Magnetic systems for cancer immunotherapy

Abstract

Immunotherapy is a rapidly developing area of cancer treatment due to its higher specificity and potential for greater efficacy than traditional therapies. Immune cell modulation through the administration of drugs, proteins, and cells can enhance antitumoral responses through pathways that may be otherwise inhibited in the presence of immunosuppressive tumors. Magnetic systems offer several advantages for improving the performance of immunotherapies, including increased spatiotemporal control over transport, release, and dosing of immunomodulatory drugs within the body, resulting in reduced off-target effects and improved efficacy. Compared to alternative methods for stimulating drug release such as light and pH, magnetic systems enable several distinct methods for programming immune responses. First, we discuss how magnetic hyperthermia can stimulate immune cells and trigger thermoresponsive drug release. Second, we summarize how magnetically targeted delivery of drug carriers can increase the accumulation of drugs in target sites. Third, we review how biomaterials can undergo magnetically driven structural changes to enable remote release of encapsulated drugs. Fourth, we describe the use of magnetic particles for targeted interactions with cellular receptors for promoting antitumor activity. Finally, we discuss translational considerations of these systems, such as toxicity, clinical compatibility, and future opportunities for improving cancer treatment.

Keywords: BW, body weight; Biomaterials; CpG, cytosine-phosphate-guanine; DAMP, damage associated molecular pattern; Drug delivery; EPR, enhanced permeability and retention; FFR, field free region; HS-TEX, heat-stressed tumor cell exosomes; HSP, heat shock protein; ICD, immunogenic cell death; IVIS, in vivo imaging system; Immunotherapy; MICA, MHC class I-related chain A; MPI, magnetic particle imaging; Magnetic hyperthermia; Magnetic nanoparticles; Microrobotics; ODNs, oligodeoxynucleotides; PARP, poly(adenosine diphosphate-ribose) polymerase; PDMS, polydimethylsiloxane; PEG, polyethylene glycol; PLGA, poly(lactic-co-glycolic acid); PNIPAM, poly(N-isopropylacrylamide); PVA, poly(vinyl alcohol); SDF, stromal cell derived-factor; SID, small implantable device; SLP, specific loss power.

Graphical abstract

Figure 1

Different approaches that exploit magnetic materials for immunotherapy. Created with BioRender.

Figure 2

Generalized magnetization curves of diamagnetic, paramagnetic, superparamagnetic, and ferromagnetic materials. M_S, saturation magnetization; M_R, remanent magnetization; H_C, coercive field threshold; χ_i, magnetic susceptibility.

Figure 3

Mechanisms of immune modulation by magnetic hyperthermia. (A) Cellular release of heat shock proteins (green) due to heat stress results in natural killer cell activation and proliferation, cytotoxic CD8⁺ T cell education, and proinflammatory cytokine response. (B) Dendritic cells, T cells, and macrophages have enhanced anticancer activity in response to local heating. (C) MCH I and MICA are upregulated on tumor cells. (D) Increased exosome release enhances cytotoxic T cell education by dendritic cells. (E) Tumor vasculature responds to temperature increase by allowing increased immune cell permeation. Created with BioRender. Adapted with permission from Ref. . Copyright © 2014 Taylor & Francis.

Figure 4

Orthogonal click reaction for release of a model fluorophore, rhodamine (Rd), using magnetic hyperthermia. (A) Scheme for attachment of iron oxide nanoparticles (IONPs) to a polymeric carrier and a drug. (B) Rd release profiles at two different concentrations over 30 min. Reproduced with permission from Ref. . Copyright © 2013 John Wiley and Sons.

Figure 5

MH plus CTLA4 blockade on an orthotopic 4T1 breast tumor model. (A) Mechanism of immunotherapy through combination of MH from iron oxide nanoparticles (FeNPs), poly (lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating imiquimod (R837) (PR), and anti-CTLA4 antibodies (α-CTLA4). T cells are educated for metastatic tumor cell clearance. (B) Schematic timeline of MH and CTLA4 blockade treatments to inhibit tumor metastases. The primary tumor was surgically removed 16 days after inoculation for monitoring of metastatic tumors. (C) Survival of mice with various treatments over 90 days. Combined MH, PR, and α-CTLA4 therapy resulted in 80% survival (n = 10 per group). (D) In vivo bioluminescence images tracking firefly luciferase-expressing 4T1 breast cancer cells after surgery alone, MH treatment, MH and α-CTLA4 treatment, MH and PR treatment, or MH, α-CTLA4, and PR treatment. Reproduced with permission from Ref. . Copyright © 2019 American Chemical Society.

Figure 6

Targeted accumulation of IFNγ (IFNγ-dimercaptosuccinic acid-coated magnetic nanoparticles, DMSA-MNP, with a magnetic field) in murine (A, B) pancreatic (Pan 02) and (C) 3-methylcholatrene (3-MCA)-induced tumors reduces mean tumor volume compared to mice treated with PBS, DMSA-MNPs, soluble IFNγ, or IFNγ-DMSA-MNP without a magnetic field. Data show mean tumor volume ± SD (n = 30; ∗P < 0.05; ∗∗P < 0.001). (D) IFNγ levels in serum and Pan02 tumors. Data show mean ± SD (n = 10; ∗∗P < 0.001). (E) Decreased concentration of nanoparticles in blood samples with magnetic targeting. (F) IFNγ levels in serum and 3-MCA tumors. Data show mean ± SD (n = 10; ∗P < 0.05; ∗∗P < 0.001). Reproduced with permission from Ref. . Copyright © 2011 Elsevier.

Figure 7

Magnetic targeting of CpG ODNs (CpG for convenience) to DCs increases therapeutic efficacy. (A) Schedule for treatment with iron nanoparticle (FeNP)/CpG particles in C26 colon cancer and 4T1 breast cancer-inoculated mice through intratumoral injection. (B) 4T1 tumor growth over 31 days in response to normal saline (NS), FeNP, free CpG, and targeted FeNP/CpG treatment. (C) Average 4T1 tumor weight after treatment. (D) Average number of tumorous nodules in the lung as an indication of metastasis. (E) C26 tumor growth over 31 days. (F) Average C26 tumor weight after treatment. All data mean ± SEM (n = 10), ∗P < 0.05, ∗P < 0.01, and ∗∗∗P < 0.001. Reproduced with permission from Ref. . Copyright © 2018 Springer Nature.

Figure 8

Macroporous alginate-SPION ferrogels enable controlled release of payloads in response to a magnetic field. (A) Nano- and macroporous ferrogel compression data. (B) A nanoporous ferrogel cylinder compresses ∼5% in response to a vertical ∼38 A/m² magnetic field gradient. (C) A macroporous ferrogel cylinder compresses ∼70% in response to the same magnetic field. (D) SEM images of a lyophilized macroporous gel in an undeformed and a deformed state (scale bar = 500 μm). (E) Cumulative mitoxantrone release from the macroporous ferrogel, subject to no magnetic stimulation (control) or to 2 min of magnetic stimulation every 30 min (experimental). (F) Cumulative plasmid DNA release from the macroporous ferrogel, subject to no magnetic stimulation (control) or to 2 min of magnetic stimulation every 2 h (experimental). (G) Cumulative SDF-1α release from macroporous ferrogel, subject to the same conditions described in F. Data show mean ± SD (n = 3–5). (A)‒(G) Reproduced with permission from Ref. . Copyright © 2011 National Academy of Science of the United State of America. (H) Non-macroporous microbeads show negligible volume change when exposed to a 500 mT magnetic field. (I) Macroporous microbeads undergo significant collective volume change due to pore collapse when exposed to the same magnetic field. (J) Cumulative dextran release from the macroporous ferrogel microbeads, subject to no magnetic stimulation (control) or to 1 min of magnetic stimulation every 10 min (experimental). (K) Viability of 4T1 tumor cells after 15 min of incubation with empty microparticles (control) or particles containing mitoxantrone without magnetic stimulation (no actuation) or with magnetic stimulation (magnetic actuation). Data show mean ± SD, ∗P < 0.05. (H)‒(K) Reproduced with permission from Ref. . Copyright © 2017 American Chemical Society.

Figure 9

Small implantable device (SID) with magnetic actuation for controlled drug release. SID with an 18 mm diameter and a 13 mm height, with a total volume of ∼3.3 mL. (A) Schematic illustration of SID operation. ① External magnet is applied, ② moving the plunger upward, and ③ sucking the drug solution into the barrel. ④ Magnet is removed, ⑤ releasing the plunger, and ⑥ pushing the drug solution out of the outlet port. The port and barrel are oppositely polarized for tight attachment and prevention of drug release without an external magnet. (B) Cumulative release of model drug, 5-fluorouracil (5-FU) in PBS in vitro over 30 actuations of the SID with 1, 2, or 3 outlet ports (port diameter = 700 μm). (C) Long-term cumulative release of 5-FU from SID3, with either 1 or 3 actuations at each time point. (D) 5-FU concentration in blood after SID3 implantation in a subcutaneous pocket in the dorsal area of rats with several short-term actuations. Error bars = mean ± SD. Reproduced with permission from Ref. . Copyright © 2018 Elsevier.

Figure 10

MPI gradient field improves specificity of MH in vivo. (A) 20 kHz, 20 mT MPI fields enable high contrast visualization of SPIONs in the tumor and liver of a U87MG xenograft mouse (diagnosis). The tumor is selected for localization of MH treatment by centering the FFR on the tumor target (therapy). MH conducted at 354 kHz, 13 mT heats the tumor only with the maintenance of MPI gradients. (B) Schematic illustration of the field created by coils traditionally used for MH treatment compared to the highly precise MPI gradient field. (C) Specific absorption rate (SAR) of SPIONs in the tumor is negligible when the MPI gradient is off. Reproduced with permission from Ref. . Copyright © 2018 American Chemical Society.