In vivo behavior and safety of lapatinib-incorporated lipid nanoparticles.

To improve the solubility, bioavailability and anti-tumor effect of lapatinib, lapatinib-incorporated lipid nanoparticles (LTNPs) were prepared and characterized. The particle size of LTNPs was 88.6 nm with a zeta potential of 20 mV. Laptinib was loaded into LTNPs with a non-crystal structure as determined by FT-IR. In vitro, LTNPs could be effectively uptaken into C6 glioma cells at a concentration-dependent manner. In vivo, LTNPs showed a relative higher AUC, which was 5.27- and 3.21-fold as that of Tykerb and lapatinib suspension (LTS) group. LTNPs also showed highest glioma concentration, which may benefit from the enhanced permeability and retention effect and active targeting ability. In toxicity studies, LTNPs displayed a half lethal dose over 250 mg/kg. Repeated administering 30 mg/kg of LTNPs could led to toxicity to hematology which might owe to the bovine serum albumin, a foreign protein to mice. However, there was no organic change observed through HE staining. In conclusion, LTNPs could target to glioma with high concentration and low side effect.

Incorporation of lapatinib into lipoprotein-like nanoparticles with enhanced water solubility and anti-tumor effect in breast cancer.

AIM: The poor water solubility of many active compounds is a serious deterrent to their use as commercial drugs. Lapatinib is a dual inhibitor of the EGF receptor and EGF receptor 2 approved by the US FDA to treat advanced breast cancer. This study prepares lapatinib-incorporated lipoprotein-like nanoparticles (LTNPs) to enhance the water solubility and elevate the anti-tumor effect of lapatinib. MATERIALS & METHODS: Bovine albumin was used to bind with lapatinib, and egg yolk lecithin was used to stabilize the conjugation of bovine albumin and lapatinib. The characteristics of LTNPs were evaluated by several experiments. Cell uptake and toxicity were performed on BT-474 cells. In vivo anti-tumor effect was performed on BT-474 xenograft-bearing mice. RESULTS: LTNPs contained a lipid corona and a core of lapatinib and albumin. LTNPs could be effectively taken up by BT-474 cells and induced apoptosis. An in vivo study demonstrated that LTNPs could passively distribute into a tumor via the enhanced permeability and retention effect and induce anti-tumor activity in breast cancer. CONCLUSION: The authors present a convenient nanoformulation with improved anti-tumor effect, which is a promising candidate for clinical trials.

Behavior and anti-glioma effect of lapatinib-incorporated lipoprotein-like nanoparticles.

The purpose of the investigation was to prepare a new type of nanoparticle, namely lapatinib-incorporated lipoprotein-like nanoparticles (LTNPs), and to evaluate the behavior and anti-glioma effect of LTNPs. LTNPs were prepared and characterized using the Cyro-transmission electron microscope (Cryo-TEM) and Raman scan methods. Cellular uptake and subcellular localization studies were performed to evaluate the in vitro behavior of LTNPs. An in vivo imaging technique was used for the evaluation of the targeting of LTNPs. To study the anti-glioma effect, glioma xenografts were used. The particle size of LTNPs was 92.6 nm, and the zeta potential was 28.40 mV. LTNPs contained a surface layer that was obviously different from the core, according to the Cryo-TEM analysis. A Raman scan analysis demonstrated the incorporation of lapatinib in LTNPs, and it also revealed a structure different from free lapatinib. The uptake of LTNP by U87 cells occurred in a concentration- and time-dependent manner. According to the subcellular study, the uptake of LTNPs was endosome mediated. LTNPs could distribute and accumulate in the tumor site by an enhanced permeation and retention effect. Both LTNPs (10 mg kg(-1)) and LTNPs (30 mg kg(-1)) could significantly inhibit the growth of U87 xenografts. For a similar antitumor effect, the required cumulative dose of LTNPs was only 5% compared to that of Tykerb (the commercial formulation of lapatinib). This study demonstrated the effective uptake of LTNPs by U87 cells, the passive targeting of LTNPs at tumors and the better antitumor effect of LTNPs.

Whole-cell SELEX aptamer-functionalised poly(ethyleneglycol)-poly(ε-caprolactone) nanoparticles for enhanced targeted glioblastoma therapy.

Though there has been substantial advancement in the knowledge about tumour development and treatment in the past 40 years, the prognosis of brain glioblastoma is still very grim due to the difficulty of targeting drugs to glioblastoma cells. An active targeting delivery system helps increase intracellular drug delivery, which is promising for the treatment of glioblastoma. For an active targeting delivery system, targeting ligands are crucial for efficient intracellular drug delivery. Current methods include systematic evolution of ligands by exponential enrichment (SELEX), which has been utilised for selecting specific ligands with better targeting effects. The GMT8 aptamer was a short DNA sequence selected by SELEX that could specifically bind with U87 cells. In this study, nanoparticles functionalised with GMT8 aptamers (ApNP) were utilised for glioblastoma therapy. In vitro cell uptake and U87 tumour spheroid uptake demonstrated that nanoparticles functionalised with GMT8 aptamer significantly enhanced intracellular drug delivery and tumour spheroid penetration. Assays for cell apoptosis and growth inhibition of tumour spheroids identified docetaxel-loaded ApNP to significantly induce cell apoptosis and inhibit tumour spheroid growth. In vivo imaging of glioblastoma-bearing mice demonstrated that ApNP could target glioblastoma and accumulate at the tumour site, which was further verified by fluorescence imaging of brain slices. Pharmacodynamic results indicated that docetaxel-loaded ApNP significantly prolonged the median survival time of glioblastoma-bearing mice compared to NP, DTX and control. In conclusion, GMT8 aptamer-functionalised nanoparticles enhanced tumour penetration and targeted glioblastoma therapy, which is promising for the prognosis of brain glioblastoma.

Precise glioma targeting of and penetration by aptamer and peptide dual-functioned nanoparticles.

The treatment of a brain glioma is still one of the most difficult challenges in oncology. To effectively treat brain glioma and reduce the side effects, drugs must be transported across the blood brain barrier (BBB) and then targeted to the brain cancer cells because most anti-tumor drugs are highly toxic to the normal brain tissue. A cascade delivery strategy was developed to perform these two aims and to achieve enhanced and precisely targeted delivery. Herein, we utilize a phage-displayed TGN peptide and an AS1411 aptamer, which are specific targeting ligands of the BBB and cancer cells, respectively and we conjugate them with nanoparticles to establish the brain glioma cascade delivery system (AsTNP). In vitro cell uptake and three-dimensional tumor spheroid penetration studies demonstrated that the system could not only target endothelial and tumor cells but also penetrate the endothelial monolayers and tumor cells to reach the core of the tumor spheroids, which was extremely important but mostly ignored in glioma therapy. In vivo imaging further demonstrated that the AsTNP provided the highest tumor distribution and tumor/normal brain ratio. The distribution was also reconfirmed by fluorescent images of the brain slides. As a result, the docetaxel-loaded AsTNP presents the best anti-glioma effect with improved glioma bearing survival. In conclusion, the AsTNP could precisely target to the brain glioma, which was a valuable target for glioma imaging and therapy.

The targeted delivery of anticancer drugs to brain glioma by PEGylated oxidized multi-walled carbon nanotubes modified with angiopep-2.

In this study, a dual-targeting drug delivery system based on PEGylated oxidized multi-walled carbon nanotubes (O-MWNTs) modified with angiopep-2 (O-MWNTs-PEG-ANG) was successfully developed for treatment of brain glioma. O-MWNTs can not only distribute in brains but also accumulate in tumors, and have ultrahigh surface area with remarkably high loading anticancer drug of doxorubicin (DOX), which was selected as drug carrier. Angiopep-2 can specifically combine to the low-density lipoprotein receptor-related protein (LRP) receptor overexpressed on the blood-brain barrier (BBB) and glioma cells, which was selected as targeting ligand. The cooperative dual-targeting to brain glioma by O-MWNTs-PEG-ANG was evaluated by intracellular tracking in vitro and fluorescence imaging in vivo, which demonstrated that the combination of O-MWNTs-PEG and angiopep-2 constituted an ideal dual-targeting drug delivery system. The anti-glioma effect of DOX-loaded O-MWNTs-PEG-ANG (DOX-O-MWNTs-PEG-ANG) was assessed by C6 cytotoxicity and median survival time of glioma bearing mice, which showed a better anti-glioma effect than DOX. The biological safety of O-MWNTs-PEG-ANG was evaluated by BCEC and C6 cytotoxicity, hematology analysis and CD68 immunohistochemical analysis, which proved O-MWNTs-PEG-ANG was good biocompatibility and low toxicity. The biological safety of DOX-O-MWNTs-PEG-ANG was evaluated by histopathological analysis, which suggested a lower cardiac toxicity than DOX. In conclusion, O-MWNTs-PEG-ANG is a promising dual-targeting carrier to deliver DOX for the treatment of brain tumor.