A Triphenylphosphonium-Functionalized Mitochondriotropic Nanocarrier for Efficient Co-Delivery of Doxorubicin and Chloroquine and Enhanced Antineoplastic Activity.

Katerina N Panagiotaki,Zili Sideratou,Spiros A Vlahopoulos,Maria Paravatou-Petsotas,Dimitris Tsiourvas,Vassilis Zoumpourlis,Nikolas Khoury,Michael Zachariadis

doi:10.3390/ph10040091

Abstract

Drug delivery systems that target subcellular organelles and, in particular, mitochondria are considered to have great potential in treating disorders that are associated with mitochondrial dysfunction, including cancer or neurodegenerative diseases. To this end, a novel hyperbranched mitochondriotropic nanocarrier was developed for the efficient co-delivery of two different (both in chemical and pharmacological terms) bioactive compounds. The carrier is based on hyperbranched poly(ethyleneimine) functionalized with triphenylphosphonium groups that forms ~100 nm diameter nanoparticles in aqueous media and can encapsulate doxorubicin (DOX), a well-known anti-cancer drug, and chloroquine (CQ), a known chemosensitizer with arising potential in anticancer medication. The anticancer activity of this system against two aggressive DOX-resistant human prostate adenocarcinoma cell lines and in in vivo animal studies was assessed. The co-administration of encapsulated DOX and CQ leads to improved cell proliferation inhibition at extremely low DOX concentrations (0.25 μΜ). In vivo experiments against DU145 human prostate cancer cells grafted on immunodeficient mice resulted in tumor growth arrest during the three-week administration period and no pervasive side effects. The findings put forward the potential of such targeted low dose combination treatments as a therapeutic scheme with minimal adverse effects.

Highlights

One common theme in several types of antineoplastic drugs is their capacity to induce detectable levels of cell stress, which results in the stimulation of systems that degrade biomolecules [1]
We previously demonstrated the capacity of a nanocarrier based on an oligolysine scaffold by addition of two triphenylphosphonium cations per oligomer to target mitochondria [30]
By precisely selecting the molar ratio of the interacting moieties and the synthetic conditions, it is possible to fine-tune the number of decylTPP groups attached in each poly(ethyleneimine) scaffold

Summary

Introduction

One common theme in several types of antineoplastic drugs is their capacity to induce detectable levels of cell stress, which results in the stimulation of systems that degrade biomolecules [1]. Increased proteolysis of apoptosis mediators enables neoplastic cells to survive in spite of targeted biological therapy and treatment with established antineoplastic drugs [1,2]. Analysis of intracellular signal transduction pathways operating in cancer leads to the conclusion that interactions between transcription factors, which mediate coordination between innate and adaptive immunity, are compromised in neoplastic tissue [5]. This aberrant function of transcription regulators occurs in parallel with changes in organelle homeostasis that encompass both cancer cells, as well as their microenvironment [1,5,6]. A drug that interferes potently with the response of cancer cells to cell stress is chloroquine

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