Co-Delivery of Chloroquine and Doxorubicin by Hypoxia-Responsive Liposomes for Enhanced Synergistic Antitumor Activity in Treating Solid Tumor

2020 ◽  
Vol 12 (11) ◽  
pp. 1309-1314
Author(s):  
Xuemeng Liu ◽  
Qianqian Luo ◽  
Zhongping Chen
Keyword(s):  
Antitumor Activity ◽  
Drug Release ◽  
Solid Tumors ◽  
Solid Tumor ◽  
High Sensitivity ◽  
Hypoxic Condition ◽  
Good Stability ◽  
Normoxic Condition ◽  
Synergistic Antitumor Activity

Chloroquine, initially used to treat malaria, has been discovered as a sensitizer to augment antitumor activity of other clinically used chemotherapeutics. In this work, chloroquine and doxorubicin were co-loaded into hypoxia-responsive liposomes to synergistically treat solid tumor. In vitro drug release profiles demonstrated that the liposomes were of not only good stability under normoxic condition but also high sensitivity under hypoxic condition. In vitro cell experiments demonstrated that chloroquine augmented doxorubicin cytotoxicity, and co-loaded liposomes were thus more toxic than single-loaded liposomes, especially under hypoxic condition, as a result of hypoxia-responsive drug release. These findings highlighted the potential for chloroquine and doxorubicin co-loaded hypoxia-responsive liposomes in treating solid tumors.

Assessment of amentoflavone loaded sub-micron particle preparation using supercritical antisolvent for its antitumor activity

2021 ◽  
Vol 18 ◽  
Author(s):  
Shulei Duan ◽  
Jingfu Jia ◽  
Biao Hong ◽  
Jie Zhou ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Drug Release ◽  
Spherical Shape ◽  
Inhibitory Effect ◽  
Supercritical Antisolvent ◽  
Micron Particle ◽  
Release Assay ◽  
Particle Preparation ◽  
Release Speed

Introduction: The amentoflavone (AMF) loaded polymeric sub-micron particles were prepared using supercritical antisolvent (SAS) technology with the aim of improving the anticancer activity of AMF. Materials and Methods: Zein and phospholipid mixtures composed of hydrogenated phosphatidylcholine (HPC) and egg lecithin (EPC) were used as carrier materials and, the effects of carrier composition on the product morphology and drug release behavior were investigated. When the mass ratio of Zein/HPC/EPC was 7/2/1, the AMF loaded particles were spherical shape and sub-micron sized around 400 nm, with a drug load of 4.3±0.3 w% and entrapment efficacy of 87.8±1.8%. The in vitro drug release assay showed that adding EPC in the wall materials could improve the dispersion stability of the released AMF in an aqueous medium, and the introduction of HPC could accelerate the drug release speed. Results: MTT assay demonstrated that AMF-loaded micron particles have an improved inhibitory effect on A375 cells, whose IC50 was 37.39μg/ml, compared with that of free AMF(130.2μg/ml). Conclusion: It proved that the AMF loaded sub-micron particles prepared by SAS were a prospective strategy to improve the antitumor activity of AMF, and possibly promote the clinical use of AMF preparations.

SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models

2021 ◽  
Vol 13 (591) ◽  
pp. eabd8836
Author(s):  
Axel Hyrenius-Wittsten ◽  
Yang Su ◽  
Minhee Park ◽  
Julie M. Garcia ◽  
Josef Alavi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Mouse Models ◽  
Solid Tumor ◽  
Car T Cells ◽  
Therapeutic Benefits ◽  
Car T

The first clinically approved engineered chimeric antigen receptor (CAR) T cell therapies are remarkably effective in a subset of hematological malignancies with few therapeutic options. Although these clinical successes have been exciting, CAR T cells have hit roadblocks in solid tumors that include the lack of highly tumor-specific antigens to target, opening up the possibility of life-threatening “on-target/off-tumor” toxicities, and problems with T cell entry into solid tumor and persistent activity in suppressive tumor microenvironments. Here, we improve the specificity and persistent antitumor activity of therapeutic T cells with synthetic Notch (synNotch) CAR circuits. We identify alkaline phosphatase placental-like 2 (ALPPL2) as a tumor-specific antigen expressed in a spectrum of solid tumors, including mesothelioma and ovarian cancer. ALPPL2 can act as a sole target for CAR therapy or be combined with tumor-associated antigens such as melanoma cell adhesion molecule (MCAM), mesothelin, or human epidermal growth factor receptor 2 (HER2) in synNotch CAR combinatorial antigen circuits. SynNotch CAR T cells display superior control of tumor burden when compared to T cells constitutively expressing a CAR targeting the same antigens in mouse models of human mesothelioma and ovarian cancer. This was achieved by preventing CAR-mediated tonic signaling through synNotch-controlled expression, allowing T cells to maintain a long-lived memory and non-exhausted phenotype. Collectively, we establish ALPPL2 as a clinically viable cell therapy target for multiple solid tumors and demonstrate the multifaceted therapeutic benefits of synNotch CAR T cells.

scholarly journals Correction: In Vitro and In Vivo Synergistic Antitumor Activity of the Combination of BKM120 and Erlotinib in Head and Neck Cancer: Mechanism of Apoptosis and Resistance

2020 ◽  
Vol 19 (9) ◽  
pp. 1955-1955
Author(s):  
Abu Syed Md Anisuzzaman ◽  
Abedul Haque ◽  
Dongsheng Wang ◽  
Mohammad Aminur Rahman ◽  
Chao Zhang ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Antitumor Activity ◽  
Head And Neck ◽  
Neck Cancer ◽  
Synergistic Antitumor Activity

scholarly journals In vitro and in vivo evaluation of antitumor activity of methanolic extract of Argyreia nervosa leaves on Ehrlich ascites carcinoma

2015 ◽  
Vol 10 (2) ◽  
pp. 399
Author(s):  
Bhawna Sharma ◽  
Isha Dhamija ◽  
Sandeep Kumar ◽  
Hema Chaudhary
Keyword(s):  
Antitumor Activity ◽  
Solid Tumor ◽  
Methanolic Extract ◽  
Ehrlich Ascites Carcinoma ◽  
Ehrlich Ascites ◽  
Wide Range ◽  
Antioxidant Parameters ◽  
Argyreia Nervosa

<p>The herb of importance like <em>Argyreia nervosa</em> has shown wide range of pharmacological activities. Its methanolic extract of <em>A. nervosa</em> has been explored against Ehrlich ascites carcinoma (EAC) induced liquid and solid tumor in mice. Liquid and solid tumors were induced by intraperitoneal and subcutaneous transplantation of EAC cells in Balb/C mice. Significant and dose dependant results are observed when the mice are sacrificed on 15<sup>th</sup> day for estimation of tumor proliferation, hematological, biochemical and hepatic antioxidant parameters. Mean survival time (days) was increased to 36.5 from 20.5 extract treated mice. The extract also showed a decrease (p&lt;0.001) in body weight and percentage reduction in tumor volume respectively when it was evaluated in solid tumor induced mice for a period of 30 days.  From the result it was concluded that the extract has as a potent antitumor activity and that is comparable to 5-fluorouracil.</p><p> </p>

PEG−Doxorubicin Conjugates:  Influence of Polymer Structure on Drug Release, in Vitro Cytotoxicity, Biodistribution, and Antitumor Activity

2005 ◽  
Vol 16 (4) ◽  
pp. 775-784 ◽  
Author(s):  
Francesco M Veronese ◽  
Oddone Schiavon ◽  
Gianfranco Pasut ◽  
Raniero Mendichi ◽  
Lars Andersson ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Drug Release ◽  
Polymer Structure ◽  
In Vitro Cytotoxicity ◽  
Release In Vitro

Targeting a single mismatched minor histocompatibility antigen with tumor-restricted expression eradicates human solid tumors

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 1844-1852 ◽  
Author(s):  
Lothar Hambach ◽  
Marcel Vermeij ◽  
Andreas Buser ◽  
Zohara Aghai ◽  
Theodorus van der Kwast ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Graft Versus Host Reaction ◽  
Aberrant Expression ◽  
Immunodeficient Mice ◽  
Graft Versus Host ◽  
Specific Ctls ◽  
Human Solid Tumors

Abstract Regressions of metastatic solid tumors after allogeneic human leukocyte antigen (HLA)–matched stem cell transplantation (SCT) are often associated with detrimental graft-versus-host disease (GVHD). The graft-versus-host reaction of the HLA-matched donor is directed mainly against the multiple mismatched minor histocompatibility antigens (mHags) of the patient. mHags are strong HLA-restricted alloantigens with differential tissue distribution. Ubiquitously expressed mHags are the prime in situ targets of GVHD. The mHag HA-1 is hematopoiesis restricted, but displays additionally an aberrant expression on solid tumors. Thus, HA-1 might be an excellent target to boost the anti–solid tumor effect of allogeneic SCT without inducing severe GVHD. Here, we show that cytotoxic T lymphocytes (CTLs) solely targeting the human mHag HA-1 are capable of eradicating 3-dimensional human solid tumors in a highly mHag-specific manner in vitro, accompanied by interferon-γ release. In vivo, HA-1–specific CTLs distribute systemically and prevent human breast cancer metastases in immunodeficient mice. Moreover, HA-1–specific CTLs infiltrate and inhibit the progression of fully established metastases. Our study provides the first proof for the efficacy of a clinically applicable concept to exploit single mismatched mHags with hematopoiesis- and solid tumor–restricted expression for boosting the anti–solid tumor effect of allogeneic SCT.

scholarly journals BOXR1030, an anti-GPC3 CAR with exogenous GOT2 expression, shows enhanced T cell metabolism and improved antitumor activity

2021 ◽  
Author(s):  
Taylor L Hickman ◽  
Eugene Choi ◽  
Kathleen R Whiteman ◽  
Sujatha Muralidharan ◽  
Tapasya Pai ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Solid Tumor ◽  
Cell Function ◽  
Cell Metabolism ◽  
Car T Cells ◽  
Car T

Purpose: The solid tumor microenvironment (TME) drives T cell dysfunction and inhibits the effectiveness of immunotherapies such as chimeric antigen receptor-based T cell (CAR T) cells. Early data has shown that modulation of T cell metabolism can improve intratumoral T cell function in preclinical models. Experimental Design: We evaluated GPC3 expression in human normal and tumor tissue specimens. We developed and evaluated BOXR1030, a novel CAR T therapeutic co-expressing glypican-3 (GPC3)-targeted CAR and exogenous glutamic-oxaloacetic transaminase 2 (GOT2) in terms of CAR T cell function both in vitro and in vivo. Results: Expression of tumor antigen GPC3 was observed by immunohistochemical staining in tumor biopsies from hepatocellular carcinoma, liposarcoma, squamous lung cancer, and Merkel cell carcinoma patients. Compared to control GPC3 CAR alone, BOXR1030 (GPC3-targeted CAR T cell that co-expressed GOT2) demonstrated superior in vivo efficacy in aggressive solid tumor xenograft models, and showed favorable attributes in vitro including an enhanced cytokine production profile, a less-differentiated T cell phenotype with lower expression of stress and exhaustion markers, an enhanced metabolic profile and increased proliferation in TME-like conditions. Conclusions: Together, these results demonstrated that co-expression of GOT2 can substantially improve the overall antitumor activity of CAR T cells by inducing broad changes in cellular function and phenotype. These data show that BOXR1030 is an attractive approach to targeting select solid tumors. To this end, BOXR1030 will be explored in the clinic to assess safety, dose-finding, and preliminary efficacy (NCT05120271).

First-in-human study of PM14 in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3078-3078
Author(s):  
Maria Vieito ◽  
Santiago Ponce Aix ◽  
Luis G. Paz-Ares ◽  
Rastilav Bahleda ◽  
Christophe Massard ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Geometric Mean ◽  
Human Study ◽  
Fine Tuning ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Ecog Ps ◽  
Tumor Types

3078 Background: PM14 is a new chemical entity that forms DNA adducts which specifically inhibit RNA synthesis and block active transcription of protein-coding genes. Antitumor activity has been demonstrated in vitro in several cell lines (e.g. lung, kidney, prostate), and in vivo in mice bearing xenografted human-derived tumors (soft tissue sarcoma, small cell lung cancer, ovarian, gastric, breast and renal cancer). Methods: Open-label, dose-escalating, phase I trial of PM14 administered as a 3-hour infusion i.v. every 3 weeks (q3wk) in patients (pts) with advanced solid tumors, adequate organ function and ECOG PS score of 0-1. Two schedules were explored: Schedule A (Day 1 [D1], Day 8 [D8]) and Schedule B (D1). Results: 37 pts were treated (Schedule A/B: 28/9 pts). Baseline characteristics of pts (A/B): median age 56/47 years; male 57%/56%; ECOG PS 0: 57%/56%; median of prior lines (range): 3 (1-8)/4 (1-10). Most common tumor types (A + B): STS (n=7 pts), ovarian (n=6), pancreatic (n=4), prostate cancer (n=3). The maximum tolerated dose was 4.5 mg/m2 for A (dose-limiting toxicities [DLTs]: D8 omission due to lack of recovery of lab parameters for re-treatment [n=2 pts]) and 5.6 mg/m2 (DLTs: G4 febrile neutropenia [n=1], G4 transaminase increase [n=1]) for B. The recommended dose (RD) was 3.0 mg/m2 on D1,D8 (A), and 4.5 mg/m2 on D1 (B). No DLTs were present at the RDs. Most common toxicities were hematological abnormalities and transaminase increase. Main toxicities at the RDs are shown below. Antitumor activity comprised stable disease ≥4 months in 7 heavily pretreated pts (6 in A; 1 in B) at all dose levels. Linear pharmacokinetics were observed for PM14 at tested doses (0.25-5.6 mg/m²), with geometric mean (CV%) total plasma clearance 5.9 L/h (88%), volume of distribution 128 L (81%) and median (range) terminal half-life 15.9 h (7.5-34.3 h). Less than 1.6% of administered dose was recovered in urine. Conclusions: RDs were determined for two PM14 schedules in pts with advanced solid tumors. At the RDs, PM14 is well tolerated and has a manageable safety profile. An expansion phase in specific tumor types, with an optional Bayesian continual reassessment method for RD fine-tuning, is ongoing with both schedules.[Table: see text]

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