Tumor-specific Sites Research Articles

Fe3O4@Chitosan@ZIF-8@RVG29, an anti-glioma nanoplatform guided by fixed and activated by alternating magnetic field

There is considerable interest in developing anti-glioma nanoplatforms. They make the all-in-one combination of therapies possible. Here we show how the selective Glioblastoma multiforme (GBM) cell killing of the here-established nanoplatforms increased after each coating and how the here-established vibration-inducing Alternating magnetic field (AMF) decreased the treatment time from 72 h to 30 s. Thanks to their magnetite core, these nanoplatforms can be guided to the tumor's specific site by a Fixed magnetic field, they bypass the Blood–Brain Barrier (BBB) and accumulate at the tumor site thanks to the RVG29 bonding to the G-protein on the ion-gated channel receptor known as the nicotinic acetylcholine receptor (nAchR), which expresses on BBB cells and overexpresses on GBM cells, and thanks to the positive charge gained by both chitosan and RVG29's peptide. Both ZIF-8 and its mediate adherence, Chitosan increases the drug loading capacity that stimuli response to the tumor's acidic environment. The Zn2+ ions generated from ZIF-8 sustained degradation in such an environment kill the GBM cells. Dynamic Light Scattering (DLS) evaluated these nanoplatform's mean size 155 nm indicating their almost optimum size for brain applications. Based on their elements' intrinsic properties, these nanoplatforms can enhance and combine other adjuvant therapies.

Bio-Responsive Macromolecular Drug and Small-Molecular Drug Conjugates: Nanoparticulate Prodrugs for Tumor Microenvironment Heterogeneity Management and Therapeutic Response Enhancement.

How to break through the poor response of current drug therapy, which often resulted from tumor microenvironment heterogeneity (TMH), remains an enormous challenge in the treatment of critical diseases. In this work, a practical solution on bio-responsive dual-drug conjugates for overcoming TMH and improving antitumor treatment, which integrates the advantages of macromolecular drugs and small-molecular drugs, is proposed. Nanoparticulate prodrugs based on small-molecular drug and macromolecular drug conjugates are designed as a robust weapon for programmable multidrug delivery at tumor-specific sites: the tumor microenvironment acid condition triggers delivery of macromolecular aptamer drugs (AX102) to manage TMH (including tumor stroma matrix, interstitial fluid pressure, vasculature network, blood perfusion, and oxygen distribution), and intracellular lysosomal acid condition activates rapid release of small-molecular drugs (doxorubicin and dactolisib) to enhance curative effects. As compared with doxorubicin chemotherapy, the tumor growth inhibition rate is enhanced by 47.94% after multiple tumor heterogeneity management. This work verifies that the nanoparticulate prodrugs facilitate TMH management and therapeutic response enhancements, as well as elucidates synergetic mechanisms for drug resistance reversal and metastasis inhibition. It is hoped that the nanoparticulate prodrugs will be an excellent demonstration of the co-delivery of small-molecular drugs and macromolecular drugs.

Safety of Direct Acting Oral Anticoagulants (DOACs) in Comparison to Low Molecular Weight Heparin (LWMH) in Gastrointestinal and Genito-Urinary Cancers

Introduction:DOACs are absorbed in the gastrointestinal (GI) tract and DOAC elimination is primarily through the GI and genitourinary (GU) systems. The safety of DOACs in cancer associated thrombosis in subjects with malignant lesions in GI and GU malignancies has been of concern. Studies have been sparse and data conflicting.Methods:We identified patients with active GI and GU malignancies from July 2001 to July 2020 with confirmed VTE at our institution. Patients who received either enoxaparin or a DOAC (apixaban or rivaroxaban) were included in the study. Demographic, disease characteristics, VTE data and events were extracted from electronic medical records (EMR). Date of anticoagulation (AC) initiation was based on the first order and/or prescription of the anticoagulant. Patients were followed either to the earliest bleeding event (BE) or one year from initiation, whichever occurred first. BEs were categorized based on ISTH guidelines. Variables were compared between LMWH and DOAC cohorts, as well as between the apixaban and rivaroxaban cohorts, using t-tests for continuous variables and chi-squared tests or Fisher's exact test for categorical variables.Results:We identified a total of 206 patients, 159 in the DOAC and 47 in the LWMH groups. Table 1 describes the baseline characteristics of the study populations. Median age of patients, gender and BMI were comparable for all groups. When evaluated for type of cancer, 66.6% of patients had active GI malignancy while 33.3% had active GU tumors. The majority of the patients given DOACs had a better ECOG status than those in the LMWH group (p=0.0023), but no difference was noted for ECOG status between DOACs (p=0.69). Most patients had metastatic disease. The majority of the VTE events were in the form of DVTs. Concomitant aspirin intake was 9.4% in DOAC and 4.2% in LMWH groups. Cancer subtypes and AC choice data are given in detail in Table 2.LMWH use was higher in blacks and somewhat lower in the Hispanic population (Table 1). When anticoagulation choice was examined by primary tumor site (Table 2), disproportionately more patients with GU tumors were placed on LMWH while more GI cancers were given a DOAC (p=0.014). Extent and stage of the cancer did not appear to bias anticoagulant choice (p=0.62). Within the DOACs, rivaroxaban use was higher in the GI cancers but considerably less used in the GU malignancies (p=0.00049).There was one recurrent thrombosis in each of the apixaban (1/86) and the rivaroxaban (1/73) cohorts. There were no recurrent events in the LMWH (0/47) cohort.The majority of patients in the DOAC and LMWH groups, 88.1% and 86.4%, had no CRNMB or major bleeding events in the 1-year period after the initiation of the therapeutic AC (Table 3). Combined BE (clinically relevant non-major bleeding [CRNMB] and major bleeding rates) with apixaban, rivaroxaban and LMWH were 17.4% (15/86), 20.5% (15/73), and 19.1% (9/47) respectively. There were no fatal bleeding episodes in any of the groups. Most of the bleeding events on DOACs and LMWHs occurred in the same organ system as the primary cancer (Table 3) but there was no statistically significant difference in bleeding events between patients on DOACs or LMWH for GI, GU or all cancer types (p=0.63, 0.75 and 0.97 respectively). Within DOACs, we also noted no statistically significant difference in the bleeding events with apixaban as compared to rivaroxaban in patients with GI primary, GU primary or all cancer types together, (p=0.47, 0.94 and 0.62 respectively).Conclusion:No significant differences in major/CRNM bleeding events were found for patients with GI or GU cancer associated thrombosis given DOACs (apixaban/rivaroxaban) vs enoxaparin. The tumor site is often the site of bleeding, but no differences in tumor-specific site bleeding could be shown by anticoagulant choice. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Smart stimuli-responsive nanocarriers for the cancer therapy – nanomedicine

Abstract Nanomedicine is ongoing current research in the applications of nanotechnology for cancer therapy. Simply from a technology perspective, this field of research has an enormous broadening and success to date. Recently, nanomedicine has also made inroads in the treatment of cancer. Stimuli-responsive nanoparticles are an emerging field of research because its targeting capacity is of great interest in the treatment of cancer. The responsive nanoparticles are efficient in encountering different internal biological stimuli (acidic, pH, redox, and enzyme) and external stimuli (temperature, ultrasounds, magnetic field, and light), which are used as smart nanocarriers for delivery of the chemotherapeutic and imaging agents for cancer therapy. In-depth, the responsive nanocarrier that responds to the biological cues is of pronounced interest due to its capability to provide a controlled release profile at the tumor-specific site. The outlook of this review focuses on the stimuli-responsive nanocarrier drug delivery systems in sequence to address the biological challenges that need to be evaluated to overcome conventional cancer therapy.

Tumor biology and multidisciplinary strategies of oligometastasis in gastrointestinal cancers.

More than 70% of gastrointestinal (GI) cancers are diagnosed with metastases, leading to poor prognosis. For some cancer patients with limited sites of metastatic tumors, the term oligometastatic disease (OMD) has been coined as opposed to systemic polymetastasis (PMD) disease. Stephan Paget first described an organ-specific pattern of metastasis in 1889, now known as the "seed and soil" theory where distinct cancer types are found to metastasize to different tumor-specific sites. Our understanding of the biology of tumor metastasis and specifically the molecular mechanisms driving their formation are still limited, in particular, as it relates to the genesis of oligometastasis. In the following review, we discuss recent advances in general understanding of this metastatic behavior including the role of specific signaling pathways, various molecular features and biomarkers, as well as the interaction of carcinoma cells with their tissue microenvironments (both primary and metastatic niches). The unique features that underlie OMD provide potential targets for localized therapy. As it relates to clinical practice, OMD is emerging as treatable with surgical resection and/or other local therapy options. Strategies currently being applied in the clinical management of OMD will be discussed including surgical, radiation-based therapy, ablation procedures, and the results of emerging clinical trials involving immunotherapy.

Drug-Carrying Capacity and Anticancer Effect of the Folic Acid- and Berberine-Loaded Silver Nanomaterial To Regulate the AKT-ERK Pathway in Breast Cancer.

Currently, in clinics, breast cancer is treated with free chemotherapeutic drugs, as a result there is not much therapeutic effect in treated models, leading to substantial systemic toxicity. To overcome these critical problems for the primary outcome, we developed the formulated nanomaterial (FA-PEG@BBR-AgNPs) aimed to specifically target cancer cells via nanoscopic-based drug delivery for getting better therapeutic effectiveness. In the present study, an isoquinoline alkaloid, berberine (BBR), was chosen as a cancer therapeutic agent, encapsulated on citrate-capped silver nanoparticles (AgNPs) through electrostatic interactions (BBR-AgNPs). Then, BBR-AgNPs were conjugated with polyethylene glycol-functionalized folic acid (FA-PEG) via hydrogen bonding interactions (FA-PEG@BBR-AgNPs). The transmission electron microscopy study shows the cellular invasion of the formulated FA-PEG@BBR-AgNPs, indicating the accretion of the nanomaterial at the tumor-specific site. Hence, FA conjugated with the nanomaterial suggests an efficient release of BBR molecules into the specific cancer site. Consequently, the results showed an increase in apoptotic induction via reactive oxygen species and condensed nuclei in cancer cells. Moreover, the western blotting analysis shows reduced/increased expression of PI3K, AKT, Ras, Raf, ERK, VEGF, HIF1α, Bcl-2, Bax, cytochrome c, caspase-9, and caspase-3, thereby enhancing apoptosis. Likewise, the in vivo antitumor efficiency of FA-PEG@BBR-AgNPs showed a significant restraint of tumor progression, and histopathological observations of lung, liver, kidney, heart, and brain tissues proved lesser toxicity of FA-PEG@BBR-AgNPs. Thus, the successfully formulated nanomaterial can serve as a potential drug-discharging vehicle to combat cancer cells by a molecular-based targeting approach.

Tailoring the Efficacy of Multifunctional Biopolymeric Graphene Oxide Quantum Dot-Based Nanomaterial as Nanocargo in Cancer Therapeutic Application.

Nanotechnology has acquired an immense recognition in cancer theranostics. Considerable progress has been made in the development of targeted drug delivery system for potent delivery of anticancer drugs to tumor-specific sites. Recently, multifunctional nanomaterials have been explored and used as nanovehicles to carry drug molecules with enhanced therapeutic efficacy. In this present work, graphene oxide quantum dot (GOQD) was conjugated with folic acid functionalized chitosan (FA-CH) to develop a nanocargo (FA-CH-GOQD) for drug delivery in cancer therapy. The synthesized nanomaterials were characterized using Fourier transform infrared spectroscopy, ultraviolet-visible spectroscopy, scanning electron microscopy, transmission electron microscopy, and dynamic light scattering. Photoluminescence spectroscopy was also employed to characterize the formation of GOQD. To validate the efficacy of FA-CH-GOQD as nanocarriers, doxorubicin (DOX) drug was chosen for encapsulation. The in vitro release pattern of DOX was examined in various pH ranges. The drug release rate in a tumor cell microenvironment at pH 5.5 was found higher than that under a physiological range of pH 6.5 and 7.4. An MTT assay was performed to understand the cytotoxic behavior of GOQD and FA-CH-GOQD/DOX. Cytomorphological micrographs of the A549 cell exhibited the various morphological arrangements subject to apoptosis of the cell. Cellular uptake studies manifested that FA-CH-GOQD could specifically transport DOX within a cancerous cell. Further anticancer efficacy of this nanomaterial was corroborated in a breast cancer cell line and demonstrated through 4',6-diamidino-2-phenylindole dihydrochloride staining micrographs.

Targeted nano-delivery of novel omega-3 conjugate against hepatocellular carcinoma: Regulating COX-2/bcl-2 expression in an animal model.

The present approach enumerates the effectiveness of tuftsin tagged nano-liposome for the cytosolic transport of 2,6-di-isopropylphenol-linolenic acid conjugate against liver cancer in mice. Initially, the conjugate in its free form was examined for anticancer potential on HepG2 liver cancer cells. Induction of apoptosis and suppression of migration and adhesion of HepG2 cells confirmed the effectiveness of conjugate as an anticancer agent. After this, role of the conjugate entrapped in a nano-carrier was evaluated in animal model. The nano-formulation comprising of conjugate bearing tuftsin tagged liposome was firsly characterized and then its therapeutic effect was determined. The nano-formulation had 100-130nm size nanoparticles and showed sustained release of the conjugate in the surrounding milieu. The nano-formulation distinctly reduced the expression of COX-2, an important molecule that is vastly expressed in hepatocellular carcinoma. The utilization of in-house engineered nano-formulation was also successful in significantly up-regulating Bax and down-regulating bcl-2 gene expression eventually helping in better survival of treated mice. Histopathological analysis also revealed positive recovery of the general architecture and the violent death of cancer cells by apoptosis at tumor specific site. The site specific delivery of conjugate entrapped in tuftsin tagged liposomes was highly safe as well as efficaceous. Nano-formulation based approach showed a visible chemotherapeutic effect on liver cancer progression in experimental mice thereby making it a potential candidate for treatment of liver cancer in clinical settings.

Human umbilical cord blood-derived mesenchymal stem cells producing IL15 eradicate established pancreatic tumor in syngeneic mice.

Mesenchymal stem cells (MSC) represent a new tool for delivery of therapeutic agents to cancer sites because of their strong tropism toward tumors. IL15 has demonstrated a potent antitumor activity in various animal models as well as clinical trials. However, because of its short half-life, effective therapeutic effects usually require a high dose, which often results in undesired side effects; thus, new strategies for overcoming this disadvantage are needed. In this study, human MSCs were isolated from umbilical cord blood as delivery vehicles and transduced with lentivirus vector expressing murine IL15 (MSC-IL15). In vitro assays of lymphocyte activation and proliferation demonstrated that IL15 produced by MSCs was biofunctional. In syngeneic mice bearing Pan02 pancreatic tumors, systemic administration of MSC-IL15 significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice, which were associated with tumor cell apoptosis, and natural killer (NK)- and T-cell accumulation. Furthermore, we confirmed that MSC-IL15 could migrate toward tumor and secreted IL15 in tumor-specific sites. Depletion of NK and CD8(+) T cells abolished the antitumor activity of MSC-IL15, suggesting that NK and CD8(+) T cells play a key role for MSC-IL15-mediated effect. Interestingly, cured mice after MSC-IL15 treatment were resistant to Pan02 pancreatic tumor rechallenge, and adoptive transfer of lymphocytes from cured mice also could cause rejection of Pan02 tumor inoculation in naïve mice, indicating that MSC-IL15 induced tumor-specific T-cell immune memory response. Overall, these data support that MSCs producing IL15 might represent an innovative strategy for therapy of pancreatic tumor.

Dual Targeted Polymeric Nanoparticles Based on Tumor Endothelium and Tumor Cells for Enhanced Antitumor Drug Delivery

Some specific types of tumor cells and tumor endothelial cells represented CD13 proteins and act as receptors for Asn-Gly-Arg (NGR) motifs containing peptide. These CD13 receptors can be specifically recognized and bind through the specific sequence of cyclic NGR (cNGR) peptide and presented more affinity and specificity toward them. The cNGR peptide was conjugated to the poly(ethylene glycol) (PEG) terminal end in the poly(lactic-co-glycolic) acid PLGA-PEG block copolymer. Then, the ligand conjugated nanoparticles (cNGR-DNB-NPs) encapsulating docetaxel (DTX) were synthesized from preformed block copolymer by the emulsion/solvent evaporation method and characterized for different parameters. The various studies such as in vitro cytotoxicity, cell apoptosis, and cell cycle analysis presented the enhanced therapeutic potential of cNGR-DNB-NPs. The higher cellular uptake was also found in cNGR peptide anchored NPs into HUVEC and HT-1080 cells. However, free cNGR could inhibit receptor mediated intracellular uptake of NPs into both types of cells at 37 and 4 °C temperatures, revealing the involvement of receptor-mediated endocytosis. The in vivo biodistribution and antitumor efficacy studies indicated that targeted NPs have a higher therapeutic efficacy through targeting the tumor-specific site. Therefore, the study exhibited that cNGR-functionalized PEG-PLGA-NPs could be a promising approach for therapeutic applications to efficient antitumor drug delivery.

Loss of NAPRT1 Expression by Tumor-Specific Promoter Methylation Provides a Novel Predictive Biomarker for NAMPT Inhibitors

We sought to identify predictive biomarkers for a novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitor. We use a NAMPT inhibitor, GNE-617, to evaluate nicotinic acid rescue status in a panel of more than 400 cancer cell lines. Using correlative analysis and RNA interference (RNAi), we identify a specific biomarker for nicotinic acid rescue status. We next determine the mechanism of regulation of expression of the biomarker. Finally, we develop immunohistochemical (IHC) and DNA methylation assays and evaluate cancer tissue for prevalence of the biomarker across indications. Nicotinate phosphoribosyltransferase (NAPRT1) is necessary for nicotinic acid rescue and its expression is the major determinant of rescue status. We demonstrate that NAPRT1 promoter methylation accounts for NAPRT1 deficiency in cancer cells, and NAPRT1 methylation is predictive of rescue status in cancer cell lines. Bisulfite next-generation sequencing mapping of the NAPRT1 promoter identified tumor-specific sites of NAPRT1 DNA methylation and enabled the development of a quantitative methylation-specific PCR (QMSP) assay suitable for use on archival formalin-fixed paraffin-embedded tumor tissue. Tumor-specific promoter hypermethylation of NAPRT1 inactivates one of two NAD salvage pathways, resulting in synthetic lethality with the coadministration of a NAMPT inhibitor. NAPRT1 expression is lost due to promoter hypermethylation in most cancer types evaluated at frequencies ranging from 5% to 65%. NAPRT1-specific immunohistochemical or DNA methylation assays can be used on archival formalin paraffin-embedded cancer tissue to identify patients likely to benefit from coadministration of a Nampt inhibitor and nicotinic acid.

Immunochemical Studies of the Intramolecular Heterogeneity of the Carcinoembryonic Antigen (CEA) of the Human Digestive System

Abstract Previous studies have shown that in addition to the tumor-specific site on the carcinoembryonic antigen (CEA), this molecule also contains a blood group A-like grouping. To study the A-like site on the CEA molecule, we devised a radioimmunoassay in which anti-A antibodies were coupled to either Sepharose or Sephadex beads. The following observations were made. 1) The monosaccharide, N-acetyl-D-galactosamine was capable of inhibiting the interaction between 125I-CEA and a preparation of anti-A antibodies. 2) A glycopeptide (GP-1), containing the tumor-specific antigenic site of the CEA, which was obtained by the enzymatic degradation of the CEA molecule was capable of binding to anti-A antibodies. The ratio, by weight, of GP-1 to N-acetyl-D-galactosamine required to achieve equivalent binding was 10-3 to 10-4 to 1. GP-1 has a molecular weight of about 4000 daltons, and although it contains N-acetyl-D-glucosamine, D-mannose, D-galactose, and L-fucose, the glycopeptide is apparently devoid of N-acetyl-D-galactosamine.