The brain targeting mechanism of Angiopep-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone) nanoparticles.

In order to evaluate the potential and mechanism of Angiopep-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone)nanoparticles (ANG-PEG-NP) as brain targeting drug delivery system, Rhodamine B isothiocyanate (RBITC) was used as a fluorescent probe molecule to label ANG-PEG-NP through covalent bonding. The brain transcytosis across the blood-brain barrier (BBB) and brain delivery in mice of RBITC labeled ANG-PEG-NP were investigated in this paper. Results showed that ANG-PEG-NP enhanced significantly the uptake by BCECs compared with that of PEG-NP through caveolae- and clathrin-mediated endocytosis, involving a time-dependent, concentration-dependent and energy-dependent mode. The transport of ANG-PEG-NP across the in vitro BBB model was significantly increased than that of PEG-NP. After injection a dose of 100 mg/kg RBITC labeled ANG-PEG-NP or PEG-NP in mouse caudal vein, the brain coronal section showed a higher accumulation of ANG-PEG-NP in the cortical layer, lateral ventricle, third ventricles and hippocampus than that of PEG-NP. By using an excess of free LRP ligand (Angiopep-2 and/or Aprotinin) as a specific receptor inhibitor, it was evidenced that the uptake by BCECs in vitro, transport across in vitro BBB model and penetration into brain tissue in vivo of RBITC labeled ANG-PEG-NP could be inhibited significantly, which demonstrated the brain targeting mechanism of Angiopep-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone)nanoparticles might be a LRP receptor mediated transcytosis process. Understanding these issues is important for the future development of ANG-PEG-NP as a brain targeting drug delivery system for neurodegenerative disorders including glioma and Alzheimer's disease.

Self-aggregated pegylated poly (trimethylene carbonate) nanoparticles decorated with c(RGDyK) peptide for targeted paclitaxel delivery to integrin-rich tumors.

Cyclic RGD peptide-decorated polymeric micellar-like nanoparticles (MNP) based on PEGylated poly (trimethylene carbonate) (PEG-PTMC) were prepared for active targeting to integrin-rich cancer cells. An amphiphilic diblock copolymer, α-carboxyl poly (ethylene glycol)-poly (trimethylene carbonate) (HOOC-PEG-PTMC), was synthesized by ring-opening polymerization. The c(RGDyK) ligand, a cyclic RGD peptide that can bind to the integrin proteins predominantly expressed on the surface of tumor cells with high affinity and specificity, was conjugated to the NHS-Activated PEG terminus of the copolymer. The c(RGDyK)-functionalized PEG-PTMC micellar nanoparticles encapsulating PTX (c(RGDyK)-MNP/PTX) was fabricated by the emulsion/solvent evaporation technique and characterized in terms of morphology, size and zeta potential. Cellular uptake of c(RGDyK)-MNP/PTX was found to be higher than that of MNP/PTX due to the integrin protein-mediated endocytosis effect. In vitro cytotoxicity, cell apoptosis and cell cycle arrest studies also revealed that c(RGDyK)-MNP/PTX was more potent than those of MNP/PTX and Taxol. Pharmacokinetic study in rats demonstrated that the polymeric micellar nanoparticles significantly enhanced the bioavailability of PTX than Taxol. In vivo multispectral fluorescent imaging indicated that c(RGDyK)-MNP/PTX had high specificity and efficiency in tumor active targeting. Therefore, the results demonstrated that c(RGDyK)-decorated PEG-PTMC MNP developed in this study could be a potential vehicle for delivering hydrophobic chemotherapeutic agents to integrin-rich tumors.

PEGylated poly(trimethylene carbonate) nanoparticles loaded with paclitaxel for the treatment of advanced glioma: in vitro and in vivo evaluation.

The aim of this study was to investigate the antitumor effect of paclitaxel (PTX)-loaded poly(ethylene glycol)-poly(trimethylene carbonate) (MPEG-PTMC) nanoparticles (NP) against gioblastoma multiforme (GMB). PTX-loaded NP (NP/PTX) were prepared with synthesized MPEG-PTMC by the emulsion/solvent evaporation technique. In vitro physiochemical characterization of those NP/PTX showed satisfactory encapsulation efficiency and loading capacity and size distribution. Cytotoxicity assay revealed that encapsulation in nanoparticles did not compromise the antitumor efficacy of PTX against U87MG cells. Pharmacokinetic study in rats demonstrated that the polymer micellar nanoparticles significantly enhanced the bioavailability of PTX than Taxol. In intracranial xenograft tumor-bearing mice, the accumulation of nanoparticles in tumor tissues increased distinctly after 12 h post i.v. More importantly, in vivo anti-tumor effect exhibited the median survival time of NP/PTX treated mice (27 days) was significantly longer than those of mice treated with Taxol (24 days), physiological saline (21 days) and blank MPEG-PTMC NP (21 days). Therefore, our results suggested that PTX-loaded MPEG-PTMC nanoparticles significantly enhanced the anti-glioblastoma activity of PTX and may be a potential vehicle in the treatment of high-grade glioma.

Enhanced anti-tumor effect of 9-nitro-camptothecin complexed by hydroxypropyl-ß-cyclodextrin and safety evaluation.

The aim of this study was to evaluate the safety and anti-tumor effect of 9-nitro-camptothecin/hydroxypropyl-ß-cyclodextrin (9-NC/HP-ß-CD) complex on tumor-bearing mice. The in vitro anti-tumor activity was tested by MTT assay. Our study revealed that the 9-NC/HP-ß-CD complex showed significant anti-tumor activity towards Skov-3, MCF-7, HeLa and S180 cell lines with IC(50) values of 0.24 ± 0.09, 0.59 ± 0.20, 0.83 ± 0.11, and 6.30 ± 2.42 µg/ml, respectively, significantly superior to the free 9-NC. The in vivo therapeutic efficacy was investigated in ICR mice bearing mouse sarcoma S180. Both the high (3mg/kg) and low (1mg/kg) doses of 9-NC/HP-ß-CD complex demonstrated high inhibition ratio of tumor growth (>75%). The subacute toxicity test was performed by measuring the body weight, histopathology, blood cell counts and clinical chemistry parameters (total bilirubin, alanine transferase, aspartate transferase, blood urea nitrogen and creatinine), and the results indicated the good safety profile of the complex. Taken together, the results suggested that the 9-NC complexed in HP-ß-CD, instead of dissolved in the organic solvent, presented significant anti-tumor activity and low toxicity for the treatment of cancer.

Angiopep-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone) nanoparticles as dual-targeting drug delivery system for brain glioma.

Dual-targeting nanoparticle drug delivery system was developed by conjugating Angiopep with PEG-PCL nanoparticles (ANG-NP) through bifunctional PEG to overcome the limitations of low transport of chemotherapeutics across the Blood-brain barrier (BBB) and poor penetration into tumor tissue. ANG-NP can target the low-density lipoprotein receptor-related protein (LRP) which is over-expressed on the BBB and glioma cells. Compared with non-targeting nanoparticles, a significantly higher amount of rhodamine isothiocyanate-labeled dual-targeting nanoparticles were endocytosed by U87 MG cells. The antiproliferative and cell apoptosis assay of paclitaxel-loaded ANG-NP (ANG-NP-PTX) demonstrated that ANG-NP-PTX resulted in enhanced inhibitory effects to U87 MG glioma cells. The transport ratios across the BBB model in vitro were significantly increased and the cell viability of U87 MG glioma cells after crossing the BBB was obviously decreased by ANG-NP-PTX. Enhanced accumulation of ANG-NP in the glioma bed and infiltrating margin of intracranial U87 MG glioma tumor-bearing in vivo model were observed by real time fluorescence image. In conclusion, Angiopep-conjugated PEG-PCL nanoparticles were prospective in dual-targeting drug delivery system for targeting therapy of brain glioma.