The pH partition theory predicts the accumulation and toxicity of doxorubicin in normal and low-pH-adapted cells

Abstract

SummaryThe accumulation and toxicity of the weak base doxorubicin has been investigated as a function of extracellular pH, intracellular pH and the cellular pH gradient in cells previously cultured under normal (pH 7.4) and low-pH (6.8) conditions. Low-pH-adapted cells exhibit transmembrane pH gradients which substantially differ from normal cells at the same extracellular pH. No relationship was obtained between intracellular pH and the uptake or toxicity of doxorubicin in the two cell types. In contrast, doxorubicin accumulation and toxicity increased with increasing extracellular pH in both normal and low-pH-adapted cells. However, at the same extracellular pH, drug cytotoxicity was more pronounced in normal than in low-pH-adapted cells. The difference in doxorubicin accumulation and cytotoxicity at the same extracellular pH was found to be dependent on the difference in the transmembrane pH gradient of the two cell types. As the cellular pH gradient differs between tumour and normal tissue, this observation suggests a basis for enhancing cellular drug uptake in either tissue type.

Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics

“…It is to be noted that the above analysis is based on the assumption that a linear increase in intracellular drug concentration results in an exponential decrease in the tumor cell surviving fraction, and that surviving tumor cells grow exponentially as shown in Fig. 1A and B. A linear-log relationship between cell drug concentration and cell surviving fraction assessed by colony formation assays has previously been shown by ourselves and others for doxorubicin and chlorambucil over a substantial drug concentration range (13,14,22,23,26).…”

Oxaprozin-Loaded Lipid Nanoparticles towards Overcoming NSAIDs Side-Effects

“…The pH of an inflammation site environment is significantly lower than the surrounding environment being around 6.4 for inflammation sites and 7.4 for healthy tissues [82]. So, this factor can be used in the creation of pH sensitive targeting systems that will only release the drug in low pH.…”

Overcoming Physiologic Barriers to Cancer Treatment by Molecularly Targeting the Tumor Microenvironment

“…Low pHe and the resulting pH gradient across the plasma membrane of tumor cells also present a barrier to drug delivery for many chemotherapeutic agents (46). Large lipophilic molecules pass through biological membranes most efficiently in an uncharged state.…”