The Treatment of Heterotopic Human Colon Xenograft Tumors in Mice with 5-Fluorouracil Attached to Magnetic Nanoparticles in Combination with Magnetic Hyperthermia Is More Efficient than Either Therapy Alone

Abstract

Magnetic nanoparticles (MNPs) have shown promising features to be utilized in combinatorial magnetic hyperthermia and chemotherapy. Here, we assessed if a thermo-chemotherapeutic approach consisting of the intratumoral application of functionalized chitosan-coated MNPs (CS-MNPs) with 5-fluorouracil (5FU) and magnetic hyperthermia prospectively improves the treatment of colorectal cancer. With utilization of a human colorectal cancer (HT29) heterotopic tumor model in mice, we showed that the thermo-chemotherapeutic treatment is more efficient in inactivating colon cancer than either tumor treatments alone (i.e., magnetic hyperthermia vs. the presence of 5FU attached to MNPs). In particular, the thermo-chemotherapeutic treatment significantly (p < 0.01) impacts tumor volume and tumor cell proliferation (Ki67 expression, p < 0.001) compared to the single therapy modalities. The thermo-chemotherapeutic treatment: (a) affects DNA replication and repair as measured by H2AX and phosphorylated H2AX expression (p < 0.05 to 0.001), (b) it does not distinctly induce apoptosis nor necroptosis in target cells, since expression of p53, PARP cleaved-PARP, caspases and phosphorylated-RIP3 was non-conspicuous, (c) it renders tumor cells surviving therapy more sensitive to further therapy sessions as indicated by an increased expression of p53, reduced expression of NF-κB and HSPs, albeit by tendency with p > 0.05), and (d) that it impacts tumor vascularity (reduced expression of CD31 and αvβ3 integrin (p < 0.01 to 0.001) and consequently nutrient supply to tumors. We further hypothesize that tumor cells die, at least in parts, via a ROS dependent mechanism called oxeiptosis. Taken together, a very effective elimination of colon cancers seems to be feasible by utilization of repeated thermo-chemotherapeutic therapy sessions in the long-term.

Iron Oxide Nanoparticles Carrying 5-Fluorouracil in Combination with Magnetic Hyperthermia Induce Thrombogenic Collagen Fibers, Cellular Stress, and Immune Responses in Heterotopic Human Colon Cancer in Mice

“…the induction of thrombogenic collagen fibers. Beyond the previously reported DNA damage and increased stress levels in surviving tumor cells after using themo-combinatorial therapies [8,10,56], we showed that there is also a distinct impact on second messenger and nuclear receptor signaling. The fact that the combined thermo-chemotherapy shared most of the pathways with magnetic hyperthermia illustrates its prominent impact and the synergistically increased effects in presence of very low concentrations of 5FU.…”

Effect of Matrix-Modulating Enzymes on the Cellular Uptake of Magnetic Nanoparticles and on Magnetic Hyperthermia Treatment of Pancreatic Cancer Models In Vivo

“…The reduced interstitial pressure, in turn, enhances permeability of the tumor stroma [ 43 , 44 ] to Dex-MNP. Despite the increased infiltration and consequent low overall heat doses acquired with the use of hyaluronidase, it was hypothesized that tumor growth inhibition would take place and tumor regrowth, which has been repeatedly observed when conducting mild hyperthermia alone [ 34 , 53 ], would also be circumvented. Consistently, tumor depletion was slow but persistent, due to the effects of hyaluronidase I-S.…”

Iron Oxide Nanoparticle-Based Hyperthermia as a Treatment Option in Various Gastrointestinal Malignancies

“…In contrast, over the same time period the cytotoxic effects of thermo-chemotherapy remained stronger than such resulting from MFH monotherapy. Dabaghi et al later demonstrated significant superiority of thermo-chemotherapy compared with 5-Fluouracil monotherapy in vivo in a heterotopic HT 29 xenograft mouse model regarding tumor volume reduction and attenuation of proliferation activity [39]. Interestingly, exclusive MFH treatment also showed significant tumor volume reduction, which was partially attributed to DNA damage in terms of DNA double-strand breaks.…”

“…Given this sheer number and the resulting urge for improvement, nanoparticle-based hyperthermia has found its way into the research for novel treatment strategies in colorectal cancer. [38] as well as in vivo [39] in heterotopic xenograft mouse models using the chemotherapeutic doxorubicin and 5-Fluouracil, respectively. Both constituted an additive anti-tumorigenic effect of MFH to the toxicity of the chemotherapeutic agent.…”