Polyethylenimine-Based Theranostic Nanoplatform for Glioma-Targeting Single-Photon Emission Computed Tomography Imaging and Anticancer Drug Delivery

Abstract Background: Glioma is the deadliest brain cancer in adults because the blood-brain-barrier (BBB) prevents the vast majority of therapeutic drugs from entering into the central nervous system. The development of BBB-penetrating drug delivery systems for glioma therapy still remains a great challenge. In this study, we aimed to design and develop a theranostic nanocomplex with enhanced BBB penetrability and tumor-targeting efficiency for glioma single-photon emission computed tomography (SPECT) imaging and anticancer drug delivery.Results: This multifunctional nanocomplex was manufactured using branched polyethylenimine (PEI) as a template to sequentially conjugate with methoxypolyethylene glycol (mPEG), glioma-targeting peptide chlorotoxin (CTX), and diethylenetriaminepentaacetic acid (DTPA) for 99mTc radiolabeling on the surface of PEI. After the acetylation of the remaining PEI surface amines using acetic anhydride (Ac2O), the CTX-modified PEI (mPEI-CTX) was utilized as a carrier to load chemotherapeutic drug doxorubicin (DOX) in its interior cavity. The formed mPEI-CTX/DOX complex had excellent water dispersibility and released DOX in a sustainable and pH-dependent manner; furthermore, it showed targeting specificity and therapeutic effect of DOX toward glioma cells in vitro and in vivo (a subcutaneous tumor mouse model). Owing to the unique biological properties of CTX, the mPEI-CTX/DOX complex was able to cross the BBB and accumulate at the tumor site in an orthotopic rat glioma model. In addition, after efficient radiolabeling of PEI with 99mTc via DTPA, the 99mTc-labeled complex could help to visualize the drug accumulation in tumors of glioma-bearing mice and the drug delivery into the brains of rats through SPECT imaging.Conclusions: These results indicate the potential of the developed PEI-based nanocomplex in facilitating glioma-targeting SPECT imaging and chemotherapy.

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Polyethylenimine-based theranostic nanoplatform for glioma-targeting single-photon emission computed tomography imaging and anticancer drug delivery

Journal of Nanobiotechnology ◽

10.1186/s12951-020-00705-3 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Lingzhou Zhao ◽

Jingyi Zhu ◽

Jiali Gong ◽

Ningning Song ◽

Shan Wu ◽

...

Keyword(s):

Computed Tomography ◽

Drug Delivery ◽

Single Photon ◽

Photon Emission ◽

Spect Imaging ◽

Emission Computed Tomography ◽

Single Photon Emission ◽

Anticancer Drug Delivery ◽

Single Photon Emission Computed ◽

Photon Emission Computed Tomography

Abstract Background Glioma is the deadliest brain cancer in adults because the blood–brain-barrier (BBB) prevents the vast majority of therapeutic drugs from entering into the central nervous system. The development of BBB-penetrating drug delivery systems for glioma therapy still remains a great challenge. In this study, we aimed to design and develop a theranostic nanocomplex with enhanced BBB penetrability and tumor-targeting efficiency for glioma single-photon emission computed tomography (SPECT) imaging and anticancer drug delivery. Results This multifunctional nanocomplex was manufactured using branched polyethylenimine (PEI) as a template to sequentially conjugate with methoxypolyethylene glycol (mPEG), glioma-targeting peptide chlorotoxin (CTX), and diethylenetriaminepentaacetic acid (DTPA) for 99mTc radiolabeling on the surface of PEI. After the acetylation of the remaining PEI surface amines using acetic anhydride (Ac2O), the CTX-modified PEI (mPEI-CTX) was utilized as a carrier to load chemotherapeutic drug doxorubicin (DOX) in its interior cavity. The formed mPEI-CTX/DOX complex had excellent water dispersibility and released DOX in a sustainable and pH-dependent manner; furthermore, it showed targeting specificity and therapeutic effect of DOX toward glioma cells in vitro and in vivo (a subcutaneous tumor mouse model). Owing to the unique biological properties of CTX, the mPEI-CTX/DOX complex was able to cross the BBB and accumulate at the tumor site in an orthotopic rat glioma model. In addition, after efficient radiolabeling of PEI with 99mTc via DTPA, the 99mTc-labeled complex could help to visualize the drug accumulation in tumors of glioma-bearing mice and the drug delivery into the brains of rats through SPECT imaging. Conclusions These results indicate the potential of the developed PEI-based nanocomplex in facilitating glioma-targeting SPECT imaging and chemotherapy.

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Single photon emission-computed tomography (SPECT) for functional investigation of the proximal tubule in conscious mice

AJP Renal Physiology ◽

10.1152/ajprenal.00413.2009 ◽

2010 ◽

Vol 298 (2) ◽

pp. F454-F460 ◽

Cited By ~ 13

Author(s):

François Jouret ◽

Stéphan Walrand ◽

Kleber S. Parreira ◽

Pierre J. Courtoy ◽

Stanislas Pauwels ◽

...

Keyword(s):

Computed Tomography ◽

Proximal Tubule ◽

Knockout Mice ◽

Single Photon ◽

Photon Emission ◽

Spect Imaging ◽

Emission Computed Tomography ◽

Single Photon Emission ◽

Single Photon Emission Computed ◽

Photon Emission Computed Tomography

Noninvasive analysis of renal function in conscious mice is necessary to optimize the use of mouse models. In this study, we evaluated whether single photon emission-computed tomography (SPECT) using specific radionuclear tracers can be used to analyze changes in renal proximal tubule functions. The tracers included 99mTC- dimercaptosuccinic acid (99mTc-DMSA), which is used for cortex imaging; 99mTc-mercaptoacetyltriglycine (99mTc-MAG3), used for dynamic renography; and 123I-β2-microglobulin, which monitors receptor-mediated endocytosis. 99mTc-DMSA SPECT imaging was shown to delineate the functional renal cortex with a ∼1-mm spatial resolution and accumulated in the cortex reaching a plateau 5 h after injection. The cortical uptake of 99mTc-DMSA was abolished in Clcn5 knockout mice, a model of proximal tubule dysfunction. Dynamic renography with 99mTc-MAG3 in conscious mice demonstrated rapid extraction from blood, renal accumulation, and subsequent tubular secretion. Anesthesia induced a significant delay in the 99mTc-MAG3 clearance. The tubular reabsorption of 123I-β2-microglobulin was strongly impaired in the Clcn5 knockout mice, with defective tubular processing and loss of the native tracer in urine, reflecting proximal tubule dysfunction. Longitudinal studies in a model of cisplatin-induced acute tubular injury revealed a correlation between tubular recovery and 123I-β2-microglobulin uptake. These data show that SPECT imaging with well-validated radiotracers allows in vivo investigations of specific proximal tubule functions in conscious mice.

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