Thermally-responsive and reduced glutathione-sensitive folate-targeted nanocarrier based on alginate and pluronic F127 for on-demand release of methotrexate.

A specific rheumatoid arthritis (RA)-microenvironment-triggered nanocarrier for RA treatment of a first-line antirheumatic drug (Methotrexate, MTX) has been proposed. Reduced glutathione (GSH) responsivity, cystamine, was first introduced on the alginate backbone, which was then used as the bridge to connect pluronic F127 (temperature-responsive factor) and folic acid (targeting factor for active immune cells), resulting in dual-responsive triggered targeting carrier, PCAC-FA. In vitro study demonstrated that PCAC-FA was preferentially taken up by activated macrophage cells rather than normal ones, suggesting the targeting of PCAC-FA to inflamed tissue. The loading capacity of the designed carrier was 21.23 ± 0.91 %. MTX from the PCAC-FA carrier was significantly accelerated release in the presentation of glutathione or in cold shock condition, proposing the efficacy-controlled release. MTX@PCAC-FA showed excellent hemocompatibility, confirming a suitable application with parenteral administration. Notably, the acute and subacute toxicity in the mice model showed that the toxicity of MTX had significantly reduced after encapsulating in the PCAC-FA carrier. These nanoplatforms not only provide an alternative safe strategy for the clinical treatment of rheumatoid arthritis with MTX but also deliver MTX selectively and provide on-demand drug release via external and internal signals, thus emerging as a promising therapeutic option for precise RA therapy.

Development of modified polymer dot as stimuli-sensitive and 67Ga radio-carrier, for investigation of in vitro drug delivery, in vivo imaging and drug release kinetic.

A polymer dot modified histidine-functionalized graphene quantum dot carrier, PD@His.GQD, was synthesized to investigate the in vitro sunitinib (STB) deliveryvia luminescence spectrometer. The carrier's synthesis, with an average size of 34 nm, was proved by Fourier transform infrared (FTIR), Transmission Electron Microscopy (TEM), and Dynamic Light Scattering (DLS) analyses. In the in vitro, STB delivery investigation showed that for healthy tissue, the STB was loaded at pH  = 7.2 and at 25  = 5.4 at 37 °C with a maximum loading efficiency percentage of 99 % while it was released at pH = 5.4 at 37 °C with a release percentage of 97 %. In the sequel, the STB loaded carrier was labeled with Gallium-67 (67Ga-STB.PD@His.GQD) to produce exceedingly transparent radio-carrier for in vivo kidney cancerous mice imaging via the single photon emission computed tomography (SPECT) device. The radiochemical purity of the 67Ga-STB.PD@His.GQD was obtained as 95 % by Radio Thin Layer Chromatography (RTLC) and High-Performance Liquid Chromatography (HPLC) analysis. All obtained results affirmed that the synthesized PD@His.GQD is an STB stimuli-sensitive and selective targeting carrier. All cancerous mice in vivo images at 10 and 20 h of 67Ga-STB.PD@His.GQD post-injection and its bio-distribution calculations showed its most accumulation in the kidney cancerous tissue. Also, the STB release kinetic was studied via Zero-order, First-order, Higuchi, and Korsmeyer-Peppas models, and the release data were fitted with Korsmeyer-Peppas model that expresses the STB release mechanism is controlled by diffusion.

Preparation and characterization of multi-functional targeting nano-carrier based on pH-redox tumor microenvironment / 中国药科大学学报

In order to construct a novel multifunctional targeting nano-carrier based on pH-redox characteristics of tumor microenvironment,ketone bonds and disulfide bonds were bonded to the oligomeric hyaluronic acid (oHA) being sensitive to pH and the reduction environment.The chemical structure of oligomeric hyaluronic acid-8-mercaptomenthone 1,2-glycerolketal (oHMST) was characterized by 1H NMR,IR and ESI-MS.Curcuminloaded micelles were prepared by dialysis.The single factor investigation was carried out on the dosage form.Some properties,including particle size zeta potential,the morphology of micelles,and pH-sensitivity were studied.The materials were synthesized successfully.The micelles were spheric with a diameter of about 100 nm.The Zeta potential of the micelles was-(21.97 ± 1.08) mV.The in vitro test showed that oHMST carriers have good pH-sensitivity and redox-sensitivity.

Biocompatibility and brain-targeting ability of nano-micelles on glioma cells / 吉林大学学报(医学版)

Objective To investigate the biocompatibility and safety of nanoscale brain-targeting-carrier micelles [poly (ethylene)-b-poly (lactic acid)/OX26 conjugate micells (copolymer/OX26)],and to explore its possibility as brain-targeted-drug carrier for brain glioma.Methods The C6 glioma cells were cultured in vitro and divided into experimental groups with different concentrations (10, 20, 40, 80 mg · L-1 )of nano micelle, and the medium without micelle was used as control group.The inhibitory effect of nano-micelles on the rat brain glioma C6 cells was examined by Trypan blue cell counting assay.Flow cytometry (FCM)was used to detect the changes of apoptosis and cell cycle of C6 cells,and confocal laser scanning microscope (CLSM)was performed to analyze the distribution of copolymer/OX26 into C6 cells. Results The results of Trypan blue cell counting assay showed copolymer/OX26 didn’t affect the growth of C6 cells,and there were no significant differences in the number of C6 cells between control group and expreimental groups (P >0.05).The results of FCM showed that the cell cycle and and the apoptotic rates of C6 cells had no changes compared with control group (P > 0.05).The results of CLSM showed that the fluorescence intensities in experimental groups were higher than those in blank micelles group and blank control group (P < 0.05 ), and they were increased in dose- and time-dependent manner (P <0.05).Conclusion Copolymer/OX26 has no effect on the growth and apoptosis of glioma cells.By bonding OX26,copolymer/OX26 can significantly increase the intake of C6 cells on the nano micelles.

Tumor targeting HPMA-porphyrin-99mTc copolymer molecular imaging agent.

Porphyrins typically show preferential uptake and retention by tumor tissues via receptor-mediated endocytosis of low-density lipoproteins. To investigate the relative importance of active and passive targeting strategies, the synthesis, characterization, in vitro uptake, and in vivo biodistribution of specific targeting porphyrin HPMA [HPMA: N-(2-hydroxypropyl)methacrylamide] copolymer tracer poly(HPMA)-porphyrin-DTPA-(99m)Tc (DTPA: diethylenetriaminepentaacetic acid), nonspecific targeting HPMA copolymer tracer poly(HPMA)-DTPA-(99m)Tc, and nontargeting tracer DTPA-(99m)Tc are described in this study. The results showed that the cellular accumulation of poly(HPMA)-porphyrin-DTPA-(99m)Tc complex was found to be time-dependent. The uptake of poly(HPMA)-porphyrin-DTPA-(99m)Tc was significantly higher than that of poly(HPMA)-DTPA-(99m)Tc, indicating that uptake of the poly(HPMA)-porphyrin-DTPA-(99m)Tc was active binding. The uptake of poly(HPMA)-DTPA-(99m)Tc was significantly higher than that of DTPA-(99m)Tc, suggesting that uptake of the poly(HPMA)-DTPA-(99m)Tc was passive binding. Twenty-four hour necropsy data in the hepatocellular carcinoma tumor model showed significantly higher (p < 0.001) tumor localization for poly(HPMA)-porphyrin-DTPA-(99m)Tc (5.18 ± 0.50% ID/g [percentage injected dose per gram tissue]) compared with poly(HPMA)-DTPA-(99m)Tc (2.69 ± 0.15% ID/g) and DTPA-(99m)Tc (0.83 ± 0.03% ID/g). Moreover, higher T/B for poly(HPMA)-porphyrin-DTPA-(99m)Tc indicated reduced extravasation of the targeted polymeric conjugates in normal tissues. Thus, the poly(HPMA)-porphyrin-DTPA-(99m)Tc is a potential macromolecular tumor targeting molecular agent.

Peptide fragments of human serum albumin as novel renal targeting carriers.

To develop the proper renal targeting carrier for clinical therapy, human serum albumin, as starting material, was firstly cleaved into albumin fragments and Superdex 75 and CM-Sepharose FF were used to separate and purify the degradation products. Consequently, three peptide fragments (PFs) with certain sequence named PF-A1-123, PF-A124-298 and PF-A299-585 were obtained as candidates of renal targeting carrier. Then, cytotoxicity and cellular uptake of three PFs was studied preliminarily. The results showed that three PFs had no adverse effects on the HeLa and MDCK cell even up to 5.00mg/mL and PF-A299-585 exhibited highest affinity to MDCK cells. After that, we found that PFs selectively accumulated in the kidneys, especially in the renal tubules after intravenous injection in mice by optical imaging study. Finally, Tissues distribution in vivo was utilized to verify the renal targeting profiles of PFs. Three PFs exhibited renal accumulation characteristics. In particular, about 40% injected doses of PF-A299-585 were specifically distributed into kidneys for 1h. The mean area under the curve (AUC) of PF-A299-585 in kidneys increased 13 times compared with those of PF-A1-123 and PF-A124-298. Therefore, PFs can be applied as prospective carriers for renal targeting and PF-A299-585 may be the optimal carrier.

Tumor-targeting carrier equipped with cell-penetrating peptides / 中国肿瘤生物治疗杂志

Equipping tumor-targeting carrier with cell-penetrating peptide with high transduction efficacy has become a trend. According to the fusion modes and tumor-targeting mechanisms, cell-penetrating peptides can be divided into five categories: first, self-targeting cell-penetrating peptides; second, fusion carriers made of targeting ligands and cell-penetrating peptides; third, cell-penetrating peptide-modified nano-carrier; fourth, tumor-microenvironment-targeting cell-penetrating peptides; fifth, other special cell-penetrating peptides. Fusion carriers, which can not be effectively released into the cytoplasm after transducted into target cells, can be further modified to increase their efficacy. In all, cell-penetrating peptide introduced into tumor-targeting carrier should provide a new era for anti-tumor pharmacy research and cancer therapy.