RETRACTED ARTICLE: The PI3K/mTOR dual inhibitor BEZ235 nanoparticles improve radiosensitization of hepatoma cells through apoptosis and regulation DNA repair pathway

Abstract

Polymer materials encapsulating drugs have broad prospects for drug delivery. We evaluated the effectiveness of polyethylene glycol-poly (lactic-co-glycolic acid) (PLGA-PEG) encapsulation and release characteristics of PI3K/mTOR inhibitor NVP-BEZ235 (BEZ235). We proposed a strategy for targeting radiosensitization of liver cancer cells. The biocompatibility, cell interaction, and internalization of Glypican-3 (GPC3) antibody-modified, BEZ235-loaded PLGA-PEG nanoparticles (NP-BEZ235-Ab) in hepatoma cells in vitro were studied. Also, the cell killing effect of NP-BEZ235-Ab combined with γ-ray cell was evaluated. We used confocal microscopy to monitor nanoparticle-cell interactions and cellular uptake, conducted focus-formation experiments to analyze the synergistic biological effects of NP-BEZ235-Ab and priming, and studied synergy in liver cancer cells using molecular biological methods such as western blotting. We found that PLGA-PEG has good loading efficiency for BEZ235 and high selectivity to GPC3-positive HepG2 liver cancer cells, thus documenting that NP-BEZ235-Ab acts as a small-molecule drug delivery nanocarrier. At the nominal concentration, the NP-BEZ235-Ab nanoformulation synergistically kills liver cancer cells with significantly higher efficiency than does the free drug. Thus, NP-BEZ235-Ab is a potential radiosensitizer.

Nanoparticle-Based Drug Delivery in Cancer Therapy and Its Role in Overcoming Drug Resistance

“…For example, the PI3K/Akt/mTOR pathway can regulate the expression of HIF-1α, and the inhibition of this pathway down-regulates HIF-1α expression, thereby enhancing the sensitivity of MDR cells to cancer treatment ( Zhang et al, 2018 ). In this process, NPs, such as PLGA-PEG ( Tang X. et al, 2020 ) and PEGylated and non-PEGylated liposomes ( Iwase and Maitani, 2012 ), can offer better platforms to achieve combination therapy. In addition, heat shock protein 90 (HSP90) is required for HIF-1 transcriptional activity, and inhibition of HSP90 can also down-regulate HIF-1α expression ( Semenza, 2007 ).…”

Synergistic Anticancer Strategy of Sonodynamic Therapy Combined with PI-103 Against Hepatocellular Carcinoma

“…Furthermore, ROS accumulation produced an inhibitory effect on HCC proliferation via the PI3K/AKT/mTOR signaling pathway, which was mainly activated in advanced HCC due to the poor prognosis of patients. 33,34 PI-103 is a synthetic small molecule that selectively inhibits class I PI3K and mTOR. 35 It has been used in preclinical studies to demonstrate antiproliferative effects against several cancer types.…”

Hypoxia-induced therapy resistance: Available hypoxia-targeting strategies and current advances in head and neck cancer

“… Group Drug Classification Target Refs. HIF-α inhibitors PT2385 Allosteric modulator HIF-2α [37] Acriflavine Topical antiseptic HIF-1 dimerization [38] BAY 87–2243 Mitochondrial Complex I inhibitor HIF-1α/2α [39] Digoxin Cardiac Glycoside HIF-1α [40] Digitoxin Cardiac Glycoside Topoisomerases and MAPK [40] EZN-2208 PEGylated SN38 Topoisomerase I [41] BEZ-235 Imidazoquinoline derivative PI3K/Akt/mTOR [42] Metformin Type-II diabetes drug mTOR [43] Rapamycin Macrolide compound mTOR [44] Minnelide Diterpenoid triepoxide prodrug p300, Hsp70 [45] Anti-angiogenic drugs Bevacizumab Monoclonal Ab VEGF [46] Ramucirumab Monoclonal Ab VEGFR-2 [47] Axitinib Tyrosine kinase inhibitor VEGFR-1/2/3 [48] Sunitinib Tyrosine kinase inhibitor VEGFR-1/2, KIT and PDGFRα/β [49] Imatinib Tyrosine kinase inhibitor PDGFRα and c-KIT [50] …”

“…Given that one of the downstream effects of the PI3K/AKT/mTOR signalling pathway is translation of HIF-α mRNA, inhibitors of one or several components of this pathway result as well in indirect downregulation of HIF-α [63] . Amongst this group of inhibitors, we can distinguish between multi-targeted drugs such as BEZ-235 and metformin, and selective inhibitors like rapamycin [ 42 , 43 , 64 ]. Unfortunately, BEZ-235 (Dactolisib) showed high toxicity levels in preclinical studies and the completed clinical trials so far have not obtained any benefits [65] .…”