Temperature-controlled magnetic nanoparticles hyperthermia inhibits primary tumor growth and metastases dissemination.

Magnetic hyperthermia (MHT) is a promising approach for cancer therapy. However, a systematic MHT characterization as function of temperature on the therapeutic efficiency is barely analyzed. Here, we first perform comparative temperature-dependent analysis of the cobalt ferrite nanoparticles-mediated MHT effectiveness in two murine tumors models - breast (4T1) and colon (CT26) cancer in vitro and in vivo. The overall MHT killing capacity in vitro increased with the temperature and CT26 cells were more sensitive than 4T1 when heated to 43 °C. Well in line with the in vitro data, such heating cured non-metastatic CT26 tumors in vivo, while only inhibiting metastatic 4T1 tumor growth without improving the overall survival. High-temperature MHT (>47 °C) resulted in complete 4T1 primary tumor clearance, 25-40% long-term survival rates, and, importantly, more effective prevention of metastasis comparing to surgical extraction. Thus, the specific MHT temperature must be defined for each tumor individually to ensure a successful antitumor therapy.

Neutrophil-mediated transport is crucial for delivery of short-circulating magnetic nanoparticles to tumors.

Recently neutrophil-based nanoparticles (NPs) drug delivery systems have gained considerable attention in cancer therapy. Numerous studies have been conducted to identify optimal NPs parameters for passive tumor targeting, while there is a fundamental dearth of knowledge about the factors governing cell-mediated delivery. Here, by using intravital microscopy and magnetic resonance imaging, we describe accumulation dynamics of 140 nm magnetic cubes and clusters in murine breast cancer (4T1) and colon cancer (CT26) models. Notwithstanding rapid clearance from the blood flow, NPs readily accumulated in tumors at later time points. Both NPs types were captured mostly by intravascular neutrophils immediately after injection, and transmigration of NPs-bound neutrophils through the vessel wall was first shown in real-time. A dramatic drop in NPs accumulation upon Ly6G and Gr1 depletion further confirmed the role of neutrophils as a biocarrier for targeting tumors. Of note, for shorter circulating NPs, a cell-dependent delivery route was more impactful, while the accumulation of longer circulating counterpart was less compromised by neutrophil depletion. Neutrophil-mediated transport was also shown to depend on tumor type, with more efficiency noted in neutrophil-rich tumors. Revealing NPs characteristics and host factors influencing the neutrophil-based tumor targeting will help to rationally design drug delivery systems for improved cancer treatment. STATEMENT OF SIGNIFICANCE: Utilizing host cells as trojan horses for delivery nanodrugs to tumor site is a promising approach for cancer therapy. However, it is not clear yet how nanoparticles characteristics and tumor properties affect the efficiency of cell-based nanoparticles transport. Here, we compare neutrophil-based delivery of different-shaped magnetic nanoparticles (cubes and clusters) in two tumor models. The results suggest that neutrophil-mediated route is more impactful for rapidly cleared cubes, than for longer circulating clusters. The efficiency of cell-based accumulation also correlated with the level of neutrophils recruitment to different tumor types. These finding are important for rationale design of nanocarriers and predicting the efficiency of neutrophil-mediated drug delivery between patients and tumor types.

Intravital microscopy reveals a novel mechanism of nanoparticles excretion in kidney.

Developing nanocarriers that accumulate in targeted organs and are harmlessly eliminated still remains a big challenge. Nanoparticles (NP) biodistribution is governed by their size, composition, surface charge and coverage. The current thinking in bionanotechnology is that renal clearance is limited by glomerular basement membrane pore size (≈6 nm), although there is a growing evidence that NP exceeding the threshold can also be excreted with urine. Here we compare biodistribution of PEGylated 140 nm iron oxide cubes and clusters with a special focus on renal accumulation and excretion. Atomic emission spectroscopy, fluorescent microscopy and magnetic resonance imaging revealed rapid and transient accumulation of magnetic NP in kidney. Using intravital microscopy we tracked in real time NP translocation from peritubular capillaries to basal compartment of tubular cells and subsequent excretion to the lumen within 60 min after systemic administration. Transmission electron microscopy revealed persistence of intact full-sized NP in urine 2 h post injection. The results suggest that translocation through peritubular endothelium to tubular epithelial cells is an alternative mechanism of renal clearance enabling excretion of NP above glomerular cut-off size.