Macrophage entrapped silica coated superparamagnetic iron oxide particles for controlled drug release in a 3D cancer model

Abstract

28Targeted delivery of drugs is a major challenge in treatment of diverse diseases. Systemically 29 administered drugs demand high doses and are accompanied by poor selectivity and side 30 effects on non-target cells. Here, we introduce a new principle for targeted drug delivery. It is 31 based on macrophages as transporters for nanoparticle-coupled drugs as well as controlled 32 release of drugs by hyperthermia mediated disruption of the cargo cells and simultaneous 33 deliberation of nanoparticle-linked drugs. Hyperthermia is induced by an alternating 34 electromagnetic field (AMF) that induces heat from silica-coated superparamagnetic iron 35 oxide nanoparticles (SPIONs). Here, we show proof-of-principle of controlled release by the 36 simultaneous disruption of the cargo cells and the controlled, AMF induced release of a toxin, 37 which was covalently linked to silica-coated SPIONs via a thermo-sensitive linker. Cells that 38 had not been loaded with SPIONs remain unaffected. Moreover, in a 3D co-culture model we 39 demonstrate specific killing of associated tumour cells when employing a ratio as low as 1:40 40 (SPION-loaded macrophage : tumour cells). Overall, our results demonstrate that AMF 41 induced drug release from macrophage-entrapped nanoparticles is tightly controlled and may 42 be an attractive novel strategy for targeted drug release. 43 Keywords: 44 Cell based drug delivery; macrophages; magnetic silica nanoparticles; hyperthermia; 45 controlled drug delivery, 3D tumor model 46 47 48 102 tumor size was observed, indicating that the therapeutic potential of hyperthermia induced by 103such an approach might be limited [42]. 104 In the last years, macrophages emerged as another/an interesting cell type for take up of 105 nanoparticles [43, 44]. However, controlled drug release from macrophage entrapped 106 nanoparticles remains to be explored. Here, we explore macrophages as carriers for SPIONs 107 carrying a silica shell. We show that macrophages efficiently take up the silica-coated SPION 108 nanoparticles. AMF-induced hyperthermia can induce death of loaded macrophages in a cell 109 type specific manner. Using silica-coated SPION nanoparticles functionalized with a toxin via 110 a thermosensitive linker (T-SPIONs) we demonstrate that AMF is sufficient to liberate the 111 toxin from T-SPION loaded cells, with negligible spontaneous release. The release of the 112 toxin could specifically induce the death of Kaposi's sarcoma cells in 3D spheroid co-113 cultures, thereby potentiating the efficiency of heat-induced killing of tumour cells.114 5 Materials and Methods 115 Cell culture 116 The mouse macrophage cell lines IC21, J774a.1, RAW264.7 as well as the human breast 117 carcinoma cell line MCF-7 and the human monocyte cell line U937 were obtained from 118 DSMZ (Braunschweig, Germany). IC21 and U937 cells were cultured in RPMI media 119 supplemented with 10% fetal calf serum, 60 µg/mL penicillin and 100 µg/mL streptomycin. 120 J774a.1 and RAW264.7 cells were cultured in DMEM media supplemented w...

Biodistribution, biocompatibility and targeted accumulation of magnetic nanoporous silica nanoparticles as drug carrier in orthopedics

“…Magnetic nanoparticles are already versatilely used in research and partly in clinical issues for hyperthermia or drug delivery in tumor [31][32][33][34][35] and infection treatment [36,37], as contrast agents for magnetic resonance imaging [38][39][40], and others [41,42]. The biocompatibility of certain magnetic nanoparticles with different composition, magnetic properties or size has already been published [43,44].…”

Chemically Engineered Immune Cell‐Derived Microrobots and Biomimetic Nanoparticles: Emerging Biodiagnostic and Therapeutic Tools

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“…It was revealed that incorporating albumin–PTX conjugate within mesoporous silica NPs could increase its uptake efficiency by M ϕ s. Transwell migration assay confirmed an enhanced migration ability of loaded M ϕ s toward breast cancer cells. [ 49b ]…”

Applications of superparamagnetic iron oxide nanoparticles in drug and therapeutic delivery, and biotechnological advancements

“…Ullah et al used the rapid macrophage endocytosis of silica-coated SPIONs loaded with maytansin, an antiproliferative toxin. They infiltrated these macrophages in spheroids of tumor cells and destroyed the cells by hyperthermia in vitro [ 125 ]. Moghimi et al [ 124 ] found that liposomes and polymeric nanospheres used as nanocarriers are also opsonized, which promotes their clearance by macrophage activation.…”