Platelet Membranes Coated Gold Nanocages for Tumor Targeted Drug Delivery and Amplificated Low-Dose Radiotherapy

Continuous high doses of radiation can cause irreversible side effects and radiation resistance; thus, advanced radiosensitizers are urgently needed. To overcome this problem, we developed a nano platelet radiosensitization system (PCA) by coating the chemotherapeutic drug cisplatin (CDDP) loaded gold nanocages (AuNs) within the platelet membrane. The developed PCA system may enable AuNs to have immune escape and targeting capabilities. After administration, PCA will actively target tumor cells and avoid being cleared by the immune system. Subsequently, CDDP, which destroys tumor cell DNA, can not only kill tumor cells directly but also combine with AuNs, which deposit radiation energy into tumor tissues, reducing RT resistance. In vivo and in vitro studies revealed that the combination of PCA with RT (2Gy) efficiently inhibits tumor proliferation without causing side effects such as inflammation. To conclude, this is the first attempt to use platelet membranes to correctly transport AuNs while also accomplishing low-dose RT, which could help AuNs-based tumor RT become more effective.

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Tumor-derived biomimetic nanozyme with immune evasion ability for synergistically enhanced low dose radiotherapy

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01182-y ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Chunyu Huang ◽

Zeming Liu ◽

Mingzhu Chen ◽

Liang Du ◽

Chunping Liu ◽

...

Keyword(s):

Immune Evasion ◽

Low Dose ◽

Immune Escape ◽

Redox Homeostasis ◽

Low Dose Radiotherapy ◽

Tumor Tissues ◽

High Doses ◽

Intracellular Hydrogen Peroxide

AbstractHigh doses of radiation can cause serious side effects and efficient radiosensitizers are urgently needed. To overcome this problem, we developed a biomimetic nanozyme system (CF) by coating pyrite (FeS2) into tumor-derived exosomes for enhanced low-dose radiotherapy (RT). CF system give FeS2 with immune escape and homologous targeting abilities. After administration, CF with both glutathione oxidase (GSH-OXD) and peroxidase (POD) activities can significantly lower the content of GSH in tumor tissues and catalyze intracellular hydrogen peroxide (H2O2) to produce a large amount of ·OH for intracellular redox homeostasis disruption and mitochondria destruction, thus reducing RT resistance. Experiments in vivo and in vitro showed that combining CF with RT (2 Gy) can provide a substantial suppression of tumor proliferation. This is the first attempt to use exosomes bionic FeS2 nanozyme for realizing low-dose RT, which broaden the prospects of nanozymes. Graphical Abstract

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Tumor-Derived Biomimetic Nanozyme With Immune Evasion Ability For Synergistically Enhanced Low Dose Radiotherapy

10.21203/rs.3.rs-927124/v1 ◽

2021 ◽

Author(s):

Chunyu Huang ◽

Zeming Liu ◽

Mingzhu Chen ◽

Liang Du ◽

Yongfa Zheng ◽

...

Keyword(s):

High Performance ◽

Low Dose ◽

Immune Escape ◽

Redox Homeostasis ◽

Low Dose Radiotherapy ◽

Tumor Tissues ◽

High Doses ◽

Intracellular Hydrogen Peroxide

Abstract High doses of radiation can cause serious side effects and drug resistance, high-performance radiosensitizers are urgently needed. To overcome this issue, we developed a biomimetic nanozyme system (CF) by coating pyrite (FeS2) into tumor-derived exosomes for use in combination with low-dose RT. CF system give FeS2 with immune escape and homologous targeting abilities. After administration, CF with both glutathione oxidase (GSH) and peroxidase activities can significantly lower the content of GSH in tumor tissues and catalyze intracellular hydrogen peroxide (H2O2) to produce a large amount of ·OH for intracellular redox homeostasis disruption and mitochondria destruction, thus reducing RT resistance. Experiments in vivo and in vitro showed that combining CF with RT (2Gy) can provide a substantial suppression of tumor proliferation. To summarize, this is the first attempt to use exosomes bionic FeS2 nanozyme for realizing low-dose RT, which broaden the prospects of nanozymes.

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Low dose amiodarone reduces tumor growth and angiogenesis

Scientific Reports ◽

10.1038/s41598-020-75142-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Eliana Steinberg ◽

Arnon Fluksman ◽

Chalom Zemmour ◽

Katerina Tischenko ◽

Adi Karsch-Bluman ◽

...

Keyword(s):

Side Effects ◽

Cancer Cells ◽

Low Dose ◽

Tumor Model ◽

In Vitro Assays ◽

Potential Candidate ◽

Key Factor ◽

Angiogenic Effect

Abstract Amiodarone is an anti-arrhythmic drug that was approved by the US Food and Drug Administration (FDA) in 1985. Pre-clinical studies suggest that Amiodarone induces cytotoxicity in several types of cancer cells, thus making it a potential candidate for use as an anti-cancer treatment. However, it is also known to cause a variety of severe side effects. We hypothesized that in addition to the cytotoxic effects observed in cancer cells Amiodarone also has an indirect effect on angiogensis, a key factor in the tumor microenvironment. In this study, we examined Amiodarone's effects on a murine tumor model comprised of U-87 MG glioblastoma multiforme (GBM) cells, known to form highly vascularized tumors. We performed several in vitro assays using tumor and endothelial cells, along with in vivo assays utilizing three murine models. Low dose Amiodarone markedly reduced the size of GBM xenograft tumors and displayed a strong anti-angiogenic effect, suggesting dual cancer fighting properties. Our findings lay the ground for further research of Amiodarone as a possible clinical agent that, used in safe doses, maintains its dual properties while averting the drug’s harmful side effects.

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SCIDOT-28. TARGETED NANOPARTICLES FOR IMPROVED DRUG DELIVERY TO MEDULLOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.1164 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi277-vi277

Author(s):

Joelle P Straehla ◽

Natalie Boehnke ◽

Tamara G Dacoba ◽

Paula T Hammond

Keyword(s):

Drug Delivery ◽

Endothelial Cells ◽

Side Effects ◽

Tumor Cells ◽

Chemical Engineering ◽

Xenograft Model ◽

In Vivo Studies ◽

Layer By Layer

Abstract Platinum-based agents remain a key component of therapy for children with medulloblastoma, despite significant systemic side effects and only modest blood-brain barrier (BBB) penetration. Cisplatin has a cerebrospinal fluid-to-plasma ratio <5% and dose-limiting side effects of nephrotoxicity, ototoxicity, and myelosuppression. Improving delivery of cisplatin across the BBB and selectively accumulating in tumors could improve its therapeutic index. To this end, we are leveraging chemical engineering techniques to rationally design cisplatin nanoparticles (NPs) to cross the BBB and preferentially enter medulloblastoma tumor cells. Using the layer-by-layer (LbL) platform to ‘wrap’ polyelectrolytes around a NP core by iterative electrostatic adsorption, we screened six negatively charged polypeptide and polysaccharide outer layers in medulloblastoma cell lines. Poly-L-aspartic acid (PLD) layered NPs had significant accumulation in tumor cells after 24 hours incubation, with an uptake index of 18±4 over unlayered control NPs. Next, we generated propargyl-functionalized PLD and used click chemistry to covalently conjugate the BBB shuttle ligands glutathione, angiopep-2, and transferrin, which have been shown to mediate transcytosis across brain endothelial cells. PLD layered NPs functionalized with angiopep-2 and transferrin had enhanced uptake in medulloblastoma tumor cells and NPs functionalized with glutathione were non-inferior to PLD layered NPs. After incubation with endothelial cells in vitro, all three BBB shuttle ligands enhanced uptake of PLD layered NPs over unlayered and non-functionalized control NPs. We then incorporated cisplatin into the nanoparticle core of this platform. Cisplatin-loaded NPs with PLD layering and ligand functionalization were more effective than free cisplatin as measured by IC50 over 72 hours in culture, and led to faster apoptosis as assessed by flow cytometry with annexin V and propidium iodide staining. In summary, functionalized nanoparticles are a promising platform to modulate drug delivery to medulloblastoma. In vivo studies using an orthotopic xenograft model are underway to investigate biodistribution, efficacy, and toxicity.

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Injectable Hydrogel for Synergetic Low Dose Radiotherapy, Chemodynamic Therapy and Photothermal Therapy

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.757428 ◽

2021 ◽

Vol 9 ◽

Author(s):

Mingzhu Chen ◽

Ziqi Wang ◽

Weilong Suo ◽

Zhirong Bao ◽

Hong Quan

Keyword(s):

Photothermal Therapy ◽

Low Dose ◽

Tumor Therapy ◽

Intratumoral Injection ◽

Low Dose Radiation ◽

Injectable Hydrogel ◽

Low Dose Radiotherapy ◽

Dose Radiation

Higher doses of radiotherapy (RT) are associated with resistance induction, therefore highly selective and controllable radiosensitizers are urgently needed. To address this issue, we developed a FeGA-based injectable hydrogel system (FH) that can be used in combination with low-dose radiation. Our FH can deliver FeGA directly to the tumor site via intratumoral injection, where it is a reservoir-based system to conserve FeGA. The photothermal properties of FeGA steadily dissolve FH under laser irradiation, and, simultaneously, FeGA reacts with a large amount of H2O2 in the cell to produce OH (Fenton reaction) which is highly toxic to mitochondria, rendering the cell inactive and reducing radiotherapy resistance. In vivo and in vitro studies suggest that combining the FH and NIR irradiation with RT (2Gy) can significantly reduce tumor proliferation without side effects such as inflammation. To conclude, this is the first study to achieve combined chemodynamic therapy (CDT) and photothermal therapy (PTT) in situ treatment, and the best therapeutic effect can be obtained with a low-dose radiation combination, thus expanding the prospects of FeGA-based tumor therapy.

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Wogonin sensitizes resistant malignant cells to TNFα- and TRAIL-induced apoptosis

Blood ◽

10.1182/blood-2006-03-011973 ◽

2006 ◽

Vol 108 (12) ◽

pp. 3700-3706 ◽

Cited By ~ 79

Author(s):

Stefanie C. Fas ◽

Sven Baumann ◽

Jia Yun Zhu ◽

Marco Giaisi ◽

Monika K. Treiber ◽

...

Keyword(s):

Side Effects ◽

Tumor Cells ◽

Chinese Herb ◽

Protein Synthesis Inhibitors ◽

Normal Peripheral Blood ◽

Herbal Compound ◽

Induced Apoptosis ◽

Potential Use

AbstractTNFα has previously been used in anticancer therapy. However, the therapeutic application of TNFα was largely limited due to its general toxicity and the fact that it activates the NF-κB–family transcription factors, which are proinflammatory and antiapoptotic. To overcome this problem in vitro, specific NF-κB inhibitors or transcription or protein synthesis inhibitors such as actinomycin D and cycloheximide are usually used in combination to increase TNFα killing of tumor cells. However, these agents also cause harmful side effects in vivo. We show here that wogonin, derived from the popular Chinese herb Huang-Qin, attenuates NF-κB activity by shifting TNFα-induced free radical ·O2– to a more reduced nonradical product, H2O2, and thereby sensitizes TNFα-resistant leukemia cells to TNFα-induced apoptosis. Importantly, wogonin does not affect the viability of normal peripheral blood T cells. Wogonin also sensitizes TRAIL-induced apoptosis. Our data suggest a potential use of wogonin as a TNFα or TRAIL adjuvant for cancer treatment. Our data also demonstrate how a herbal compound enhances killing of tumor cells with reduced side effects compared with other treatments.

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Our experience of low-dose consecutive CDDP and intermittent S-1 (LP/IS) therapy for advanced gastric cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.14145 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 14145-14145

Author(s):

K. Kobayashi ◽

A. Enjoji ◽

Y. Nagata ◽

Y. Tajima ◽

T. Kanematsu

Keyword(s):

Gastric Cancer ◽

Advanced Gastric Cancer ◽

Tumor Cells ◽

Low Dose ◽

Locally Advanced ◽

Outpatient Basis ◽

Taste Disturbance ◽

Low Toxicity

14145 Background: 5-FU and CDDP combination chemotherapy (FP) has been widely used as standard therapy for advanced gastric cancer (AGC), and in Japan FP therapy was modified into [5-FU (CVI) and low-dose consecutive CDDP (LC-P)](LFP) Therapy from 1990. LFP therapy has been widely used for the treatment of AGC, because of low toxicity and high response rate. We observed that CDDP inhibited metionine transport into tumor cells, both in vitro and in vivo, with synergistic interaction by CDDP functioning as a modulator of 5-FU. However LFP Therapy needs 24-hour continuous infusion of 5-FU, the applicants for LFP must be hospitalized. Therefore we used S-1, novel oral fluoropyrimidine as effector of 5-FU, and combined LC-P aiming the same synergy as LFP therapy. In addition, utilizing the difference in cell cycle between normal cells and tumor cells, we applied intermittent administration of S-1, which leads lower toxicity than conventional LFP therapy. We tried this LC-P and intermittent S-1 (LP/IS) Therapy for AGC, examining whether LP/IS was possible as outpatient-basis. Methods: Patients with AGC received LP/IS therapy. S-1 (80 mg/m2/day) was administered per orally and CDDP (10 mg/body/day) was infused for half an hour. The administration schedule consisted of S-1 for 1,3,5 days intermittently and CDDP for 2,5 days twice a week for each four weeks. RESIST criteria and NCI-CTC (ver.3) were used to assess LP/IS. Results: Between July and November 2005, four patients (A/B/C/D) were entered into this trial. Information is available for all patients. Characteristics were: age (A/B/C/D=75/59/65/54): sex (A/B/C=M, D=F): disease status (A/B= locally advanced, C/D= postoperative recurrence). S-1 and CDDP were administered to 97.9% and 84.4% of planned dose, respectively. As for toxicity, only grade 2 taste disturbance and anorexia occurred in two patients. All the patients had one course LP/IS and are evaluable for anti-tumor effects; primary (A/B=NC/NC), metastatic (A/B/C/D=NC/NC/NC/PD), respectively. A and B could undergo total gastrectomy. TTF was (A/B/C/D=42/35/55/29 days), and survival time was (A/B/C/D=164/94/104/71 days, C: dead). Conclusions: Because of low toxicity and high feasibility, LP/IS therapy is appropriate for out-patient basis chemotherapy for AGC. No significant financial relationships to disclose.

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Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1921445117 ◽

2020 ◽

Vol 117 (12) ◽

pp. 6640-6650 ◽

Cited By ~ 11

Author(s):

Xiaodong Wang ◽

Xiaohui Yang ◽

Chang Zhang ◽

Yang Wang ◽

Tianyou Cheng ◽

...

Keyword(s):

Cell Proliferation ◽

Tumor Suppressor ◽

Tumor Growth ◽

Tumor Cell ◽

Tumor Cells ◽

Colony Formation ◽

Immune Escape ◽

Potential Biomarker

The programmed cell death 1 (PD-1) receptor on the surface of immune cells is an immune checkpoint molecule that mediates the immune escape of tumor cells. Consequently, antibodies targeting PD-1 have shown efficacy in enhancing the antitumor activity of T cells in some types of cancers. However, the potential effects of PD-1 on tumor cells remain largely unknown. Here, we show that PD-1 is expressed across a broad range of tumor cells. The silencing of PD-1 or its ligand, PD-1 ligand 1 (PD-L1), promotes cell proliferation and colony formation in vitro and tumor growth in vivo. Conversely, overexpression of PD-1 or PD-L1 inhibits tumor cell proliferation and colony formation. Moreover, blocking antibodies targeting PD-1 or PD-L1 promote tumor growth in cell cultures and xenografts. Mechanistically, the coordination of PD-1 and PD-L1 activates its major downstream signaling pathways including the AKT and ERK1/2 pathways, thus enhancing tumor cell growth. This study demonstrates that PD-1/PD-L1 is a potential tumor suppressor and potentially regulates the response to anti-PD-1/PD-L1 treatments, thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment.

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Promotion of tumor progression induced by continuous low-dose administration of antineoplastic agent gemcitabine or gemcitabine combined with cisplatin

10.21203/rs.3.rs-665968/v1 ◽

2021 ◽

Author(s):

Yanshen CHEN ◽

Hua LIU ◽

Qiaowei ZHENG ◽

Houli LI ◽

Huining YOU ◽

...

Keyword(s):

Cell Cycle ◽

Tumor Cells ◽

Antineoplastic Agents ◽

Low Dose ◽

Tumor Formation ◽

Dose Administration ◽

Tumor Tissues ◽

Low Dose Chemotherapy

Abstract Background: There are indications that certain antineoplastic agents at low dosages may exhibit abnormal pharmacological actions, such as promoting tumor growth. However, the phenomenon still needs to be further confirmed, and its underlying mechanisms have not yet been fully elucidated.Methods: Gemcitabine (GEM) and cisplatin (CDDP) were employed as representative antineoplastic agents to observe effects of continuous low-dose chemotherapy with GEM or GEM combined with CDDP (GEM+CDDP) on tumor formation and growthin xenograft tumor models in vivo. Tumor and endothelial cell functions, apoptosis, cell cycle analysis, as well as bone marrow derived cells (BMDCs) mobilization, were evaluated with transwell, MTT or flow cytometry analysis in vitro, respectively. Histological methods were employed to assess angiogenesis in tumor tissues.Results: The results showed that tumor formation and growth were both significantly promoted by GEM or GEM+CDDP at as low as half of the metronomic dosages, which were accompanied by enhancements of angiogenesis in tumor tissues and the release of proangiogenic BMDCs in the circulating blood. Additionally, GEM or GEM+CDDP at low concentrations dramatically facilitated the proliferation, migration, and invasion of tumor cells in vitro. Cell-cycle arrest, activation of associated apoptotic proteins, and inhibition of apoptosis were also observed in tumor cells. Conclusions: These findings indicate that, the continuous low-dose administration of GEM and GEM+CDDP can promote tumorigenesis and tumor progression in vivo by inhibiting apoptosis, mobilizing BMDCs, and promoting angiogenesis in certain dose ranges. These findings urge further investigations to avoid the potential risks in current empiric continuous low-dose chemotherapy regimens with antineoplastic agents.

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