<p>Proton Pump Inhibitors Modulate Transport Of Doxorubicin And Its Liposomal Form Into 2D And 3D Breast Cancer Cell Cultures</p>

Abstract

PurposeThe purpose of our study was to evaluate the influence of two PPIs (omeprazole (OME) and lansoprazole (LANSO)) on weakly basic anticancer drug doxorubicin (DOX) and pegylated liposomal doxorubicin (PLD) delivery to monolayer-cultured 4T1 murine breast cancer cells and tumor spheroids.MethodsThe effect of PPIs on cell viability was evaluated by MTT assay. 3D cell cultures (spheroids) were formed using 3D bioprinting method. DOX and PLD penetration into cancer cells and spheroids at pH 6.0 and 7.4 was assessed using fluorescence microscopy.ResultsBoth OME and LANSO did not reduce the viability of 4T1 cells at 100 μM and lower concentrations, and therefore, in further experiments, 100 μM of PPIs was used. At pH 7.4, both tested PPIs did not enhance DOX (5 µM) and PLD (concentration corresponding to 5 µM DOX) delivery into 2D cell cultures. However, in acidic conditions, both PPIs increased the amount of drug in cancer cells and their nucleus. At physiological pH they were not effective at improving DOX delivery into spheroids, but after 2 hrs of incubation, OME slightly increased PLD delivery into edge and middle zones. At pH 6.0, both tested PPIs significantly enhanced DOX and PLD transport into spheroids, but the positive effect on delivery was observed only within the first 4 hrs of incubation.ConclusionBoth OME and LANSO increased DOX and PLD penetration into monolayer-cultured cells at acidic conditions but did not show a positive effect on drug delivery at physiological pH. Also, pretreatment with tested PPIs slightly increased DOX and PLD delivery in the edge and middle zones of tumor spheroids. Thus, OME and LANSO are promising transport modulators of weakly basic drugs.

In Vitro Cell Toxicity and Intracellular Uptake of Doxorubicin Exposed as a Solution or Liposomes: Implications for Treatment of Hepatocellular Carcinoma

“…In our in vitro study, the 2-h pretreatment of lansoprazole had no consistent effect on the observed IC 50 values for DOXs or DOX PL in the examined cell lines. One plausible explanation is that slightly acidic conditions (pH 6) are required in order to have a PPI-effect on DOX potency [ 55 ].…”

Three-Dimensional Spheroids as In Vitro Preclinical Models for Cancer Research

“…As pH levels decrease, metalloproteinases become activated, destroying cell interactions which facilitates tumor migration and invasion [46]. Acidic microenvironment causes the "ion trapping" phenomenon, process in which basic anticancer drugs are transformed into a cation substance, reducing their transmembrane permeability and, consequently, their effectiveness [47]. Immune cells such as macrophages, neutrophils, mast cells, myeloid-derived suppressor cells, and natural killer cells, secret many soluble factors that promote immunosuppression, angiogenesis, chronic inflammation, and drug resistance [43,[48][49][50].…”

The reversed intra- and extracellular pH in tumors as a unified strategy to chemotherapeutic delivery using targeted nanocarriers

“…In fact, numerous preclinical studies and some ongoing clinical trials can be found in the literature about the usefulness of these PPIs to increase the pH e and avoid MDR in cancer 17 , 23 , 32 . Paškevičiūtė and Petrikaitė 33 reported the use of two PPIs, omeprazole (OPZ) and lansoprazole (LPZ), to enhance delivery of doxorubicin in its free form or inside PEGylated liposomes to 4T1 breast cancer cells and 3D cell cultures (4T1) at simulated pH e of 6.0, not observing this effect at physiological pH and being LPZ more effective than OPZ.…”

“…Despite the advantages of using targeted nanocarriers in combination with V-ATPase inhibitors to enhance the delivery of weakly basic chemotherapeutic agents, to the best of our knowledge, apart from the reports by Paškevičiūtė 33 and Bhattacharya 37 ( Table S1 ), no other papers have been published in this regard.…”