Stem cell-based gene therapy activated using magnetic hyperthermia to enhance the treatment of cancer

Yin, Perry T.; Shah, Shreyas; Pasquale, Nicholas; Garbuzenko, Olga B.; Minko, Tamara; Lee, Ki‐Bum

doi:10.1016/j.biomaterials.2015.11.023

Cited by 96 publications

(64 citation statements)

References 56 publications

(61 reference statements)

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“…They are upregulated by heavy metals and toxic chemicals, and especially by heat stress, thus protecting cells from hyperthermic damage . Small interfering RNA (siRNA) against HSP70 (HSP70‐siRNA) can inhibit HSP70 synthesis and protein levels, thereby lowering the temperature required to kill cancer cells during hyperthermic treatment. That is, the therapeutic efficacy of PTT should be enhanced by HSP70‐siRNA gene silencing …”

Section: Introductionmentioning

confidence: 99%

Cypate‐Conjugated Porous Upconversion Nanocomposites for Programmed Delivery of Heat Shock Protein 70 Small Interfering RNA for Gene Silencing and Photothermal Ablation

Wang

Gao

Liu

et al. 2016

Adv Funct Materials

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wileyonlinelibrary.comtoxic chemicals, and especially by heat stress, thus protecting cells from hyperthermic damage. [ 8 ] Small interfering RNA (siRNA) against HSP70 (HSP70-siRNA) can inhibit HSP70 synthesis and protein levels, [ 9 ] thereby lowering the temperature required to kill cancer cells during hyperthermic treatment. That is, the therapeutic effi cacy of PTT should be enhanced by HSP70-siRNA gene silencing. [ 10 ] Molecular imaging techniques have been developed to visualize the structure of biological tissues, which is crucial for guiding oncotherapies. [ 11 ] Upconversion nanoparticles (UCNP) are ideal fl uorescent probes for upconversion luminescence (UCL) imaging [ 12 ] because of their splendid sensitivity and depth of penetration, [ 13 ] and lack of autofl uorescence interference. [ 14 ] NaLuF 4 nanocrystals doped with Yb 3+ and Er 3+ ions are one of the most-studied upconversion nanomaterials. [ 15 ] However, UCL imaging is unable to provide detailed anatomical and physiological images in vivo. In contrast, magnetic resonance imaging (MRI) is an effective non-invasive technique for in vivo imaging and 3D tomography. [ 16 ] A combination of MRI and UCL is therefore needed to combine the merits of both these imaging modalities. [ 17 ] Therefore, UCNP doped with Gd 3+ also show magnetic resonance performance making MRI possible. [ 18 ] In this study, we prepared NaLuF 4 :Gd,Yb,Er UCNP by a one-step microemulsion method, which were further linked with cypate through a hydrazide bond. Based on their UCL and magnetic properties, the obtained nanocomposites were applied as a dual-modality contrast agent for UCL and MRI to guide oncotherapy. We also attached HSP70-siRNA to the porous UCNP (UCNP-cy-siRNA). The combinational effects of gene silencing and PTT have been investigated on a small-animal model. Moreover, the poisonousness of the UCNP-cy-siRNA has also been evaluated. Results and Discussion Design Strategy and CharacterizationsNaLuF 4 -based upconversion nanoparticles (UCNP-COOH) were fi rst prepared by a modifi ed reverse microemulsion method ( Figure 1 a), using glutarate containing carboxyl groups Synergistic therapy is an accepted method of enhancing the effi cacy of cancer therapies. In this study, cypate-conjugated porous NaLuF 4 doped with Yb 3+ , Er 3+ , and Gd 3+ is synthesized and its potential for upconversion luminescence/magnetic resonance dual-modality molecular imaging for guiding oncotherapy is tested. Loading cypate-conjugated upconversion nanoparticles (UCNP-cy) with small interfering RNA gene against heat shock protein 70 (UCNP-cy-siRNA) enhances the cell damage. UCNP-cy-siRNA exhibits remarkable antitumor effi cacy in vivo as a result of the synergistic effects of gene silencing and photothermal therapy, with low drug dose and minimal side effects. This result thus provides an explicit strategy for developing next-generation multifunctional nanoplatforms for multimodal imaging-guided synergistic oncotherapy.

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Section: Introductionmentioning

confidence: 99%

Cypate‐Conjugated Porous Upconversion Nanocomposites for Programmed Delivery of Heat Shock Protein 70 Small Interfering RNA for Gene Silencing and Photothermal Ablation

Wang

Gao

Liu

et al. 2016

Adv Funct Materials

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“…Lee et al reported a novel application of magnetic core-shell nanoparticles for the dual purpose of delivering and activating a heat-inducible gene vector that encodes TRAIL in adipose-derived mesenchymal stem cells (AD-MSCs) [86]. This group developed a plasmid harboring the heat shock protein 70B' (HSP70B0) promoter.…”

Section: Trail-based Cell Therapymentioning

confidence: 99%

TRAIL-based gene delivery and therapeutic strategies

Zhong

Wang

et al. 2019

Acta Pharmacol Sin

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TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), also known as APO2L, belongs to the tumor necrosis factor family. By binding to the death receptor 4 (DR4) or DR5, TRAIL induces apoptosis of tumor cells without causing side toxicity in normal tissues. In recent years TRAIL-based therapy has attracted great attention for its promise of serving as a cancer drug candidate. However, the treatment efficacy of TRAIL protein was under expectation in the clinical trials because of the short half-life and the resistance of cancer cells. TRAIL gene transfection can produce a "bystander effect" of tumor cell killing and provide a potential solution to TRAIL-based cancer therapy. In this review we focus on TRAIL gene therapy and various design strategies of TRAIL DNA delivery including non-viral vectors and cell-based TRAIL therapy. In order to sensitize the tumor cells to TRAIL-induced apoptosis, combination therapy of TRAIL DNA with other drugs by the codelivery methods for yielding a synergistic antitumor efficacy is summarized. The opportunities and challenges of TRAIL-based gene delivery and therapy are discussed.

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“…We next tested thermal specificity using hypoxia and heavy metal toxicity as two representative non-thermal stresses [38][39][40] . As a benchmark, we compared with the endogenous HSPA6 promoter, which is a highly stress-inducible HSP promoter 41 previously used for thermal control of gene expression [42][43][44][45] . We tested the gene switches by incubating transduced Jurkat T cells with the hypoxia-mimetic agent CoCl2a stabilizer of the hypoxia response's master regulator Hypoxia Inducible Factor-1α (Hif-1α) 46 as well as the heavy metal complex cadmium chloride (CdCl2).…”

Section: Engineering Thermal-specific Gene Switchesmentioning

confidence: 99%

Remote control of CAR T cell therapies by thermal targeting

Miller

Sun

Harris

et al. 2020

Preprint

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The limited ability to control anti-tumor activity within tumor sites contributes to poor CAR T cell responses against solid malignancies. Systemic delivery of biologic drugs such as cytokines can augment CAR T cell activity despite off-target toxicity in healthy tissues that narrow their therapeutic window. Here we develop a platform for remote control of CAR T therapies by thermal targeting. To enable CAR T cells to respond to heat, we construct synthetic thermal gene switches that trigger expression of transgenes in response to mild elevations in local temperature (40-42 °C) but not to orthogonal cellular stresses such as hypoxia. We show that short pulses of heat (15-30 min) lead to more than 60-fold increases in gene expression without affecting key T cell functions including proliferation, migration, and cytotoxicity. We demonstrate thermal control of broad classes of immunostimulatory agents including CARs, Bispecific T cell Engagers (BiTEs), and cytokine superagonists to enhance proliferation and cell targeting. In mouse models of adoptive transfer, photothermal targeting of intratumoral CAR T cells to control the production of an IL-15 superagonist significantly enhances anti-tumor activity and overall survival. We envision that thermal targeting could improve the safety and efficacy of next-generation therapies by allowing remote control of CAR T cell activity.

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Stem cell-based gene therapy activated using magnetic hyperthermia to enhance the treatment of cancer

Cited by 96 publications

References 56 publications

Cypate‐Conjugated Porous Upconversion Nanocomposites for Programmed Delivery of Heat Shock Protein 70 Small Interfering RNA for Gene Silencing and Photothermal Ablation

Cypate‐Conjugated Porous Upconversion Nanocomposites for Programmed Delivery of Heat Shock Protein 70 Small Interfering RNA for Gene Silencing and Photothermal Ablation

TRAIL-based gene delivery and therapeutic strategies

Remote control of CAR T cell therapies by thermal targeting

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