Controlled intracellular aggregation of magnetic particles improves permeation and retention for magnetic hyperthermia promotion and immune activation.

Rationale: Magnetic nanoparticles (MNPs) are the most used inorganic nanoparticles in clinics with therapeutic and imaging functions, but the inefficient magneto-thermal conversion efficiency, fast leakage, and uneven distribution impair their imaging sensitivity and therapeutic efficacy in tumors. Methods: Herein, we rationally designed a system containing pH-controllable charge-reversible MNPs (M20@DPA/HA) and negatively charged MMPs with different sizes (M5 and M20), which could induce intracellular aggregation. The dynamic hydrazone bonds with pH controllability were formed by the surface hydrazides on MNPs and aldehydes of hyaluronic acid (HA). Under the acidic pH, intracellular aggregation of the complex composed by M20@DPA/HA and M5 (M5&20), or M20@DPA/HA and M20 (M20&20) were investigated. In addition, the magnetic hyperthermia therapy (MHT) efficiency of tumor cells, tumor-associated macrophages polarization, giant cells formation and immune activation of tumor microenvironment were explored via a series of cell and animal model experiments. Results: Through physical and chemical characterization, the aggregation system (M20&20) exhibited a remarkable 20-fold increase in magnetothermal conversion efficiency compared to individual MNPs, together with enhanced penetration and retention inside the tumor tissues. In addition, it could promote immune activation, including repolarization of tumor-associated macrophages, as well as the formation of giant cells for T cell recruitment. As a result, the M20&20 aggregation system achieved a high degree of inhibition in 4T1 mouse mammary tumor model, with little tumor growth and metastasis after magnetic hyperthermia therapy. Conclusions: A controlled intracellular aggregation system was herein developed, which displayed an aggregation behavior under the acidic tumor microenvironment. The system significantly enhanced MHT effect on tumor cells as well as induced M1 polarization and multinucleated giant cells (MGC) formation of TAM for immune activation. This controlled aggregation system achieved barely tumor growth and metastasis, showing a promising strategy to improve MNPs based MHT on deteriorate cancers.

Integration of PEG-conjugated gadolinium complex and superparamagnetic iron oxide nanoparticles as T 1-T 2 dual-mode magnetic resonance imaging probes.

The T 1-T 2 dual-mode probes for magnetic resonance imaging (MRI) can non-invasively acquire comprehensive information of different tissues or generate self-complementary information of the same tissue at the same time, making MRI a more flexible imaging modality for complicated applications. In this work, three Gadolinium-diethylene-triaminepentaaceticacid (Gd-DTPA) complex conjugated superparamagnetic iron oxide (SPIO) nanoparticles with different Gd/Fe molar ratio (0.94, 1.28 and 1.67) were prepared as T 1-T 2 dual-mode MRI probes, named as SPIO@PEG-GdDTPA0.94, SPIO@PEG-GdDTPA1.28 and SPIO@PEG-GdDTPA1.67, respectively. All SPIO@PEG-GdDTPA nanocomposites with 8 nm spherical SPIO nanocrystals showed good Gd3+ chelate stability. SPIO@PEG-GdDTPA0.94 nanocomposites with lowest Gd/Fe molar ratio show no cytotoxicity to Raw 264.7 cells as compared to SPIO@PEG-GdDTPA1.28 and SPIO@PEG-GdDTPA1.67. SPIO@PEG-GdDTPA0.94 nanocomposites with r 1 (8.4 mM-1s-1), r 2 (83.2 mM-1s-1) and relatively ideal r 2/r 1 ratio (9.9) were selected for T 1-T 2 dual-mode MRI of blood vessels and liver tissue in vivo. Good contrast images were obtained for both cardiovascular system and liver in animal studies under a clinical 3 T scanner. Importantly, one can get high-quality contrast-enhanced blood vessel images within the first 2 h after contrast agent administration and acquire liver tissue anatomy information up to 24 h. Overall, the strategy of one shot of the dual mode MRI agent could bring numerous benefits not only for patients but also to the radiologists and clinicians, e.g. saving time, lowering side effects and collecting data of different organs sequentially.