Improvement of Cellular Uptake and Transfection Ability of pDNA Using α-Cyclodextrin-Polyamidoamine Conjugates as Gene Delivery System.

Polyamidoamine (PAMAM) dendrimers are a class of unique nanomaterials which attracted attention because of their extraordinary properties, such as highly branched structure and types of terminal primary groups. In addition, development in PAMAM chemical modification has broadened its biological application especially for drug and gene delivery. In this study, PAMAMs are covalently conjugated onto α-Cyclodextrin (α-CD) via amide bonds obtaining the starburst cationic polymers (CD-PG2). The chemical structure and composition of CD-PG2 was characterized by IH NMR. Physicochemical and biological properties of CD-PG2/pDNA polyplex were evaluated by agarose gel retardation, stability test against DNasecñ, MTT assay, DLS measurement, CLSM observation, LDH leakage test, cellular uptake route analysis and in-vitro cell transfection. Results showed that CD-PG2 can efficiently condense pDNA into nanoscale particles with a narrow size distribution, and protect pDNA form DNase I degradation. Compared with free PEI-25K and commercial product Lipofectamine2000, CD-PG2 shows excellent gene transfection efficiency without serum interference as well as relatively low cytotoxicity. Cellular uptake of CD-PG2/pDNA polyplex is mainly through CME and CvME route and further investigations demonstrate that α-CD can regulate CvME pathway to improve polyplex transfection behavior. In conclusion, CD-PG2 can be considered as a versatile tool for gene delivery, especially for gene transfer in-vivo.

Preparation of novel curcumin-loaded multifunctional nanodroplets for combining ultrasonic development and targeted chemotherapy.

Recently, a new class of multifunctional nanodroplets that combine the properties of polymeric drug carriers, ultrasound imaging contrast agents, and enhancers of ultrasound-mediated drug delivery has been developed. We studied the formation mechanism of nanodroplets of a drug and its application in chemotherapy. Curcumin was loaded in polymeric micelles as a anti-cancer drug using polyethylene glycol block-poly(caprolactone) with encapsulation efficiency of 95.60%. At room temperature, the developed systems comprised perfluorocarbon nanodroplets stabilized by walls comprising biodegradable block copolymers. Upon heating to 37°C, the nanodroplets were converted to nano/microbubbles. Under ultrasound, nanobubbles cavitated and collapsed, resulting in release of the encapsulated drug. The percentage release of curcumin-loaded nanodroplets by insonation was 90.95%, showing enhancement compared with the non-ultrasound group. Nanodroplets strongly retained the loaded drugs in vivo yet, under ultrasound-mediated vaporization, they released the drugs, thereby implementing effective targeting into the tumor. The tumor inhibition of the group in which curcumin-loaded nanodroplets were combined with ultrasound was 71.30%, more than that of the group of curcumin-loaded nanodroplets (53.00%). Nanodroplets showed high enhancement of anti-cancer effects under ultrasound. Upon intravenous injection, a long-lasting, strong and selective ultrasound contrast was observed, suggesting their coalescence into larger, highly echogenic microbubbles. These multifunctional nanodroplets, which manifest excellent therapeutic and ultrasound properties, could be promising anti-cancer drug delivery systems.

Targeted delivery of the RGD-labeled biodegradable polymersomes loaded with the hydrophilic drug oxymatrine on cultured hepatic stellate cells and liver fibrosis in rats.

Oxymatrine (OM) is an alkaloid extracted from a Chinese herb that has been found to possess an anti-hepatic fibrosis effect, although its anti-fibrotic potential is limited due to a lack of targeting specificity, a short half-life and adverse effects. Polymersomes (PM) assembled from amphiphilic block copolymers represent promising vesicles for applications that include drug delivery and surface functionalization. The aim of this study was to develop a novel drug carrier based on PM modified with the peptide RGD and evaluate its therapeutic effect on liver fibrosis. A series of PM based on poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) were prepared and characterized. OM was loaded into PM by a pH-gradient method then the OM-loaded PM was modified with RGD peptide to obtain RGD-PM-OM. The average drug loading of RGD-PM-OM, with a size of 95 nm, was 6.8%. The targeting effects of the system were determined in cultured hepatic stellate cells (HSCs) and bile duct-ligated rats (BLD). RGD-PM-OM displayed better suppression of HSCs proliferation and significantly reduced the expression of the genes for α-SMA and collagen lα1 in cultured HSCs. Furthermore, RGD-PM-OM exhibited markedly superior anti-fibrosis activity by reducing the levels of PC-III and IV-C in serum and connective tissue deposition in BLD compared with PM-OM and OM. These results indicate that targeted RGD-PM-OM markedly attenuates the effects of hepatic fibrosis.