Yiyun Cheng

Targeting cancer cells with biotin–dendrimer conjugates

Star-burst dendrimers represent a superior carrier platform for targeted drug delivery. Partially acetylated generation 5 (G5) polyamidoamine (PAMAM) dendrimer was conjugated with the targeting moiety (biotin) and the imaging moiety (fluoresceinisothiocyanate, FITC), and the resulting dendrimer-biotin conjugate was characterized by (1)H NMR, UV-vis spectrum. As revealed by flow cytometry and confocal microscopy, the bifunctional conjugate (dendrimer-biotin-FITC) exhibited much higher cellular uptake into HeLa cells than the conjugate without biotin. The uptake was energy-dependent, dose-dependent, and could be effectively blocked by dendrimer-conjugated biotin. Our results indicated that the biocompatible biotin-dendrimer conjugate might be a promising nano-platform for cancer therapy and cancer diagnosis.

Pharmaceutical applications of dendrimers: promising nanocarriers for drug delivery.

Dendrimers are new artificial macromolecules which have the structure like a tree. They are hyperbranched and monodisperse three-dimensional molecules with defined molecular weights, large numbers of functional groups on the surface and well-established host-guest entrapment properties. Recently, dendrimers have successfully proved themselves as promising nanocarriers for drug delivery because they can render drug molecules a greater water-solubility, bioavailability, and biocompatibility. In this review, recent progress in the pharmaceutical applications of dendrimers as delivery systems for drugs, particularly, the non-steroidal anti-inflammatory, anti-microbial/anti-viral and potent anti-cancer drugs is discussed. Three possible interaction mechanisms between dendrimers and drug molecules are presented. In addition, the pharmacodynamic and pharmacokinetic properties of both dendrimer/drug complex and dendrimer-drug conjugation after their administration to animals are evaluated.

The effect of dendrimers on the pharmacodynamic and pharmacokinetic behaviors of non-covalently or covalently attached drugs.

Dendrimers are a new class of artificial macromolecules with several attractive properties that show promises in several biomedical applications. They can be widely used to increase the cellular uptake, bioavailability and therapeutic efficacy, to optimize the biodistribution and intracellular release profile, and to reduce the systemic toxicity, clearance and degradation rate of non-covalently or covalently attached drugs. Recent studies in this aspect clearly point to the potential advantages of dendrimers for the design of new drug delivery systems. Before final applications of dendrimer-based drug delivery systems in humans, we should not only address the benefits of these systems, but also assess the long-term pharmacodynamic (PD) and pharmacokinetic (PK) behaviors and health risk of them. In this mini-review, we will mainly discuss the influence of dendrimers on the PD and PK behaviors of drugs complexed or conjugated to them.

Potential of poly(amidoamine) dendrimers as drug carriers of camptothecin based on encapsulation studies

Camptothecin (CPT), a plant alkaloid isolated from Camptotheca acuminata, has an extremely low solubility in aqueous medium, which presents a major challenge during drug formulation in clinical trails. In the present study we investigated the potential of poly(amidoamine) (PAMAM) dendrimers as drug carriers of CPT through aqueous solubility studies. Results showed that the aqueous solubility of CPT was significantly increased by PAMAM dendrimers. The effect of PAMAM generation on CPT solubility was also evaluated. These studies indicated that PAMAM dendrimers might be considered as biocompatible carriers of CPT.

Evaluation of phenylbutazone and poly(amidoamine) dendrimers interactions by a combination of solubility, 2D-NOESY NMR, and isothermal titration calorimetry studies.

The interactions between phenylbutazone, a well-established nonsteroidal anti-inflammatory drug, with different generations of poly(amidoamine) (PAMAM) dendrimers, have been investigated by aqueous solubility, two dimensional nuclear Overhauser effect spectroscopy (2D-NOESY) and isothermal titration calorimetry (ITC) studies. Solubility results showed that PAMAM dendrimers significantly enhanced the aqueous solubility of phenylbutazone and the solubilization was much influenced by dendrimer concentration, generation, surface function group and pH value. The 2D-NOESY spectra clearly showed that there were several kinds of cross-peaks from NOE interactions between the protons of phenylbutazone and the protons in interior cavities of both generation 6 and generation 3 PAMAM dendrimers. The solubility, 2D-NOESY results and ITC analysis suggest that encapsulation and electrostatic interaction together caused the solubility enhancement of phenylbutazone. The new techniques such as 2D-NOESY and ITC used in this study are useful tools in investigating the interactions between dendrimers and guest molecules.

Generation-dependent encapsulation/electrostatic attachment of phenobarbital molecules by poly(amidoamine) dendrimers: Evidence from 2D-NOESY investigations.

The interactions of phenobarbital with different generations of amine-terminated poly(amidoamine) (PAMAM) dendrimers were investigated by using two dimensional-nuclear Overhauser effect spectroscopic (2D-NOESY) investigations. The NOESY spectra clearly showed that there were cross-peaks from NOE interactions between the protons of phenobarbital and the protons in interior cavities of generation 5 or generation 6 PAMAM dendrimers but none of such cross-peaks was found in the case of generation 3 or generation 4 dendrimers. The NOESY analysis, together with aqueous solubility data, suggested that higher generation dendrimers are more capable of encapsulating phenobarbital molecules into the interior cavities than lower generation dendrimers, and that lower generation dendrimers are much easier for the electrostatic attachment of phenobarbital molecules than higher ones at a fixed mass concentration.

Colorimetric Determination of Polyamidoamine Dendrimers and their Derivates using a Simple and Rapid Ninhydrin Assay

Abstract A simple, accurate and rapid colorimetric method using ninhydrin reagent was developed for the determination of polyamidoamine (PAMAM) dendrimers (G4, G5, and G6) and their derivates in aqueous medium. This method was based on the interaction of the primary amino group of PAMAM dendrimers with ninhydrin reagent to form a blue‐colored product with λmax at 570 nm. Beers law was obeyed in the concentration range of 25–200 µg/ml of all the three investigated PAMAM dendrimers. The effects of experimental parameters such as reagent concentration and reaction time were studied to optimize the colorimetric method. Accuracy and precision of the colorimetric method were assessed by statistical analysis. Acetylated G5 PAMAM dendrimers with various acetylated rates were simultaneously measured by the described ninhydrin assay and NMR studies and the data obtained by the two methods approximately accorded with each other. Results showed that the suggested procedures were suitable for the determination of PAMAM dendrimers and their derivates in aqueous solutions with satisfactory accuracy and precision.