Evaluation of 188Re-labeled PEGylated nanoliposome as a radionuclide therapeutic agent in an orthotopic glioma-bearing rat model.

PURPOSE: In this study, the (188)Re-labeled PEGylated nanoliposome ((188)Re-liposome) was prepared and evaluated as a therapeutic agent for glioma. MATERIALS AND METHODS: The reporter cell line, F98(luc) was prepared via Lentivector expression kit system and used to set up the orthotopic glioma-bearing rat model for non-invasive bioluminescent imaging. The maximum tolerated dose applicable in Fischer344 rats was explored via body weight monitoring of the rats after single intravenous injection of (188)Re-liposome with varying dosages before the treatment study. The OLINDA/EXM 1.1 software was utilized for estimating the radiation dosimetry. To assess the therapeutic efficacy, tumor-bearing rats were intravenously administered (188)Re-liposome or normal saline followed by monitoring of the tumor growth and animal survival time. In addition, the histopathological examinations of tumors were conducted on the (188)Re-liposome-treated rats. RESULTS: By using bioluminescent imaging, the well-established reporter cell line (F98(luc)) showed a high relationship between cell number and its bioluminescent intensity (R(2)=0.99) in vitro; furthermore, it could also provide clear tumor imaging for monitoring tumor growth in vivo. The maximum tolerated dose of (188)Re-liposome in Fischer344 rats was estimated to be 333 MBq. According to the dosimetry results, higher equivalent doses were observed in spleen and kidneys while very less were in normal brain, red marrow, and thyroid. For therapeutic efficacy study, the progression of tumor growth in terms of tumor volume and/or tumor weight was significantly slower for the (188)Re-liposome-treated group than the control group (P<0.05). As a result, the lifespan of glioma-bearing rats treated with (188)Re-liposome was prolonged 10.67% compared to the control group. CONCLUSION: The radiotherapeutic evaluation by dosimetry and survival studies have demonstrated that passive targeting (188)Re-liposome via systemic administration can significantly prolong the lifespan of orthotopic glioma-bearing rats while maintaining reasonable systemic radiation safety. Therefore, (188)Re-liposome could be a potential therapeutic agent for glioblastoma multiforme treatment.

Poly(N-isopropylacrylamide) hydrogels with interpenetrating multiwalled carbon nanotubes for cell sheet engineering.

Hydrogels have been developed as artificial extracellular matrixes (ECMs) to mimic native tissue microenvironments for various applications. Unfortunately, poly(N-isopropylacrylamide) (PNIPAAM)-based hydrogels are not suitable for cell culturing and cell sheet preparation. Carbon nanotubes (CNTs), with their mechanical strength and electrical conductivity, have been considered as additives to increase the applicability of hydrogels to cell encapsulation and advance cardiac electrophysiological functions. A simple method for fabrication of PNIPAAM hydrogels interpenetrated with multiwalled CNTs (MWCNTs) as substrates for cell sheet preparation is reported. The results demonstrate that PNIPAAM hydrogels with interpenetrating MWCNTs still exhibit thermosensitive behavior. It is also found that epithelial Madin-Darby canine kidney (MDCK) cells can only attach and proliferate on MWCNT-interpenetrated PNIPAAM hydrogels. Furthermore, the PNIPAAM hydrogels with MWCNTs possess higher elastic moduli and hydrophobicities than those without MWCNTs, suggesting these two characteristics are necessary for the cells to attach to the hydrogel surfaces. Moreover, cell sheets can only be harvested from PNIPAAM hydrogels with MWCNTs because of their high ratio of cell attachment. Thus, this simple method provides sufficient mechanical strength to PNIPAAM hydrogels so that anchorage-dependent cells can be cultivated and provides a superior system for preparing cell sheets.

The effect of PEG-5K grafting level and particle size on tumor accumulation and cellular uptake.

PEG-modified gold nanoparticles (PEG-modified GNs) with diameters of 40 nm and 70 nm were prepared to elucidate the effect of extent of PEG (M.W. 5000) grafting and particle size on tumor accumulation and cellular uptake. Flow cytometry reveals that cellular uptake is strongly related to the size of PEG-modified GNs, rather than the extent of PEG-5K grafting level. Cytotoxicity analysis based on the intracellular release of drugs showed that the 70 nm PEG-modified GNs have the higher cytotoxicity, beccause of their greater cellular uptake. Also, particle size, rather than PEG-5K grafting level affects tumor accumulation. However, PEG-5K grafting level significantly affects the accumulation of particles in the liver and spleen. This finding is important in determining the proper PEG-5K grafting level and particle size for designing nano-medicines.

Novel geometry type of nanocarriers mitigated the phagocytosis for drug delivery.

Target geometry for mitigating phagocytosis has garnered considerable attention recently in the drug delivery field. This study examined nanoparticles (NPs) with same volume but different shapes, namely, spherical NPs (SNPs) and hexagonal nanoprisms (HNPs), and analyzed their behaviors in vitro and in vivo. These NPs were constructed with a multifunctional block copolymer component, mPEG-b-P(HEMA-co-histidine-PLA). Geometry of SNPs and HNPs was controlled by adjusting copolymer properties and particle size was controlled by adjusting formulation parameters. Nanoparticle morphology had no effect in mitigating phagocytosis when NP size was 70 nm; however, morphology had a significant effect when NP size was 120 nm. The radioactivity-time curves for (99m)Tc-labeled NPs, fitted by the two-compartment pharmacokinetic model, show that the prolonged plasma distribution half-life of HNPs is indicative in the bloodstream. The in vitro and in vivo studies reveal that dual stealth characteristics, pegylation and hexagonal prism structure, of nanocarriers can be adopted in clinical application for safe and efficient delivery of cancer therapy.

Imaging, autoradiography, and biodistribution of (188)Re-labeled PEGylated nanoliposome in orthotopic glioma bearing rat model.

The (188)Re-labeled pegylated nanoliposome (abbreviated as (188)Re-Liposome) was prepared and evaluated for its potential as a theragnostic agent for glioma. (188)Re-BMEDA complex was loaded into the pegylated liposome core with pH 5.5 ammonium sulfate gradient to produce (188)Re-Liposome. Orthotopic Fischer344/F98 glioma tumor-bearing rats were prepared and intravenously injected with (188)Re-Liposome. Biodistribution, pharmacokinetic study, autoradiography (ARG), histopathology, and nano-SPECT/CT imaging were conducted for the animal model. The result showed that (188)Re-Liposome accumulated in the brain tumor of the animal model from 0.28%±0.09% injected dose (ID)/g (n=3) at 1 hour to a maximum of 1.95%±0.35% ID/g (n=3) at 24 hours postinjection. The tumor-to-normal brain uptake ratio (T/N ratio) increased from 3.5 at 1 hour to 32.5 at 24 hours. Both ARG and histopathological images clearly showed corresponding tumor regions with high T/N ratios. Nano-SPECT/CT detected a very clear tumor image from 4 hours till 48 hours. This study reveals the potential of (188)Re-Liposome as a theragnostic agent for brain glioma.