Magneto-Activation and Magnetic Resonance Imaging of Natural Killer Cells Labeled with Magnetic Nanocomplexes for the Treatment of Solid Tumors

Abstract

Natural killer (NK) cell-based immunotherapy has been considered a promising cell-based cancer treatment strategy with low side effects for early tumors and metastasis. However, the therapeutic efficacy is generally low in established solid tumors. Ex vivo activation of NK cells with exogenous cytokines is often essential but ineffective to generate high doses of functional NK cells for cancer treatment. Image-guided local delivery of NK cells is also suggested for the therapy. However, there is a lack of noninvasive tools for monitoring NK cells. Herein, magnetic nanocomplexes are fabricated with clinically available materials (hyaluronic acid, protamine, and ferumoxytol; HAPF) for labeling NK cells. The prepared HAPF–nanocomplexes effectively attach to the NK cells (HAPF-NK). An exogenous magnetic field application effectively achieves magneto-activation of NK cells, promoting the generation and secretion of lytic granules of NK cells. The magneto-activated HAPF-NK cells also allow an MR image-guided NK cell therapy to treat hepatocellular carcinoma (HCC) solid tumors via transcatheter intra-arterial infusion. Suppressed tumor growth after the treatment of IA infused magneto-activated NK cells demonstrated a potential enhanced therapeutic efficacy of image guided local delivery of magneto-activated HAPF-NK cells. Given the potential challenges of NK cell cancer immunotherapy against established solid tumors, the effective NK cell labeling with HAPF, magneto-activation, and MRI contrast effect of NK cells will be beneficial to enhance the NK cell-therapeutic efficacy in various cancers.

Enhanced natural killer cell anti-tumor activity with nanoparticles mediated ferroptosis and potential therapeutic application in prostate cancer

“…Further immune characterization such as CD8 + T cell activation and anti-cancer immunity would be the next step to translate this ferroptosis enhanced NK cell therapy for an effective NK cell therapy approach. Considering potential toxicity and low efficacy of systemically applied ferroptosis and NK cell therapies [21,[48][49][50], the development of emerging image guided local ferroptosis and NK cell therapies is needed [7,21]. Additionally, although ferroptosis involved with iron, lipids and ROS are related with the very common metabolic pathways of cancer cells, their roles and contribution in the cancer treatment have remained unclear.…”

Citrate-Coated Superparamagnetic Iron Oxide Nanoparticles Enable a Stable Non-Spilling Loading of T Cells and Their Magnetic Accumulation

“…Exemplarily, tumor vascularization may be unfavorable, hindering the delivery of the cells or nanoparticles for drug delivery. However, others previously functionalized lymphocytes with magnetic nanoparticles and showed increased therapeutic success with the adoptive transfer of T cells and NK cells [28,35]. Further, contactless magnetic movement by permanent magnets and dynamically programmable magnetic fields is under intense investigation [29,68].…”

“…Positively charged coatings of the SPIONs such as 3-aminopropyl-triethoxysilane can enhance interaction with the negatively charged plasma membrane [31] but might also lead to nanoparticle clusters that can detach and spill from the loaded cells. Moreover, NK cells were loaded with positively charged magnetic nanocomplexes and enabled image-based guiding by MRI after intra-arterial infusion [35]. Another employed strategy was the binding of magnetic nanoclusters onto T cells via a PD-1 antibody, which enabled efficient recruiting of T cells to tumor sites, where the PD-1 antibody was released and both, together, exerted a synergistic anti-tumor effect [28].…”

Recent advances in biomaterial-boosted adoptive cell therapy

“…Interestingly, specific inorganic nanoparticles, including iron oxide NPs and copper sulfide NPs, reprogram the fate of immune cells through their intrinsic properties. 106–108 For example, Li et al developed a magnetic iron oxide nanoparticle (ION)-based strategy to generate macrophages with an antitumor M1 tropism and enhanced therapeutic functions (Fig. 8a and b).…”

“…Recently, hyaluronic acid and protamine were fabricated on the surface of ferumoxytol to form a nanocomplex (HAPF) with high internalization efficiency in NK cells. 107 Notably, such magnetic nanocomplexes could generate magneto-mechanical movements on NK cell surfaces or inside cells using an alternating magnetic field. With adjustments of the magnetic field strength, the magneto-mechanical movements of HAPF in NK cells could induce the polymerization and overexpression of the mechanosensitive actin and NKG2D, respectively, leading to potent activation of NK cells and increased secretion of lytic granules (Fig.…”