Intratumoral injection of gels containing losartan microspheres and (PLG-g-mPEG)-cisplatin nanoparticles improves drug penetration, retention and anti-tumor activity
CANCER LETTERS
Authors: Yu, Meiling; Zhang, Chunxue; Tang, Zhaohui; Tang, Xing; Xu, Hui
Abstract
Intratumoral injection of chemotherapy agents may be employed in the treatment of cancers. However, its antitumor efficacy is significantly impeded by collagen fibers in the tumor which decrease drug penetration into the tumor tissues. To improve the penetration, collagen inhibiting drug exposure is required. In this study, micro spheres were fabricated by the modified double emulsion-solvent evaporation method as the drug delivery system of losartan potassium (LP MSs), with 5% gelatin as the inner phase. The collagen inhibiting experiment analyzed by Sirius Red stains demonstrated that LP MSs may effectively inhibit collagen I synthesis in B16 tumors. In addition, 15% F127 was used as the solvent to fix the formulations at the injection site, with poly (alpha-L-glutamate) grafted polyethylene glycol mono methyl ether (PLG-g-mPEG)-cisplatin loaded nanoparticles (CDDP NPs) as the model drug. The in vivo live imaging system showed that formulations dissolved in 15% F127 had 54.91% CDDP NPs retained in tumors at the end of 10 days, in comparison with 19.72% for those solved in water, suggesting strong intratumoral retention property of the in situ gel. In addition, confocal laser scanning microscope (CLSM) and Energy-Dispersive Analysis of X-ray spectroscopy combined with scanning electron microscope (SEM-EDAX) tests showed that LP MSs can effectively enhance the distribution and penetration of CDDP NPs within tumors. Furthermore, tumors i.t. treated with LP MSs/CDDP NPs gel could be significantly halted, or even reduced to 200 mm(3), comparing with a volume of about 12000 mm(3) incontrol group at the end of the anti-tumor effect experiment. These results provided important guiding principles for prolonged and localized drug delivery system of intratumoral collagen inhibitor. The improvements of intratumoral penetration method made in this study provided practical significance for the treatment of cancer, especially for mass tumors.
Bioactive polypeptide hydrogels modified with RGD and N-cadherin mimetic peptide promote chondrogenic differentiation of bone marrow mesenchymal stem cells
SCIENCE CHINA-CHEMISTRY
Authors: Rong, Yan; Zhang, Zhen; He, Chaoliang; Chen, Xuesi
Abstract
Cell-material and cell-cell interactions represent two crucial aspects of the regulation of cell behavior. In the present study, poly (L-glutamic acid) (PLG) hydrogels were prepared by catalyst-free click crosslinkingviaa strain-promoted azide-alkyne cycloaddition (SPAAC) reaction between azido-grafted PLG (PLG-N-3) and azadibenzocyclooctyne-grafted PLG (PLG-ADIBO). The bioactive peptides c(RGDfK) and N-cadherin mimetic peptide (N-Cad) were both conjugated to the PLG hydrogel (denoted PLG+RGD/N-Cad) in order to regulate cell-material and cell-cell interactions. Gelation time and storage modulus of the hydrogels were tunable through variations in the concentration of polypeptide precursors. The hydrogels degraded gradually in the presence of proteinases. The viability of bone marrow mesenchymal stem cells (BMSCs) was maintained when cultured with extracts of the hydrogels or encapsulated within the hydrogels. Degradation was observed within 10 weeks following the subcutaneous injection of hydrogel solution in rats, displaying excellent histocompatibilityin vivo. The introduction of RGD into the PLG hydrogel promoted the adhesion of BMSCs onto the hydrogels. Moreover, when encapsulated within the PLG+RGD/N-Cad hydrogel, BMSCs secreted cartilage-specific matrix, in addition to chondrogenic gene and protein expression being significantly enhanced in comparison with BMSCs encapsulated in hydrogels without N-Cad modification. These findings suggest that these biodegradable, bioactive polypeptide hydrogels have great potential for use in 3D cell culture and in cartilage tissue engineering.