PEGylated polyamidoamine dendrimer/methotrexate complex: pharmacokinetics and anti-tumor activity in normal and tumor-bearing rodents / 药学学报

Generation 4 polyamidoamine (PAMAM) dendrimer was PEGylated with polyethylene glycol (PEG) at an average molecular weight 5 000 via amide bond. PAMAM and PEGylated PAMAM (PAMAM-PEG) dendrimer were used as drug nanocarriers. Methotrexate (MTX), an antineoplastic agent, was selected as a model drug. PAMAM/MTX and PAMAM-PEG/MTX complexes were prepared. The pharmacokinetic characters and anti-tumor activity of the PAMAM-PEG/MTX complex were studied as compared with MTX injection and PAMAM/MTX complex by intravenous injection in rats and S180 tumor bearing mice, separately. The plasma samples from normal rats were analyzed by HPLC method, and concentration-time data were analyzed using a non-compartmental analysis. Their anti-tumor effects in vivo were evaluated against S180 solid tumors in mice by measuring average tumor weight and calculating the inhibitory rate of tumor on day 17 after successive injections. The results showed that both plasma half-life and mean retention time (MRT) of the complexes were longer than that of MTX injection (P<0.01), while the area under the plasma concentration vs time curve (AUC) of PAMAM-PEG/MTX was the largest as compared with that of free drug and PAMAM/MTX complex (P<0.01). The inhibitory rate of tumor of PAMAM-PEG/MTX complex enhanced 2.1 and 1.8 times over that of free drug and PAMAM/MTX complex, respectively, indicating that PAMAM-PEG/MTX exhibited the highest antitumor activity. In summary, PEGylated PAMAM could be useful as a potential drug delivery carrier.

Influence of particle size and MePEG molecular weight on in vitro macrophage uptake and in vivo long circulating of stealth nanoparticles in rats / 药学学报

<p><b>AIM</b>To investigate the influence of particle size and methoxypolyethyleneglycol (MePEG) molecular weight on the in vitro macrophage uptake and in vivo long circulating of recombinant human tumor necrosis factor-alpha (rHuTNF-alpha)-loaded stealth nanoparticles in rats.</p><p><b>METHODS</b>Three sizes (approximately 80, 70 and 240 nm) of poly (methoxypolyethyleneglycol cyanoacrylate-co-n-hexadecyl cyanoacrylate) (PEG-PHDCA) nanoparticles loading rHuTNF-alpha were prepared at different MePEG molecular weights (Mr 2,000, 5,000, 10,000) using the double emulsion method. The in vitro macrophage uptake and in vivo long circulating properties in rats were examined and compared.</p><p><b>RESULTS</b>The uptake by macrophages decreased and the half-life of rHuTNF-alpha in rat increased with the increase of MePEG molecular weight or the decrease of particle size. The linear-ships between particle size and MePEG molecular weight and the in vitro macrophage uptake and in vivo long circulating properties were fairly good. Having the highest MePEG surface density (1.32 nm(-2)) , the shortest average distance between neighboring MePEG chain (0.87 nm) and the thicker fixed aqueous layer thickness (FALT, 5.16 nm), PEG5,000-PHDCA nanoparticles (80.0 nm) earned the strongest potency of decreasing uptake by macrophages and prolonging the half-life of rHuTNF-alpha in rat.</p><p><b>CONCLUSION</b>Within the experimental limits, particle size and MePEG molecular weight had dramatic influence on in vitro macrophage uptake and in vivo long circulating properties of rHuTNF-alpha-loaded stealth nanoparticles.</p>

Stealth PEG-PHDCA niosomes: effects of chain length of PEG on niosomes in vitro complement consumption and phagocytic uptake / 药学学报

<p><b>AIM</b>Poly (methoxypolyethyleneglycol cyanoacrylate-co-hexadecyl cyanoacrylate) (PEG-PHDCA) and PHDCA niosomes were prepared and the influence of the PEG chain length on the niosomes physicochemical characteristics, complement consumption and phagocytic uptake were studied.</p><p><b>METHODS</b>The physicochemical parameters of PEG-PHDCA niosomes were characterized in terms of particle size, zeta aqueous layer thickness. The relationship between physicochemical characteristics and in vitro complement consumption and phagocytic uptake was further illustrated.</p><p><b>RESULTS</b>Experimental results showed that PEG10,000-PHDCA had most loose structure and least PEG surface density among three groups. Configuration simulation through fixed aqueous layer thickness confirmed that PEG folding and less flexibility of the PEG chains of PEG10,000-PHDCA niosomes were accountable for its poor stealth effects. Compared with PEG2,000-PHDCA, PEG5,000-PHDCA showed a thicker fixed aqueous layer (FALT) of 4.20 nm, less negative zeta potential of -10.03 mV, and enhanced PEG surface density of 0.49 PEG x nm(-2), leading to the best effects of reduction of complement consumption and phagocytic uptake.</p><p><b>CONCLUSION</b>Excessive chain length of PEG was not necessary for stealth effects of PEG-PHDCA niosomes. PEG5,000-PHDCA niosomes had best effects on evading complement consumption and subsequent phagocytic uptake.</p>

Preparation and stability of recombinant human tumor necrosis factor-alpha-loaded stealth nanoparticles / 药学学报

<p><b>AIM</b>To prepare recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) -loaded stealth nanoparticles with different PEG chain lengths and sizes, and investigate the stability of nanoparticle suspensions.</p><p><b>METHODS</b>The poly( MePEG cyanoacrylate-co-hexadecyl cyanoacrylate) (MePEG-PHDCA) and poly(hexadecyl cyanoacrylate) (PHDCA) were synthesized and characterized with Fourier transform infrared spectrum (FTIR), 1HNMR, 13CNMR and gel permeation chromatography (GPC). Uniform design was used to optimize the entrapment efficiency. The nanoparticle suspensions were stored at 2 - 8 degrees C for 4 weeks, and the particle size evolution was studied.</p><p><b>RESULTS</b>FTIR, 1HNMR and 13CNMR were consistent with the structures of MePEG-PHDCA and PHDCA whose polydispersity indexes were all less than 1.1, indicating narrow distributions. The entrapment efficiency of all nanoparticles was satisfactory. The three different mean diameters of MePEG-PHDCA and PHDCA nanoparticles were about 80 nm, 170 nm and 240 nm, separately. The nanoparticle suspensions maintained their sizes at 2 - 8 degrees C for 4 weeks</p><p><b>CONCLUSION</b>MePEG-PHDCA with three different molecular weight MePEG and PHDCA were synthesized successfully. There are negligible aggregations and bulk or surface erosion as for both stealth MePEG-PHDCA and conventional PHDCA nanoparticles in distilled water.</p>