Limits...
Magnetic resonance-guided regional gene delivery strategy using a tumor stroma-permeable nanocarrier for pancreatic cancer.

Wang Q, Li J, An S, Chen Y, Jiang C, Wang X - Int J Nanomedicine (2015)

Bottom Line: Third-generation dendrigraft poly-L-lysines was selected as the nanocarrier scaffold, which was modified by cell-penetrating peptides and gadolinium (Gd) chelates.Permeability of the nanoparticles modified by cell-penetrating peptides was superior to that of the unmodified counterpart, demonstrating the improved capability of nanoparticles for diffusion in tumor stroma on magnetic resonance imaging.This study demonstrated that an image-guided gene delivery system with a stroma-permeable gene vector could be a potential clinically translatable gene therapy strategy for PDAC.

View Article: PubMed Central - PubMed

Affiliation: Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China ; Shanghai Institute of Medical Imaging, Fudan University, Shanghai, People's Republic of China.

ABSTRACT

Background: Gene therapy is a very promising technology for treatment of pancreatic ductal adenocarcinoma (PDAC). However, its application has been limited by the abundant stromal response in the tumor microenvironment. The aim of this study was to prepare a dendrimer-based gene-free loading vector with high permeability in the tumor stroma and explore an imaging-guided local gene delivery strategy for PDAC to promote the efficiency of targeted gene delivery.

Methods: The experimental protocol was approved by the animal ethics committee of Zhongshan Hospital, Fudan University. Third-generation dendrigraft poly-L-lysines was selected as the nanocarrier scaffold, which was modified by cell-penetrating peptides and gadolinium (Gd) chelates. DNA plasmids were loaded with these nanocarriers via electrostatic interaction. The cellular uptake and loaded gene expression were examined in MIA PaCa-2 cell lines in vitro. Permeability of the nanoparticles in the tumor stroma and transfected gene distribution in vivo were studied using a magnetic resonance imaging-guided delivery strategy in an orthotopic nude mouse model of PDAC.

Results: The nanocarriers were synthesized with a dendrigraft poly-L-lysine to polyethylene glycol to DTPA ratio of 1:3.4:8.3 and a mean diameter of 110.9±7.7 nm. The luciferases were strictly expressed in the tumor, and the luminescence intensity in mice treated by Gd-DPT/plasmid luciferase (1.04×10(4)±9.75×10(2) p/s/cm(2)/sr) was significantly (P<0.05) higher than in those treated with Gd-DTPA (9.56×10(2)±6.15×10 p/s/cm(2)/sr) and Gd-DP (5.75×10(3)± 7.45×10(2) p/s/cm(2)/sr). Permeability of the nanoparticles modified by cell-penetrating peptides was superior to that of the unmodified counterpart, demonstrating the improved capability of nanoparticles for diffusion in tumor stroma on magnetic resonance imaging.

Conclusion: This study demonstrated that an image-guided gene delivery system with a stroma-permeable gene vector could be a potential clinically translatable gene therapy strategy for PDAC.

No MeSH data available.


Related in: MedlinePlus

Schematic illustration of nanoparticle synthesis and delivery procedure.Notes: (A) Cell-penetrating peptides (TAT) were linked using MAL-PEG-NHS. Paramagnetic Gd3+ ions were chelated with p-SCN-Bn-DTPA conjugated with dendrigraft poly-L-lysine. (B) Nanoparticles were injected intratumorally, and diffused by crossing the stroma, endocytosis, and exocytosis in the tumor microenvironment, all of which were monitored by magnetic resonance imaging.Abbreviations: Gd, gadolinium; MAL, maleimide; NHS, N-hydroxysuccinimide; PEG, polyethylene glycol; PBS, phosphate-buffered saline; p-SCN-Bn-DTPA, 2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4508066&req=5

f1-ijn-10-4479: Schematic illustration of nanoparticle synthesis and delivery procedure.Notes: (A) Cell-penetrating peptides (TAT) were linked using MAL-PEG-NHS. Paramagnetic Gd3+ ions were chelated with p-SCN-Bn-DTPA conjugated with dendrigraft poly-L-lysine. (B) Nanoparticles were injected intratumorally, and diffused by crossing the stroma, endocytosis, and exocytosis in the tumor microenvironment, all of which were monitored by magnetic resonance imaging.Abbreviations: Gd, gadolinium; MAL, maleimide; NHS, N-hydroxysuccinimide; PEG, polyethylene glycol; PBS, phosphate-buffered saline; p-SCN-Bn-DTPA, 2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid.

Mentions: As shown in Figure 1, nanocarriers (Gd-DPT) were constructed and administered regionally via an MR-guided percutaneous intratumoral delivery route. A control nanocarrier (Gd-DP) without modification of CPPs was also prepared. In the NMR spectra, the calculated molar ratio of DGL to PEG to DTPA was 1:3.4:8.3 (Figure 2A). The mean diameter of the Gd-DPT/plasmid nanoparticles was 110.9±7.7 nm (Figure 2B). Atomic force microscopy showed that the Gd-DPT/plasmid nanoparticles had a spherical shape and a compact structure (Figure 2C). A relatively lower r1 was detected for Gd-DPT/plasmid (0.88 mM−1s−1) and Gd-DP/plasmid (0.90 mM−1s−1) compared with Gd-DTPA/plasmid (3.92 mM−1s−1). Some Gd3+ ions were embedded by plasmid in the nanoparticles and limited the interaction with water protons23 (Figure 2D).


Magnetic resonance-guided regional gene delivery strategy using a tumor stroma-permeable nanocarrier for pancreatic cancer.

Wang Q, Li J, An S, Chen Y, Jiang C, Wang X - Int J Nanomedicine (2015)

Schematic illustration of nanoparticle synthesis and delivery procedure.Notes: (A) Cell-penetrating peptides (TAT) were linked using MAL-PEG-NHS. Paramagnetic Gd3+ ions were chelated with p-SCN-Bn-DTPA conjugated with dendrigraft poly-L-lysine. (B) Nanoparticles were injected intratumorally, and diffused by crossing the stroma, endocytosis, and exocytosis in the tumor microenvironment, all of which were monitored by magnetic resonance imaging.Abbreviations: Gd, gadolinium; MAL, maleimide; NHS, N-hydroxysuccinimide; PEG, polyethylene glycol; PBS, phosphate-buffered saline; p-SCN-Bn-DTPA, 2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4508066&req=5

f1-ijn-10-4479: Schematic illustration of nanoparticle synthesis and delivery procedure.Notes: (A) Cell-penetrating peptides (TAT) were linked using MAL-PEG-NHS. Paramagnetic Gd3+ ions were chelated with p-SCN-Bn-DTPA conjugated with dendrigraft poly-L-lysine. (B) Nanoparticles were injected intratumorally, and diffused by crossing the stroma, endocytosis, and exocytosis in the tumor microenvironment, all of which were monitored by magnetic resonance imaging.Abbreviations: Gd, gadolinium; MAL, maleimide; NHS, N-hydroxysuccinimide; PEG, polyethylene glycol; PBS, phosphate-buffered saline; p-SCN-Bn-DTPA, 2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid.
Mentions: As shown in Figure 1, nanocarriers (Gd-DPT) were constructed and administered regionally via an MR-guided percutaneous intratumoral delivery route. A control nanocarrier (Gd-DP) without modification of CPPs was also prepared. In the NMR spectra, the calculated molar ratio of DGL to PEG to DTPA was 1:3.4:8.3 (Figure 2A). The mean diameter of the Gd-DPT/plasmid nanoparticles was 110.9±7.7 nm (Figure 2B). Atomic force microscopy showed that the Gd-DPT/plasmid nanoparticles had a spherical shape and a compact structure (Figure 2C). A relatively lower r1 was detected for Gd-DPT/plasmid (0.88 mM−1s−1) and Gd-DP/plasmid (0.90 mM−1s−1) compared with Gd-DTPA/plasmid (3.92 mM−1s−1). Some Gd3+ ions were embedded by plasmid in the nanoparticles and limited the interaction with water protons23 (Figure 2D).

Bottom Line: Third-generation dendrigraft poly-L-lysines was selected as the nanocarrier scaffold, which was modified by cell-penetrating peptides and gadolinium (Gd) chelates.Permeability of the nanoparticles modified by cell-penetrating peptides was superior to that of the unmodified counterpart, demonstrating the improved capability of nanoparticles for diffusion in tumor stroma on magnetic resonance imaging.This study demonstrated that an image-guided gene delivery system with a stroma-permeable gene vector could be a potential clinically translatable gene therapy strategy for PDAC.

View Article: PubMed Central - PubMed

Affiliation: Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China ; Shanghai Institute of Medical Imaging, Fudan University, Shanghai, People's Republic of China.

ABSTRACT

Background: Gene therapy is a very promising technology for treatment of pancreatic ductal adenocarcinoma (PDAC). However, its application has been limited by the abundant stromal response in the tumor microenvironment. The aim of this study was to prepare a dendrimer-based gene-free loading vector with high permeability in the tumor stroma and explore an imaging-guided local gene delivery strategy for PDAC to promote the efficiency of targeted gene delivery.

Methods: The experimental protocol was approved by the animal ethics committee of Zhongshan Hospital, Fudan University. Third-generation dendrigraft poly-L-lysines was selected as the nanocarrier scaffold, which was modified by cell-penetrating peptides and gadolinium (Gd) chelates. DNA plasmids were loaded with these nanocarriers via electrostatic interaction. The cellular uptake and loaded gene expression were examined in MIA PaCa-2 cell lines in vitro. Permeability of the nanoparticles in the tumor stroma and transfected gene distribution in vivo were studied using a magnetic resonance imaging-guided delivery strategy in an orthotopic nude mouse model of PDAC.

Results: The nanocarriers were synthesized with a dendrigraft poly-L-lysine to polyethylene glycol to DTPA ratio of 1:3.4:8.3 and a mean diameter of 110.9±7.7 nm. The luciferases were strictly expressed in the tumor, and the luminescence intensity in mice treated by Gd-DPT/plasmid luciferase (1.04×10(4)±9.75×10(2) p/s/cm(2)/sr) was significantly (P<0.05) higher than in those treated with Gd-DTPA (9.56×10(2)±6.15×10 p/s/cm(2)/sr) and Gd-DP (5.75×10(3)± 7.45×10(2) p/s/cm(2)/sr). Permeability of the nanoparticles modified by cell-penetrating peptides was superior to that of the unmodified counterpart, demonstrating the improved capability of nanoparticles for diffusion in tumor stroma on magnetic resonance imaging.

Conclusion: This study demonstrated that an image-guided gene delivery system with a stroma-permeable gene vector could be a potential clinically translatable gene therapy strategy for PDAC.

No MeSH data available.


Related in: MedlinePlus