Influence of serum protein on polycarbonate-based copolymer micelles as a delivery system for a hydrophobic anti-cancer agent.

A new micelle system formed from methoxy (polyethylene glycol)-b-poly (5-benzyloxy-trimethylene carbonate; MePEG-b-PBTMC 5000-b-4800) was investigated as a delivery system for the hydrophobic anti-cancer agent, ellipticine. The ellipticine was loaded into the MePEG-b-PBTMC micelles with a loading efficiency of 95% using a high-pressure extrusion technique. The ellipticine-loaded micelles have a spherical morphology and an average diameter of 96 nm. The anti-cancer activity of ellipticine was confirmed to be retained following formulation in the MePEG-b-PBTMC micelles. The extent of protein adsorption to the MePEG-b-PBTMC micelles was investigated by transmission electron microscopy, dynamic light scattering and gel filtration chromatography. Overall, the amount of protein both loosely and tightly associated with the micelles was found to be minimal and insignificant. The partitioning properties of ellipticine between an aqueous medium containing protein and the MePEG-b-PBTMC micelles were examined over a range of protein concentrations. Under physiologically relevant conditions, it was found that 61% of the drug remained within the micelle fraction while 39% was in the protein-containing aqueous phase. In addition, the in vitro drug release profile of ellipticine from the micelles was fit using a modified Higuchi model and found to be accelerated in the presence of protein. These studies demonstrate that although there are no significant interactions between micelle and protein, the properties of the micelle as a delivery vehicle may be strongly influenced by protein-drug interactions.     

Preferential liver gene expression with polypropylenimine dendrimers.

Previously, the lower generation (DAB 8-generation 2 and DAB 16-generation 3) polypropylenimine dendrimers have been shown to be effective gene delivery systems in vitro. In the current work, we sought to: (a) test the effect of the strength of the carrier, DNA electrostatic interaction on gene transfer and (b) to study the in vivo gene transfer activity of these low molecular weight (<1687 Da) non-amphiphilic plain and quaternary ammonium gene carriers. Towards this aim, methyl quaternary ammonium derivatives of DAB 4 (generation 1), DAB 8, DAB 16 and DAB 32 (generation 4) were synthesised to give Q4, Q8, Q16 and Q32, respectively. Quaternisation of DAB 8 proved to be critical in improving DNA binding, as evidenced by data from the ethidium bromide exclusion assay and dendrimer-DNA colloidal stability data. This improved colloidal stability had a major effect on vector tolerability, as Q8-DNA formulations were well tolerated on intravenous injection while a similar DAB 8-DNA dose was lethally toxic by the same route. Quaternisation also improved the in vitro cell biocompatibility of DAB 16-DNA and DAB 32-DNA dendrimer complexes by about 4-fold but not that of the lower generation DAB 4-DNA and DAB 8-DNA formulations. In contrast to previous reports with non-viral gene delivery systems, the intravenous administration of DAB 16-DNA and Q8-DNA formulations resulted in liver targeted gene expression as opposed to the lung targeted gene expression obtained with the control polymer-Exgen 500 [linear poly(ethylenimine)] and a lung avoidance hypothesis is postulated. We conclude that the polypropylenimine dendrimers are promising gene delivery systems which may be used to target the liver and avoid the lung and also that molecular modifications conferring colloidal stability on gene delivery formulations have a profound effect on their tolerability on intravenous administration.     

Dysphagia aortica

Three patients with dysphagia caused by compression of the distal esophagus by a tortuous nonaneurysmal atherosclerotic aorta are described. All three patients were elderly women; systemic hypertension and cardiomegaly were present in two patients. Barium studies of the esophagus showed displacement and compression of the distal esophagus by the thoracic aorta. Debilitating dysphagia was treated surgically in one patient. The other two patients had milder symptoms and were managed conservatively. Esophageal manometry in these three patients showed superimposed pulsations and elevated intraluminal pressure just proximal to the lower esophageal sphincter. To evaluate the significance of these manometric findings and their correlation with clinical symptoms, we reviewed manometric tracings in 47 normal subjects. Ten of these subjects had an elevation of baseline intraluminal esophageal pressure as a result of superimposed vascular pulsations. We conclude that (1) compression of the distal esophagus by a tortuous atherosclerotic aorta in the appropriate setting can lead to clinically significant dysphagia and (2) a manometric finding of vascular compression of the esophagus does not necessarily correlate symptomatic dysphagia.     

Improvement in the Appearance of Wrinkles with Topical Transforming Growth Factor β1 and l-Ascorbic Acid

BACKGROUND AND OBJECTIVE: Facial rhytides are a common cosmetic concern. Surgical treatment effects dramatic improvement; however, the associated risk and cost may be prohibitive. Recent focus is on developing topical products containing biologically active ingredients for at-home therapy. Our study examines the effects of a topical cream containing transforming growth factor-beta(1) (TGF-beta(1)), l-ascorbic acid, and Cimicifuga racemosa extract (CRS) (Topix Pharmaceuticals, North Amityville, NY, USA). MATERIALS AND METHODS: In the first arm of the study, 12 subjects were randomized to apply CRS to the left or right side of their face and a cream containing l-ascorbic acid and C. racemosa in silicone base (vitamin C [Vit C]) to the contralateral side twice daily for 3 months. In the second arm of the study, 20 subjects were randomized to apply CRS to the left or right side of their face and Tissue Nutrient Solution Recovery Complex (TNS) (SkinMedica, Carlsbad, CA, USA), a product containing a variety of growth factors including VEGF, PDGF-A, G-CSF, HGF, IL-6, IL-8, and TGF-beta(1) (Nouricel-MD) without l-ascorbic acid, C. racemosa extract, or silicone base, to the contralateral side of their face twice daily for 3 months. Digital photographs were scored by study-blinded physicians, and self-assessments were completed by all subjects at baseline and at the conclusion of the protocol. RESULTS: CRS and TNS were well tolerated, and all subjects completed the 3-month protocol for the CRS versus Vit C arm of the study. Physicians rated success in facial wrinkling scores on the CRS-treated side of the face for 27 of 31 subjects. Responders showed, on average, 21.7% improvement in physician-rated wrinkle scores. The mean improvement in the group of 31 patients as a whole was 12%. Eighteen of 31 subjects reported a noticeable improvement on their CRS-treated side. Both CRS and TNS demonstrate significant success between baseline and 3-month scores, and both growth factor products are superior to Vit C. Patients preferred CRS over TNS. CONCLUSION: CRS is effective in minimizing the appearance of facial rhytides. The success of the CRS product is largely attributable to the incorporation of TGF-beta(1).