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Barriers in the Tumor Microenvironment to Nanoparticle Activity
Published in Dan Peer, Handbook of Harnessing Biomaterials in Nanomedicine, 2021
Hanan Abumanhal-Masarweh, Lilach Koren, Omer Adir, Maya Kaduri, Maria Poley, Gal Chen, Aviram Avital, Noga Sharf Pauker, Yelena Mumblat, Jeny Shklover, Janna Shainsky-Roitman, Avi Schroeder
Decreased proliferation rates of cancer cells and over-expression of multidrug resistance gene 1 (MDR1) and p-glycoprotein(p-gp) efflux pump gene can be correlated with hypoxia-mediated resistance to chemotherapeutic agents that aimed toward highly proliferative cells [13]. In this manner, hypoxia-activated prodrugs, such as tirapazamine, were loaded into nanocarriers to modulate the activity of HIF-1 [197, 219, 222–225].
Nanomedicine for Radiation Therapy
Published in Sarwar Beg, Mahfoozur Rahman, Md. Abul Barkat, Farhan J. Ahmad, Nanomedicine for the Treatment of Disease, 2019
In addition to encapsulating radiosensitizers, some nanomaterials with high atomic numbers (Z) can work as radiosensitizers themselves. Gold nanoparticles are the most widely used nanoradiosensitizers. The dose absorbed by any tissue is related to the Z2 of the material. If an agent can increase the overall effective Z of tumor without affecting the Z of nearby tissue, it can lead to increased radiotherapy dose to tumors and higher therapeutic efficacy. One example is the glutathione-coated gold nanocluster. Efficient uptake of gold nanocluster by tumors (~8.1% ID/g 24 h post injection) led to a significantly increased response of tumors to radiotherapy and reduced damage to normal tissues. In addition, there’s no long-term side effect induced by nanocluster accumulation because they can be cleared by kidney (Zhang, 2015). Gadolinium (Z = 64) is another widely used radiosensitizer. Miladi et al. found DTPA modified gadolinium-based ultrasmall nanoparticles could increase nonrepairable DNA breaks by shortening the G2/M phase blockage in vitro. They also observed significant delay in tumor growth when combing with radiation in vivo. Shi et al. developed rattle nanoparticles composed of upconversion core as radiation amplifiers. Tirapazamine (a hypoxia-activated prodrug) was loaded in the nanoparticle as hypoxia-selective cytotoxin to overcome the oxygen dependency of radiotherapy. The nanoparticles showed high histocompatibility and low cytotoxicity in vivo. Moreover, hypoxic tumor cells were killed specifically when combining with low-dose radiotherapy (Liu, 2015). Other potential applications of inorganic nanoparticles in radiation therapy are still under investigation, such as superparamagnetic zinc ferrite spinel (ZnFe2O4) in treatment of human prostate cancer cells (Meidanchi, 2015), and Y2O3-based psoralen-functionalized nanoscintillators to kill cancer cells (Scaffidi, 2011).
Therapeutical potential of metal complexes of quinoxaline derivatives: a review
Published in Journal of Coordination Chemistry, 2022
Chrisant William Kayogolo, Maheswara Rao Vegi, Bajarang Bali Lal Srivastava, Mtabazi Geofrey Sahini
A study by Vieites et al. [54] reported that vanadyl complexes (69‒71) of 3-amino-6(7)-chloroquinoxaline-2-carbonitrile N1,N4-dioxide (L1 = 66), 3-amino-6(7)-bromo-quinoxaline-2-carbonitrile N1,N4-dioxide (L2 = 67) and 3-amino-6(7)-methylquinoxaline-2-carbonitrile N1,N4-dioxide (L3 = 68) (Figure 27) are very selective towards in vitro cytotoxicity in hypoxia. The resultant complexes (69 and 70) are potentially more cytotoxic in vitro than the ligands as indicated by their potencies (P69 = P70 = 3.0, P66 = 9.0, P67 = 7.2 μM) and the standard drug tirapazamine (P = 30.0 μM) with excellent selective cytotoxicity under hypoxia but inactive in oxygenated conditions. The complexes of vanadium were significantly soluble in hydrophilic solvents which could be an indication that the ligation to vanadium improved ligands′ bioavailability [54]. To search for a correlation between the reduction potentials of the complexes and their activities and hypoxia selectivities, electrochemical behavior was investigated. The results demonstrated the absence of correlation between reduction potentials of the complexes and their potencies and hypoxic selectivities as the complexes exhibited very similar redox behavior to ligands. However, the values of reduction potential fell within the range suitable for optimal bioreductive agents [54], suggesting that the complexes and the ligands work by formation of free radicals in their mode of action.