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

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.

miR‑127 aggravates myocardial failure by promoting the TGF‑β1/Smad3 signaling

“…Animals had free access to food and water. Doxorubicin (DOX), an anthracycline antibiotic commonly used as chemotherapy medication, is frequently used to establish animal models of cardiomyopathy ( 20 ). The animal model was established as previously described using 6 intraperitoneal injections with 2.5 mg/kg DOX (Adriamycin ® ; Pfizer, Inc., New York, NY, USA) every 48 h to achieve an accumulative dose of 15 mg/kg ( 21 ).…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…33 This has been the subject of various studies, from which evidence is emerging that CQ can significantly strengthen the antineoplastic immune response, at least under certain conditions. [44][45][46] Although we will show that CQ has diverse effects on tissue metabolism and homeostasis in general, the key scientific field that has the potential to enable CQ incorporation in anticancer drug combinations is the study of interference with immune functions. 35,36 It is important to note that cell stress from antineoplastic treatment and CQs can activate some transcription factors, which may reprogram the cells and thereby enable tumor cells to escape from cell death induced by drug treatment or from the immune system.…”

“…6,42,43 To this end, nanotechnology is expected to help to decrease the systemic exposure to CQs and their derivatives. [44][45][46] Although we will show that CQ has diverse effects on tissue metabolism and homeostasis in general, the key scientific field that has the potential to enable CQ incorporation in anticancer drug combinations is the study of interference with immune functions. In the next paragraphs, we will attempt to explain why we consider this field as essential to the effective use of CQ in treatment combinations.…”

“…280 Interestingly, it was reported that CQ preferentially enhances the death of Myc-overexpressing cells, in a p53dependent but not an ATM-dependent manner. 45 Therefore, a combination with inhibitors of DNA repair can be studied, as under certain conditions it might improve Th1-driven immune responses, and in parallel, provide additional cytotoxicity toward malignant cells. 14 Similarly, CQ can be combined with other drugs causing DNA damage, such as anthracyclines, especially when using nanocarriers that enable cell penetration, leading to inhibition of the growth of human prostate cancer xenografts in mice.…”

“…14 Similarly, CQ can be combined with other drugs causing DNA damage, such as anthracyclines, especially when using nanocarriers that enable cell penetration, leading to inhibition of the growth of human prostate cancer xenografts in mice. 45 Therefore, a combination with inhibitors of DNA repair can be studied, as under certain conditions it might improve Th1-driven immune responses, and in parallel, provide additional cytotoxicity toward malignant cells. 143 In human breast cancer cells, a mutant adenomatous polyposis coli gene induces STAT3, an activator of DNA repair genes, which renders cells resistant to anthracyclines.…”