Tumor targeting using magnetic nanoparticle Hsp70 conjugate in a model of C6 glioma

Shevtsov, Maxim; Yakovleva, Ludmila Y.; Nikolaev, B. P.; Marchenko, Y.; Добродумов, А. В.; Onokhin, Kirill V.; Onokhina, Y.; Selkov, S. A.; Mikhrina, A. L.; Guzhova, Irina V.; Martynova, Marina G.; Bystrova, Olga V.; Ischenko, A.; Margulis, Boris A.

doi:10.1093/neuonc/not141

Cited by 54 publications

(32 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…a ). This result correlates well with our recently published data indicating tumor‐targeting ability of the chaperone applied intravenously with magnetic nanoparticles or administered on the surface of skin corresponding to B16 melanoma tumor area …”

Section: Discussionsupporting

confidence: 92%

Effective immunotherapy of rat glioblastoma with prolonged intratumoral delivery of exogenous heat shock protein Hsp70

Shevtsov

Pozdnyakov

Mikhrina

et al. 2014

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Chaperone Hsp70 can activate adaptive immunity suggesting its possible application as an antitumor vaccine. To assess the therapeutic capacity of Hsp70 we administered purified chaperone into a C6 glioblastoma brain tumor and explored the viability and tumor size as well as interferon gamma (IFNc) production and cytotoxicity of lymphocytes in the treated animals. Targeted intratumoral injection of Hsp70 resulted in its distribution within the area of glioblastoma, and caused significant inhibition of tumor progression as confirmed by magnetic resonance imaging. The delay in tumor growth corresponded to the prolonged survival of tumor-bearing animals of up to 31 days versus 20 days in control. Continuous administration of Hsp70 with an osmotic pump increased survival even further (39 days). Therapeutic efficacy was associated with infiltration to glioblastoma of NK cells (Ly-6c1) and T lymphocytes (CD31, CD41 and CD81) as well as with an increase in the activity of NK cells (granzyme B production) and CD81 T lymphocytes as shown by IFNc ELISPOT assay. Furthermore, we found that Hsp70 treatment caused concomitantly, with a tenfold elevated IFNc production, an increase in anti-C6 tumor cytotoxicity of lymphocytes. In conclusion, continuous intratumoral delivery of Hsp70 demonstrates high therapeutic potential and therefore could be applied in the treatment of glioblastoma.Multiform glioblastoma is the most aggressive and common primary brain tumor in adults 1 with an incidence rate of 7.3 cases per 100,000 persons per year.2 The standard treatment for newly diagnosed glioblastoma currently includes surgical resection followed by radiotherapy and chemotherapy using apoptosis-inducing factors such as temozolomide, which is actively used nowadays. 3During the last two decades, increasing evidence has demonstrated that the high immunomodulatory potency of heat shock protein 70 (Hsp70) is due to its ability to specifically bind tumor antigens and present them to dendritic antigenpresenting cells (APCs).4 Several anticancer and antivirus vaccines were created based on Hsp70 chaperone. First, immunization of mice bearing tumors with Hsp70-secreting murine ovarian cancer cells caused a strong anticancer effect concomitantly with the elicitation of CD41 and CD81 Tand NK-cell activity.5 Another chaperonic vaccine contains fusion products of Hsp70 with Herpes virus VP22 peptide (aa268-301) that facilitate intracellular transport; this construct was effective in inducing a specific cytotoxic response against mouse lymphoma cells.6 Third, Ito et al. showed that the combined intratumoral delivery of pure Hsp70 with heating magnetic particles can efficiently destroy mouse melanoma B16 in a therapeutic modality. 7 More recently, we reported that the application of purified Hsp70 onto skin area covering B16/F10 melanoma significantly inhibited tumor progression and increased the survival of animals. 8Although the mechanism of antitumor activity of Hsp70 remains unclear, it is believed that the chaperone can trigger both innate and ...

show abstract

Section: Discussionsupporting

confidence: 92%

Effective immunotherapy of rat glioblastoma with prolonged intratumoral delivery of exogenous heat shock protein Hsp70

Shevtsov

Pozdnyakov

Mikhrina

et al. 2014

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…Uptake of Hsp70 by tumor cells has been reported previously in models of C6 glioblastoma and B16 melanoma 14,15,43. The preferential accumulation of Hsp70 protein in C6 glioblastoma cells could be explained by CD40 receptor-mediated uptake of chaperone 44. However, the true importance of this mechanism in overall antitumor immunomodulation by Hsp70 in patients remains debatable.…”

Section: Discussionmentioning

confidence: 99%

Pilot study of intratumoral injection of recombinant heat shock protein 70 in the treatment of malignant brain tumors in children

Shevtsov

Kim²,

Samochernych³

et al. 2014

OTT

View full text Add to dashboard Cite

Intratumoral injections of recombinant heat shock protein (Hsp)70 were explored for feasibility in patients with brain tumors. Patients aged 4.5–14 years with untreated newly diagnosed tumors (n=12) were enrolled. After tumor resection, five injections of recombinant Hsp70 (total 2.5 mg) were administered into the resection cavity through a catheter. Before administration of Hsp70 and after the last injection, specific immune responses to the autologous tumor lysate were evaluated using the delayed-type hypersensitivity test. Further, peripheral blood was monitored to identify possible changes in lymphocyte subpopulations, cytokine levels, and the cytolytic activity of natural killer cells. The follow-up period in this trial was 12 months. Intratumoral injections of Hsp70 were well tolerated by patients. One patient had a complete clinical response documented by radiologic findings and one patient had a partial response. A positive delayed-type hypersensitivity test was observed in three patients. In peripheral blood, there was a shift from cytokines provided by Th2 cells toward cytokines of a Th1-cell-mediated response. These data corresponded to changes in lymphocyte subpopulations. Immunosuppressive T-regulatory cell levels were also reduced after injection of Hsp70, as well as production of interleukin-10. The cytolytic activity of natural killer cells was unchanged. The present study demonstrates the feasibility of intratumoral delivery of recombinant Hsp70 in patients with cancer. Further randomized clinical trials are recommended to assess the optimum dose of the chaperone, the treatment schedule, and clinical efficacy.

show abstract

“…Of relevance, stress-induced mammalian Hsp70 is upregulated in T. gondii-infected cells, and inducible Hsp70 can be expressed on the cell surface (29)(30)(31)(32). While some studies reported that mammalian inducible Hsp70 is a ligand for CD40 (33,34), others could not detect binding between mammalian Hsp70 and CD40 (35)(36)(37). These contrasting results may be explained by the likely presence of contaminating proteins (Hsc70) or the source of recombinant Hsp70.…”

Section: Cd40 Restricts T Gondii Neural Invasionmentioning

confidence: 99%

CD40 in Endothelial Cells Restricts Neural Tissue Invasion by Toxoplasma gondii

et al. 2019

View full text Add to dashboard Cite

Little is known about whether pathogen invasion of neural tissue is affected by immune-based mechanisms in endothelial cells. We examined the effects of endothelial cell CD40 on Toxoplasma gondii invasion of the retina and brain, organs seeded hematogenously. T. gondii circulates in the bloodstream within infected leukocytes (including monocytes and dendritic cells) and as extracellular tachyzoites. After T. gondii infection, mice that expressed CD40 restricted to endothelial cells exhibited diminished parasite loads and histopathology in the retina and brain. These mice also had lower parasite loads in the retina and brain after intravenous (i.v.) injection of infected monocytes or dendritic cells. The protective effect of endothelial cell CD40 was not explained by changes in cellular or humoral immunity, reduced transmigration of leukocytes into neural tissue, or reduced invasion by extracellular parasites. Circulating T. gondii-infected leukocytes (dendritic cells used as a model) led to infection of neural endothelial cells. The number of foci of infection in these cells were reduced if endothelial cells expressed CD40. Infected dendritic cells and macrophages expressed membrane-associated inducible Hsp70. Infected leukocytes triggered Hsp70-dependent autophagy in CD40 ϩ endothelial cells and anti-T. gondii activity dependent on ULK1 and beclin 1. Reduced parasite load in the retina and brain not only required CD40 expression in endothelial cells but was also dependent on beclin 1 and the expression of inducible Hsp70 in dendritic cells. These studies suggest that during endothelial cell-leukocyte interaction, CD40 restricts T. gondii invasion of neural tissue through a mechanism that appears mediated by endothelial cell anti-parasitic activity stimulated by Hsp70.

show abstract

Tumor targeting using magnetic nanoparticle Hsp70 conjugate in a model of C6 glioma

Abstract: The study demonstrated that Hsp70-SPION conjugate intravenously administered in C6 glioma model accumulated in the tumors and enhanced the contrast of their MR images.

Cited by 54 publications

References 51 publications

Effective immunotherapy of rat glioblastoma with prolonged intratumoral delivery of exogenous heat shock protein Hsp70

Effective immunotherapy of rat glioblastoma with prolonged intratumoral delivery of exogenous heat shock protein Hsp70

Pilot study of intratumoral injection of recombinant heat shock protein 70 in the treatment of malignant brain tumors in children

CD40 in Endothelial Cells Restricts Neural Tissue Invasion by Toxoplasma gondii

Contact Info

Product

Resources

About