Model‐Based Nanoengineered Pharmacokinetics of Iron‐Doped Copper Oxide for Nanomedical Applications

Abstract

The progress in nanomedicine (NM) using nanoparticles (NPs) is mainly based on drug carriers for the delivery of classical chemotherapeutics.A sl ow NM delivery rates limit therapeutic efficacy,a ne ntirely different approach was investigated. Ahomologous series of engineered CuO NPs was designed for dual purposes (carrier and drug) with adirect chemical composition-biological functionality relationship. Model-based dissolution kinetics of CuO NPs in the cellular interior at post-exposure conditions were controlled through Fe-doping for intra/extra cellular Cu 2+ and biological outcome. Through controlled ion release and reactions taking place in the cellular interior,tumors could be treated selectively,invitro and in vivo.L ocally administered NPs enabled tumor cells apoptosis and stimulated systemic anti-cancer immune responses.W ec learly show therapeutic effects without tumor cells relapse post-treatment with 6% Fe-doped CuO NPs combined with myeloid-derived suppressor cell silencing.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

Role of inorganic nanoparticle degradation in cancer therapy

“…In a recent work from our group, we show that Cu 2+ released from CuO dissolution tend to complex with various amino acids and form light blue precipitates in glutamine solutions in the ratio 1 : 2, as conrmed using single-crystal X-ray diffraction (SC-XRD). 79 These ndings are in line with previously reported structural formations between Cu 2+ and glutamine. 112 In fact, several early works have described the crystal structure that results from Cu 2+ complexation with various amino acids, such as asparagine, 113 glutamic acid 114 and aspartic acid.…”

“…Similarly, the homeostasis of Cu 2+ is maintained by Cu importers such as CTR1 and ATPase that respectively increase or decrease the ux of Cu 2+ within the cell. 78,79 When the level of intracellular Cu 2+ is increased beyond normal conditions, CTR1 is internalized while ATPase is transferred to the cell membrane to eliminate the excess ions. However, during cellular uptake and subsequent dissolution of CuO NPs, the release of Cu 2+ is signicantly higher and more rapid than the capacity of ATPase to excrete the excess ions, disrupting the redox balance and inducing ROS generation and oxidative stress.…”

“…99 In a recent study from our group investigating the effects of varying Fe doping levels on CuO NP toxicity and cancer therapy, we found that the rapid release of Cu 2+ from pure CuO causes cell death in both normal and tumor cells, whereas a too slow release leaves both cell types mostly unaffected. 79 By adjusting the Fe-doping levels to t the exact desired release kinetics of the M z+ , it was possible to selectively target CCs. The most benecial response was achieved at Fe doping levels of 6%.…”

Molecular Mechanisms, Characterization Methods, and Utilities of Nanoparticle Biotransformation in Nanosafety Assessments

“…[49,126] In addition, CuO, NiO, Ag NPs, and quantum dots displayed significant dissolution in biological media and animal tissues. [127][128][129][130][131][132][133][134] While endocytosis is the major cellular internalization pathway for most ENMs, NPs may transport into an acidic and enzymatic lysosomal compartment. [19,33] Therefore, a majority of metal-based NPs may display rapid dissolution after cellular internalization.…”

Biomedical nanomaterials for immunological applications: ongoing research and clinical trials

“…Furthermore, reinjecting the tumour cells to the same mice did not generate a new tumour suggesting the successful induction of long term immune memory response. 235 Recently, Ploetz E. et al, demonstrated that hybrid metalorganic framework (MOF) nanoparticles loaded in liposomes (Lip-MOFs) could create a controllable platform for intracellular iron delivery. The high amount of realized ions by the internalized particles induced pyroptosis, a highly inammatory form of programmed cell death, which occurred only in slightly acidic extracellular environments.…”