Acetazolamide‐Loaded pH‐Responsive Nanoparticles Alleviating Tumor Acidosis to Enhance Chemotherapy Effects

Abstract

Carbonic anhydrase IX (CA IX), over‐expressed on cancer cells, catalyzes CO2 to bicarbonate and protons, contributing to the acidic extracellular pH (pHe), which enhances the multidrug resistance of tumor cells. Therefore, alleviating tumor acidosis would greatly improve the outcome of chemotherapy. This work fabricates acetazolamide (ACE)‐loaded pH‐responsive nanoparticles (ACE‐NPs), which are quickly disintegrated in an acidic solution (pH 6.8), resulting in a quick release of ACE from these NPs to inhibit the expression of CA IX, thus up‐regulating the pHe value. These ACE‐NPs have no obvious in vitro cytotoxicity and in vivo studies confirm the accumulation of ACE‐NPs in tumor tissue. In addition, mice treated with ACE and paclitaxel (PTX) co‐loaded NPs show a smaller tumor size and a higher survival rate when compared to that of mice treated with ACE‐ or PTX‐loaded NPs. This work reveals that simultaneous delivery of ACE and chemotherapy agents to tumor tissue can up‐regulate the acidic pHe value, consequently enhancing the anti‐tumor ability of chemotherapy medicine. These findings open a new window for enhancing the anti‐tumor ability of traditional chemotherapy in clinic.

A Multifunctional Graphene Oxide Platform for Targeting Cancer

“…Except one study using silica nanoparticles coated with the anti-CA IX MAb M75 [62], all other studies exploited carbonic anhydrase inhibitors. As CA inhibitors are principally acting towards diverse CA isoforms due to similarities in their active sites, selectivity to CA IX was conferred by diverse carriers [45], gold nanoparticles [46], pH-responsive nanoparticles [47], polymer-based photodynamic nanoinhibitor particles [48]. However, the approaches using inhibitors principally differ from the approach using monoclonal antibodies.…”

“…Another study demonstrated the modification of screen-printed carbon electrodes by assembling graphene oxide to obtain electrochemical immunosensors with immobilized antibodies specific to mucin 1, which is a well-known tumor marker for a variety of malignant tumors [44]. Efforts to detect or target CA IX have been mostly focused on development of diverse nanoparticles decorated by inhibitors of Carbonic anhydrases with modifications conferring selectivity towards CA IX and/or other cell surface isoforms [45,46,47,48]. These approaches require access to active site of the enzyme, whereas the antibodies can bind CA IX even in an inactive state.…”

Milk-exosome based pH/light sensitive drug system to enhance anticancer activity against oral squamous cell carcinoma

“…24 The imine bond is easily disintegrated in an acidic solution (pH ¼ 6.8). 25 Thus, if exosome membrane is conjugated chemotherapy drugs with hydrazone bond, the cleavage of the imine bond triggered by acidic TME would result in quick release of drugs in the tumor site. Next, hypoxia is another the distinct hallmarks of TME that induce irreversible tumor metastasis, as well as inict hypoxiaassociated resistance.…”

Oxygen Sensors in Atherosclerosis

“…More details can be found in chapter 2; a review addressing the position of PHD enzymes in hallmarks of atherosclerosis. In short, PHD proteins form a potentially interesting target in atherosclerosis, as HIF1 was already shown to affect plaque development in several cell types [92][93][94]. Furthermore, previous studies uncovered a role of isoform specific PHD signaling in NF-κB activation [95][96], fibrosis [97][98][99][100] and lipid/glucose metabolism [101], which are all instrumental in atherogenesis, emphasizing the possible impact of PHDs in plaque development.…”

“…Thirdly, CAIX targeting nanoparticles are under investigation [91], although this is still in a pre-clinical testing stage. Nevertheless, results from in vivo mouse models are promising, showing reduced tumor growth and higher survival rates in animals treated with CAIX inhibiting nanoparticles [92]. Altogether, multiple CAIX inhibiting compounds are being developed as we speak.…”