MDA-MB-436 cell line with a splice site mutation in BCRA1 was less sensitive to both treatments, but there was modest synergy when the two drugs were combined. In contrast the MDA-MB-231 cell line without a BRCA mutation was much less sensitive to the ADC or olaparib, and the combination did not show synergy. The HCC1806 cell line with wt BRCA was sensitive to the ADC and olaparib, but the combination resulted in antagonistic effects. Triple negative breast cancers with a BRAC2 mutation and overexpression of activated matriptase may be a subset of breast cancers that may benefit from the combination of our novel ADC and a PARP inhibitor. Citation Format: Gulam M. Rather, Zoltan Szekely, Joseph R. Bertino. An antibody drug conjugate targeting activated matriptase, exhibits synergistic cytotoxicity with a PARP inhibitor, olaparib in triple negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2212.

Biofabrication of gold nanoparticles mediated by the endophytic Cladosporium species: Photodegradation, in vitro anticancer activity and in vivo antitumor studies.

Green fabrication of nanoparticles (NPs) using biological sources is the fast-growing trend replacing chemical synthesis via toxic materials. Considering the importance and feasibility of green fabricated NPs, the present research focuses on the synthesis of gold nanoparticles (AuNPs) using the aqueous extract of the endophytic Cladosporium sp. (MycoAuNPs) isolated from Commiphora wightii. The synthesized MycoAuNPs are characterized using UV-Vis spectroscopic, FTIR, X-ray diffraction (XRD) analysis, and transmission electron microscopy (TEM). The synthesized NPs showed a sharp absorption peak at 524nm, with an average size between 5 and 10nm in a spherical shape. XRD revealed the crystalline nature, and EDX profiling confirmed the presence of gold (Au) and oxygen (O) atoms. The biological potential of MycoAuNPs were tested under both in vitro and in vivo conditions. MycoAuNPs showed anti-cancer activity in breast cancer cell line MCF-7 (IC50 38.23µg/mL) through the induction of apoptosis. Further, MycoAuNPs showed potential against growth of tumor in tumor-bearing mice models. MycoAuNPs significantly reduced the body weight, ascites volume, and increased the lifespan of EAC bearing mice. It induced apoptosis of the EAC cells, which was confirmed by DNA fragmentation and Giemsa staining. Also, they did not develop any secondary complications or side effects in normal mice. The photocatalytic activity of MycoAuNPs tested against Rhodamine B and Methylene Blue dyes showed potential dye degradation in the presence of sunlight. Thus, the present study gives a clear idea of the multifaceted therapeutic and catalytic applications of the biosynthesized MycoAuNPs.

Highly fluorinated graphene oxide nanosheets for anticancer linoleic-curcumin conjugate delivery and T2-Weighted magnetic resonance imaging: In vitro and in vivo studies

Carbon-based nanomaterials have received substantial attention as a drug delivery platform for cancer treatment. In the current study, a simple and eco-friendly method was introduced for the preparation of highly fluorinated graphene oxide (FGO), which was subsequently evaluated by standard characterization methods. It was then employed as a carrier for Linoleic acid-curcumin conjugate as an anticancer drug (FGO-Lino-CUR). Finally, the release profile and selective toxicity of FGO-Lino-CUR were investigated and compared with FGO-CUR. It was observed that the pH-sensitive release fitted to Korsmeyer–Peppas model. The accumulated release of Lino-CUR at pH 5.5 was about 20% more than that of pH 7.4. FGO-Lino-CUR exhibited relatively high toxicity (about 60%) against MCF-7 cells which was 20% more than that against MCF10A cells. In vitro MRI studies also revealed that the Lino-CUR loaded FGO with adequate relaxation rate (r2 = 67.12 (s−1mM−1)) and favorable ability to reduce signal intensity in the presence of MCF10A and MCF-7 cells, could be a potential candidate as a negative MRI contrast agent. In vivo anti-tumor studies were performed on 4T1 induced BALB/c breast cancer model. Accordingly, the higher tumor suppression capability of FGO-Lino-CUR was observed with no significant body weight changes during treatment compared with free Lino-CUR. Moreover, the MRI contrast enhancing ability of FGO-Lino-CUR for the in vivo MRI of tumor bearing BALB/c mice, indicated its noticeable ability to create negative contrast. Simple and versatile method for the preparation of the target system as well as acceptable anticancer activity and MRI contrast enhancement, make Lino-CUR loaded FGO as an encouraging candidate for the breast cancer theranostics.

The Antitumor Effect of Gene-Engineered Exosomes in the Treatment of Brain Metastasis of Breast Cancer.

Strategies for treating brain metastases of breast cancer have demonstrated limited efficacy due to the blood–brain barrier (BBB). Gene therapy could improve the efficacy of chemotherapeutic drugs. Exosomes derived from the mesenchymal stem cells (MSCs) are small membrane-based gene vectors that can pass through the BBB. CXCR4 is the most commonly found chemokine receptor in human cancer cells. Furthermore, the SDF-1/CXCR4 axis plays an important role in the homing of MSCs for tumor cell diffusion and metastasis. TRAIL can selectively induce apoptosis in transformed cells without significant toxic side effects in normal tissues. In this study, exosomes were isolated from MSCCXCR4+TRAIL transduced with CXCR4 and TRAIL using a lentiviral vector. Synergistic antitumor study showed that exosomeCXCR4+TRAIL exerted significant activity as a cooperative agent with carboplatin in an MDA-MB-231Br SCID mouse model, potentially engendering a novel strategy for advancing the treatment of brain metastases of breast cancer. Based on this study, further investigation of the effect of the vector on BBB and inducing apoptosis of brain tumors is warranted. In addition, the safety of the vector in animals during the treatment needs to be evaluated.

Synthesis and Antiproliferative Activities of OSW‐1 Analogues Bearing 2”‐O‐p‐Acylaminobenzoyl Residues†

Summary of main observation and conclusionOSW‐1 is a well‐known natural saponin with potent antitumor activities. We have designed and prepared a small library of 22 OSW‐1 analogues with a variety of p‐acylamino‐benzoyl groups installed at C2” of the xylose residue, wherein a regioselective (1→3)‐glycosylation of arabinoside 3,4‐diol has been achieved by manipulation of the protecting groups on the imidate donors. Bioassays lead to new structure‐activity relationships as well as two applicable fluorescent probes, which are found to localize to lysosomes in HeLa cells and could be used in further antitumor mechanism studies of OSW‐1 in living cells.

Theranostic Targeting of CUB Domain Containing Protein 1 (CDCP1) in Pancreatic Cancer.

The recent emergence of radioligand therapies for cancer treatment has increased enthusiasm for developing new theranostic strategies coupling both imaging and cytotoxicity in the same entity. In this study, we evaluated whether CUB domain containing protein 1 (CDCP1), a single-pass transmembrane protein highly overexpressed in diverse human cancers, might be a target for cancer theranostics. The ectodomain of CDCP1 was targeted using radiolabeled forms of 4A06, a potent and specific recombinant human antibody that we developed. Imaging and antitumor assessment studies were performed in animal models of pancreatic cancer, including two patient-derived xenograft models we developed for this study. For antitumor assessment studies, the endpoints were death due to tumor volume >3,000 mm3 or ≥20% loss in body weight. Specific tracer binding or antitumor effects were assessed with an unpaired, two-tailed Student t test and survival advantages were assessed with a log rank (Mantel-Cox) test. Differences at the 95% confidence level were interpreted to be significant. 89Zr-4A06 detected a broad dynamic range of full length or cleaved CDCP1 expression on seven human pancreatic cancer tumors (n = 4/tumor). Treating mice with single or fractionated doses of 177Lu-4A06 significantly reduced pancreatic cancer tumor volume compared with mice receiving vehicle or unlabeled 4A06 (n = 8; P < 0.01). A single dose of 225Ac-4A06 also inhibited tumor growth, although the effect was less profound compared with 177Lu-4A06 (n = 8; P < 0.01). A significant survival advantage was imparted by 225Ac-4A06 (HR = 2.56; P < 0.05). These data establish that CDCP1 can be exploited for theranostics, a finding with widespread implications given its breadth of overexpression in cancer.

Discovery of tofacitinib derivatives as orally active antitumor agents based on the scaffold hybridization strategy

In this work, a novel series of tofacitinib analogs were designed and synthesized based on the scaffold hybridization strategy and then evaluated for their antiproliferative activity toward three gastric cancer cell lines, leading to the identification of compound C18 which exhibited potent inhibitory activity against MGC-803 cell lines with an IC50 value of 2.68 μM. Compound C18 could effectively inhibit the colony formation, suppress the cell migration and induce apoptosis of MGC-803 cells through activating the p38 and JNK signaling pathways, while C18 showed no obvious effect on the cell cycle distribution in MGC-803 cells. In addition, C18 could initiate mitochondrial dysfunction of MGC-803 cells. Besides, in vivo antitumor studies indicated that C18 could inhibit gastric cancer tumor growth in vivo without obvious global toxicity.

The design, synthesis and anti-tumor mechanism study of new androgen receptor degrader

Targeted protein degradation using small molecules is a novel strategy for drug development. In order to solve the problem of drug resistance in the treatment of prostate cancer, proteolysis-targeting chimeras (PROTAC) was introduced into the design of anti-prostate cancer derivatives. In this work, we synthesized two series of selective androgen receptor degraders (SARDs) containing the hydrophobic degrons with different linker, and then investigated the structure-activity relationships of these hybrid compounds. Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Among them, compound A9 displayed potent inhibitory activity against LNCaP prostate cancer cell line with IC50 values of 1.75 μM, as well as excellent AR degradation activity. Primary mechanism studies elucidated compound A9 arrested cell cycle at G0/G1 phase and induced a mild apoptotic response in LNCaP cells. Further study indicated that the degradation of AR was mediated through proteasome-mediated process. For all these reasons, compound A9 held promising potential as anti-proliferative agent for the development of highly efficient SARDs for drug-resistance prostate cancer therapies.

Functionalization of developed bacterial cellulose with magnetite nanoparticles for nanobiotechnology and nanomedicine applications

This paper deals with the preparation of novel magnetic materials made from tetraaza macrocyclic Schiff base bacterial cellulose ligands with magnetite nanoparticles (Fe3O4NPs) through a multi-step procedure for antimicrobial and cytotoxic activities and chemotherapy in cancer treatment. First, the 2,3-dialdehyde bacterial cellulose (DABC) was chemically modified by ethylenediamine (EDA) and benzil (Bzl) in the presence of ferrous ions. Then, the magnetite nanoparticles (Fe3O4NPs) was produced inside the complex [Fe(DABC-EDA-Bzl)Cl2] through a co-precipitation method. In nanobiotechnology, the magnetic [Fe3O4NP-INS-(DABC-EDA-Bzl)] material was showed moderate antimicrobial and cytotoxic activities against different species and cells, respectively. In particular, the magnetic [Fe3O4NP-INS-(DABC-EDA-Bzl)] material have not any cytotoxic activity towards peripheral blood mononucleocyte (PBMC) cells. Anti-tumor studies demonstrated that the magnetic [Fe3O4NP-INS-(DABC-EDA-Bzl)] material effectively inhibits the growth of the CT26 tumor model in BALB/c mice compared with other resulting materials throughout the experimental period and can be effective drug delivery in nanomedicine.

Enhancement of Antitumor Efficacy of Paclitaxel-Loaded PEGylated Liposomes by N,N-Dimethyl Tertiary Amino Moiety in Pancreatic Cancer.

IntroductionPancreatic cancer, or pancreatic duct adenocarcinoma (PDAC), remains one of the most lethal cancers and features insidious onset, highly aggressive behavior and early distant metastasis. The dense fibrotic stroma surrounding tumor cells is thought to be a shield to resist the permeation of chemotherapy drugs in the treatment of PDAC. Thus, we synthesized a pancreas-targeting paclitaxel-loaded PEGylated liposome and investigated its antitumor efficacy in the patient-derived orthotopic xenograft (PDOX) nude mouse models of PDAC.MethodsThe PTX-loaded PEGylated liposomes were prepared by film dispersion-ultrasonic method and modified by an N,N-dimethyl tertiary amino residue. Morphology characteristics of the PTX-loaded liposomes were observed by transmission electron microscope (TEM). The PDOX models of PDAC were established by orthotopic implantation and imaged by a micro positron emission tomography/computed tomography (PET/CT) imaging system. The in vivo distribution and antitumor study were then carried out to observe the pancreas-targeting accumulation and the antitumor efficacy of the proposed PTX liposomes.ResultsPTX loaded well into both modified (PTX-Lip2N) and unmodified (PTX-Lip) PEGylated liposomes with spherical shapes and suitable parameters for the endocytosis process. The PDOX nude mouse models were successfully created in which high 18F-FDG intaking regions were observed by micro-PET/CT. In addition to higher cellular uptakes of PTX-Lip2N by the BxPC-3 cells, the proposed nanoparticle had a notable penetrating ability towards PDAC tumor tissues, and consequently, the antitumor ability of PTX-Lip2N was significantly superior to the unmodified PTX-Lip in vivo PDOX models and even more effective than nab-PTX in restraining tumor growth.ConclusionThe modified pancreas-targeting PTX-loaded PEGylated liposomes provide a promising platform for the treatment of pancreatic cancer.

Nanostructured lipid carriers as oral delivery systems for improving oral bioavailability of nintedanib by promoting intestinal absorption.

The aim of this study was to fabricate nanostructured lipid carriers, NLCs, of nintedanib (BIBF) to improve its oral bioavailability. Two types of NLCs loaded with BIBF (BIBF-NLCs-1 and BIBF-NLCs-2) were prepared by the melt-emulsification technique. BIBF-NLCs-1 and BIBF-NLCs-2 showed nanoscale particle sizes of 142.70±0.85nm and 7.99±0.06nm, and both were positive zeta potential. Study on Caco-2 cells showed that BIBF-NLCs-1 exhibited distinct advantages at the cytological level. The oral bioavailability of BIBF-NLCs-1 and BIBF-NLCs-2 was extremely improved 3.13-fold and 2.39-fold respectively compared with BIBF solution (BIBF-Sol). And in vivo anti-tumor efficiency study in mice bearing LLC lung tumor indicated that BIBF-NLCs-1 and BIBF-NLCs-2 had excellent tumor inhibition. Besides, the two NLCs did not increase the risk of liver damage and can even reduce the incidence of gastrointestinal irritation of BIBF to some extent. In summary, NLCs are a potential oral delivery system to improve the bioavailability of BIBF by promoting intestinal absorption.