Glioblastoma multiforme and anaplastic astrocytomas are the most common type of primary brain tumors in adults. Tumor recurrence (96% cases), adjacent to resection margin after surgical resection, is seen calling out for adjuvant therapy. Due to the presence of blood-brain barrier, the current chemotherapeutics are unable to reach the brain tumor. Noscapine, an antitussive pediatric preparation, at higher concentration induces apoptosis and metaphase arrest in dividing cells with minimal or less toxicity in primary and secondary brain tumor. Nanoparticulate-based drug delivery systems have opened new avenues for the treatment of gliomas and other types of brain tumors. Due to small size, nanometric material causes better permeability of therapeutic agents into cells compared to conventional therapy. Nanoparticulate drug delivery systems that are currently under investigation for treatment and diagnosis of primary brain tumor include liposomes, polymeric nanoparticles, quantum dots, and polymeric micelles. Nanoparticles may offer an improvement to nose-to-brain drug delivery since they are able to protect the encapsulated drug from biological and/or chemical degradation and extracellular transport by P-gp efflux proteins. This would increase central nervous system availability of the drug. To achieve the ultimate clinical translation of noscapine nanoparticles delivery system, a great deal of effort through interdisciplinary collaborations will be required to optimize dose, the design of nanocarrier, to improve the bioavailability at target site with minimal toxicity, in vivo pharmacokinetics, and targeting efficacy through intranasal route.
BackgroundTT-10 and TT-4 are potent and selective antagonists of adenosine A2A receptor (A2AR) and A2B receptor (A2BR) respectively. Both agents are being developed for the treatment of advanced cancers initially as monotherapy, using high levels of adenosine receptor expression in tumor tissue as biomarker.MethodsBalb/c mice were implanted with CT-26 cells and randomly assigned to 8 groups per study; (1) vehicle control, (2) adenosine antagonist - 1 mg/kg A2AR (TT-10) 1 mg/kg or 3 mg/kg A2BR (TT-4), (3) 10 mg/kg Anti-mPD-1, (4) 5 mg/kg Anti-mCTLA-4, (5) 100 mg/kg Irinotecan, (6) adenosine antagonist + Anti-mPD-1, (7) adenosine antagonist + Anti-mCTLA-4, (8) adenosine antagonist+ Irinotecan. Adenosine antagonists and control were given daily by oral gavage, Anti-mPD-1, Anti-mCTLA-4 and Irinotecan were administered Intraperitoneal. Treatment was started on day 1 post implant and mice were followed until individual tumor volume reached 2,000 or 3000 mm3 (as defined by protocol) or moribund. Tumor measurements and weights were taken every 2 to 3 days. In addition, a subset of mice were investigated for changes in peripheral whole blood and intra-tumor analysis on days 3 and 10 via flow cytometry. The populations of interest included CD223+, CD3+, CD4+, CD8+, CD25+FoxP3+, CD25-CD69+ and CD44+CD62L.ResultsAll implanted mice developed measurable tumors. Mean suppression of tumor growth was observed to be greater in single agent adenosine antagonists TT-10 and TT-4 when compared to the vehicle control and was observed to show overall greater suppression of tumor growth when combined with anti-mPD-1 or anti-m-CTLA-4. Tumor infiltrating lymphocyte analysis by flow cytometry, showed higher amounts of CD25+FoxP3+ present in control mice at day 3, than was observed in mice that were treated with A2AR alone, A2AR + anti-mPD-1 and A2AR + anti-m-CTLA-4.ConclusionsTT-10 and TT-4 alone was superior to vehicle control in slowing tumor growth. However, the combination of TT-10 + Anti-mPD-1 and TT-4 + Anti-mCTLA-4 showed the greatest tumor response and growth suppression. Furthermore, a striking reduction of CD25+FoxP3+ within the tumor was observed at day 3 in mice treated with A2AR alone, A2AR + anti-mPD-1 and A2AR + anti-m-CTLA-4 when compared to the vehicle control.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.