Ultrastable and Biofunctionalizable Conjugated Polymer Nanoparticles with Encapsulated Iron for Ferroptosis Assisted Chemodynamic Therapy

Abstract

We report the development of novel tumor-targeted conjugated polymer nanoparticles (CPNPs) carrying iron for chemodynamic therapy (CDT). Tumor cell killing proceeds through ferroptosis, a reactive oxygen species (ROS) mechanism that is not dependent on external activation by, for example, light, as is the case in photodynamic therapy (PDT). The ferroptosis mechanism is also not heavily reliant on oxygen availability and is, therefore, promising for the treatment of hypoxic tumors. In this work, we apply this development to the case study of melanoma, a difficult to treat cancer in advanced stages due to resistance to chemotherapy. The iron-carrying CPNPs reported here are targeted to endothelin-B receptors (EDNRB) through endothelin-3 surface moieties (EDN3-CPNPs). Our results show excellent targeting to tumor cells that overexpress EDNRB, specifically for melanoma and bladder tumor cells. In these cases, efficient cell killing, over 80% at higher doses, was found. Conversely, tumor cells not targeted by the EDN3-CPNPs show little effects of CDT, with tumor cell death under 20% in most cases. The outcomes of our work demonstrate that EDN3-CPNPs enable ferroptosis-assisted CDT and present a new therapeutic avenue for tumor treatment.

Targeting Lipid Peroxidation for Cancer Treatment

“…NPs can incorporate molecules on their surface that preferentially target cancer cells (i.e., folate [232] and 5-(4-hydroxyphenyl)-10,15,20-triphenylporphyrin [233]). The successful delivery of anticancer drugs can be achieved through this strategy [234][235][236][237].…”

“…Some recent advances have been made regarding the synthesis of NPs loaded with metals, mainly with iron, which can facilitate lipid peroxidation in cancer cells [234,238,239]. As previously indicated, iron overload produces an increase in random peroxidation products that is entirely unspecific and could lead to harmful oxidative stress in non-cancer cells.…”

“…Some recent advances have been made regarding the synthesis of NPs loaded with metals, mainly with iron, which can facilitate lipid peroxidation in cancer cells [234,238,239]. As previously indicated, iron overload produces an increase in random peroxidation products that is entirely DHODH 14 [229] 2-(4-(2,6-difluorophenoxy)-3isopropoxy-5-methy l-1H-pyrazol-1-yl) -5-ethylpyrimidine (BDBM50070908) [230] 0.02 (Jurkat cells) Human lymphocytes [231] Molecules 2020, 25 14 [229] 2-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1Hpyrazol-1-yl)-5ethylpyrimidine (BDBM50070908) [230] 0.02 (Jurkat cells) Human lymphocytes [231] Kinetic parameters were obtained from BRENDA enzyme database [89].…”

Photodynamic therapy regulates fate of cancer stem cells through reactive oxygen species

“…PDT combined with the Fenton reaction[ 176 ] is a feasible treatment method for CSCs showing strong drug resistance. In addition, a new type of programmed cell death, ferroptosis, is also closely related to Fe 2+ and the Fenton reaction[ 177 ]. Some researchers have found that ferricin chelates lysosomal iron[ 178 ].…”

Utilizing Iron for Targeted Lipid Peroxidation as Anticancer Option of Integrative Biomedicine: A Short Review of Nanosystems Containing Iron

“…In recent years, an effort has been made to develop nanoparticles with encapsulated iron for ferroptosis assisted CDT. Conjugated polymer nanoparticles (CPNPs) containing iron(III) and targeted to endothelin-B receptors selectively trigger ferroptosis of melanoma cells with no significant effect on normal cells [63]. Wang and colleagues developed redox-and light-responsive (RLR) nanoparticles that contained iron and were programmed to degrade and self-activate in an acidic environment with excessive glutathione, as is the case for a tumor microenvironment (TME).…”