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Thermoreversible poly(ethylene glycol)-g-chitosan hydrogel as a therapeutic T lymphocyte depot for localized glioblastoma immunotherapy.

Tsao CT, Kievit FM, Ravanpay A, Erickson AE, Jensen MC, Ellenbogen RG, Zhang M - Biomacromolecules (2014)

Bottom Line: Local immunotherapy has the potential to eradicate the residual infiltrative component of these tumors.Nuclear magnetic resonance spectroscopy confirmed the chemical structure of poly(ethylene glycol)-g-chitosan, and rheological studies revealed that the sol-to-gel transition of the PCgel occurred around ≥32 °C.Our study suggests that this unique PCgel depot may offer a viable approach for localized immunotherapy for glioblastoma.

View Article: PubMed Central - PubMed

Affiliation: Department of Materials Science and Engineering, University of Washington , Seattle, Washington 98195, United States.

ABSTRACT
The outcome for glioblastoma patients remains dismal for its invariably recrudesces within 2 cm of the resection cavity. Local immunotherapy has the potential to eradicate the residual infiltrative component of these tumors. Here, we report the development of a biodegradable hydrogel containing therapeutic T lymphocytes for localized delivery to glioblastoma cells for brain tumor immunotherapy. Thermoreversible poly(ethylene glycol)-g-chitosan hydrogels (PCgels) were optimized for steady T lymphocyte release. Nuclear magnetic resonance spectroscopy confirmed the chemical structure of poly(ethylene glycol)-g-chitosan, and rheological studies revealed that the sol-to-gel transition of the PCgel occurred around ≥32 °C. T lymphocyte invasion through the PCgel and subsequent cytotoxicity to glioblastoma were assessed in vitro. The PCgel was shown to be cellular compatible with T lymphocytes, and the T lymphocytes retain their anti-glioblastoma activity after being encapsulated in the PCgel. T lymphocytes in the PCgel were shown to be more effective in killing glioblastoma than those in the Matrigel control. This may be attributed to the optimal pore size of the PCgel allowing better invasion of T lymphocytes. Our study suggests that this unique PCgel depot may offer a viable approach for localized immunotherapy for glioblastoma.

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Related in: MedlinePlus

Pore size evaluation of gels. SEM imagesof T lymphocytes in theprocess of invading through (a and b) the PCgel and (d and e) Matrigelafter 20 h. The scale bars in panels a and d are 4 μm and inpanels b and e 1 μm. (c and f) Distributions of the pore sizesof the (c) PCgel and (f) Matrigel.
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fig4: Pore size evaluation of gels. SEM imagesof T lymphocytes in theprocess of invading through (a and b) the PCgel and (d and e) Matrigelafter 20 h. The scale bars in panels a and d are 4 μm and inpanels b and e 1 μm. (c and f) Distributions of the pore sizesof the (c) PCgel and (f) Matrigel.

Mentions: To act as adepot for sustained T lymphocyte release, the PCgel must have appropriatepore sizes to allow for T lymphocyte invasion out of the matrix. Previousstudies have demonstrated lymphocyte invasion through three-dimensionalgels of native collagen fibers.27 The kineticsof penetration of lymphocytes into the gel matrix indicated that lymphocytesmigrate in a “random-walk” fashion through this collagenmatrix that had a pore size of 2 μm, comparable to that of Tlymphocytes (approximately 1–2 μm in diameter). Thislarge pore size likely explains the random-walk movement of T lymphocytesbecause they were able to freely move throughout the collagen gelwith pore sizes slightly larger than the cells. To act as a controlledrelease depot for T lymphocytes, the pore sizes must be small enoughto prevent the random walk so the cells must actively invade out ofthe gel but large enough for the cells to invade through. SEM imagesof the PCgel (Figure 4a,b) and Matrigel (Figure 4d,e) revealed larger pores in the PCgel and in Matrigel.The 0.5–1 μm pore size distribution of the PCgel (Figure 4c) was more suitable for T lymphocyte invasion thanthat of Matrigel that had more small pore sizes [0.1–0.5 μm(Figure 4f)].


Thermoreversible poly(ethylene glycol)-g-chitosan hydrogel as a therapeutic T lymphocyte depot for localized glioblastoma immunotherapy.

Tsao CT, Kievit FM, Ravanpay A, Erickson AE, Jensen MC, Ellenbogen RG, Zhang M - Biomacromolecules (2014)

Pore size evaluation of gels. SEM imagesof T lymphocytes in theprocess of invading through (a and b) the PCgel and (d and e) Matrigelafter 20 h. The scale bars in panels a and d are 4 μm and inpanels b and e 1 μm. (c and f) Distributions of the pore sizesof the (c) PCgel and (f) Matrigel.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215871&req=5

fig4: Pore size evaluation of gels. SEM imagesof T lymphocytes in theprocess of invading through (a and b) the PCgel and (d and e) Matrigelafter 20 h. The scale bars in panels a and d are 4 μm and inpanels b and e 1 μm. (c and f) Distributions of the pore sizesof the (c) PCgel and (f) Matrigel.
Mentions: To act as adepot for sustained T lymphocyte release, the PCgel must have appropriatepore sizes to allow for T lymphocyte invasion out of the matrix. Previousstudies have demonstrated lymphocyte invasion through three-dimensionalgels of native collagen fibers.27 The kineticsof penetration of lymphocytes into the gel matrix indicated that lymphocytesmigrate in a “random-walk” fashion through this collagenmatrix that had a pore size of 2 μm, comparable to that of Tlymphocytes (approximately 1–2 μm in diameter). Thislarge pore size likely explains the random-walk movement of T lymphocytesbecause they were able to freely move throughout the collagen gelwith pore sizes slightly larger than the cells. To act as a controlledrelease depot for T lymphocytes, the pore sizes must be small enoughto prevent the random walk so the cells must actively invade out ofthe gel but large enough for the cells to invade through. SEM imagesof the PCgel (Figure 4a,b) and Matrigel (Figure 4d,e) revealed larger pores in the PCgel and in Matrigel.The 0.5–1 μm pore size distribution of the PCgel (Figure 4c) was more suitable for T lymphocyte invasion thanthat of Matrigel that had more small pore sizes [0.1–0.5 μm(Figure 4f)].

Bottom Line: Local immunotherapy has the potential to eradicate the residual infiltrative component of these tumors.Nuclear magnetic resonance spectroscopy confirmed the chemical structure of poly(ethylene glycol)-g-chitosan, and rheological studies revealed that the sol-to-gel transition of the PCgel occurred around ≥32 °C.Our study suggests that this unique PCgel depot may offer a viable approach for localized immunotherapy for glioblastoma.

View Article: PubMed Central - PubMed

Affiliation: Department of Materials Science and Engineering, University of Washington , Seattle, Washington 98195, United States.

ABSTRACT
The outcome for glioblastoma patients remains dismal for its invariably recrudesces within 2 cm of the resection cavity. Local immunotherapy has the potential to eradicate the residual infiltrative component of these tumors. Here, we report the development of a biodegradable hydrogel containing therapeutic T lymphocytes for localized delivery to glioblastoma cells for brain tumor immunotherapy. Thermoreversible poly(ethylene glycol)-g-chitosan hydrogels (PCgels) were optimized for steady T lymphocyte release. Nuclear magnetic resonance spectroscopy confirmed the chemical structure of poly(ethylene glycol)-g-chitosan, and rheological studies revealed that the sol-to-gel transition of the PCgel occurred around ≥32 °C. T lymphocyte invasion through the PCgel and subsequent cytotoxicity to glioblastoma were assessed in vitro. The PCgel was shown to be cellular compatible with T lymphocytes, and the T lymphocytes retain their anti-glioblastoma activity after being encapsulated in the PCgel. T lymphocytes in the PCgel were shown to be more effective in killing glioblastoma than those in the Matrigel control. This may be attributed to the optimal pore size of the PCgel allowing better invasion of T lymphocytes. Our study suggests that this unique PCgel depot may offer a viable approach for localized immunotherapy for glioblastoma.

Show MeSH
Related in: MedlinePlus