Discovery of the antitumor effects of a porphyrazine diol (Pz 285) in MDA-MB-231 breast tumor xenograft models in mice

A series of porphyrazines (Pzs) with chiral bis-acetal moieties in the β-pyrrole positions ((2R,3R)-2,3-dimethyl-2,3-dimethoxy-1,4-diox-2-ene) have been synthesized and screened as antitumor agents in MDA-MB-231 breast tumor cellsin vitro. The leadPz 285was further tested in a mouse tumor xenograft model with Td-tomato-luc2 fluorescent breast tumor cells (MDA-MB-231 LM24 Her2+) that are highly metastatic to the lungs.Pz 285shows marked antitumor effectsin vivo, with treated mice exhibiting longer median survival that we attribute to smaller primary tumor regrowth after resection and less occurrence of metastasis when compared to vehicle control groups.Pz 285is further compared to the clinically approved chemotherapeutic doxorubicin (Dox). This report lays the groundwork for development of an understudied class of compounds for classical chemotherapy

A predictive model for the selective accumulation of chemicals in tumor cells

Cationic lipophilic dyes can accumulate in mitochondria, and especially in mitochondria of tumor cells. We investigated the chemical properties and the processes allowing selective uptake into tumor cells using the Fick–Nernst–Planck equation. The model simulates uptake into cytoplasm and mitochondria and is valid for neutral molecules and ions, and thus also for weak electrolytes. The differential equation system was analytically solved for the steady-state and the dynamic case. The parameterization was for a generic human cell, with a 60 mV more negative potential at the inner mitochondrial membrane of generic tumor cells. The chemical input data were the lipophilicity (logKOW), the acid/base dissociation constant (pKa) and the electric charge (z). Accumulation in mitochondria occurred for polar acids with pKa between 5 and 9 owing to the ion trap, and for lipophilic bases with pKa>11 or permanent cations owing to electrical attraction. Selective accumulation in tumor cells was found for monovalent cations or strong bases with logKOW of the cation between −2 and 2, with the optimum near 0. The results are in agreement with experimental results for rhodamine 123, a series of cationic triarylmethane dyes, F16 and MKT-077, an anticancer drug targeting tumor mitochondria