Redox-responsive nanoparticles based on Chondroitin Sulfate and Docetaxel prodrug for tumor targeted delivery of Docetaxel.

In this paper, a novel redox-responsive nanoparticles has been designed for targeted delivery of docetaxel (DTX). Chondroitin sulfate (CS) was used to construct the nanoparticles due to the ability of tumor targeting through binding with CD44 receptor that overexpresses on the surfaces of various tumor cells. A redox-responsive small-molecular DTX prodrug was prepared through modifying with cystamine containing disulfide bonds (Cys-DTX). Then the DTX prodrug was grafted to the CS to construct the amphiphilic polymer (CS-ss-DTX). Further, Cys-DTX/CS-ss-DTX nanoparticles were formed by self-assembly of amphiphilic polymer and incorporation of free Cys-DTX prodrug. This category of nanosized DTX delivery system was expected for not only exhibiting high permeability and cytotoxicity of Cys-DTX prodrug, but also targeting transportation of encapsulated redox-responsive Cys-DTX prodrug. According to results of related researches on physicochemical properties and biological evaluation, the novel redox-responsive Cys-DTX/CS-ss-DTX nanoparticles increased amount of DTX released from the nanoparticles in reductive environment, improved permeability in tumor tissues, enhanced cytotoxicity and decreased side effects compared with free DTX. All of these results showed that this kind of Cys-DTX/CS-ss-DTX nanoparticles were worthy of being expectation in tumor chemotherapy in future.

The development of stimuli-responsive polymeric micelles for effective delivery of chemotherapeutic agents.

Stimuli-responsive polymeric micelles, a novel category of polymeric micelles with response to endogenous or exogenous environments, show variable physicochemical properties as the variation of endogenous or exogenous circumstances. Because of differences between tumour tissues and normal tissues in physicochemical properties and sensitivity to variation of endogenous or exogenous environments, the application of chemotherapeutic agents loaded stimuli-responsive polymeric micelles are regarded as promising strategies for tumour treatment. In this article, the recent developments of chemotherapeutic agents loaded stimuli-responsive polymeric micelles, for example the preparation of novel stimuli-responsive polymeric micelles and the research progresses of action mechanisms of chemotherapeutic agents loaded micelles, were reviewed and discussed in detail. The advantages of stimuli-responsive chemotherapeutic agents loaded polymeric micelles in practical tumour treatment were also illustrated with the assistance of examples of stimuli-responsive polymeric micelles for antitumor agents delivery.

The construction and characterization of hybrid paclitaxel-in-micelle-in-liposome systems for enhanced oral drug delivery.

In this study, novel paclitaxel (PTX) loaded hybrid liposomes for oral PTX delivery were prepared through incorporating PTX loaded polyion complex micelles comprised of positively charged Pluronic F127-Polyethylenimine (PF127-PEI) copolymer and negatively charged sodium cholate (CA) into liposomes consisted of phospholipid molecules. According to the results, this kind of PTX-loaded hybrid liposomes showed improved PTX encapsulation efficiency, sustained PTX release, and enhanced PTX absorption in intestine. The mechanism for enhancing absorption was demonstrated in connection with inhibition of the efflux mediated by multidrug resistance protein, intestinal P-gp. In pharmacokinetic study, the absolute oral bioavailability of PTX loaded in hybrid liposomes had reached to 37.91%. All of these results demonstrated that the application of this novel PTX loaded hybrid liposomes is a strategy with great potential for highly effective oral PTX delivery.

Intelligent polymeric micelles: development and application as drug delivery for docetaxel.

Recent years, docetaxel (DTX)-loaded intelligent polymeric micelles have been regarded as a promising vehicle for DTX for the reason that compared with conventional DTX-loaded micelles, DTX-loaded intelligent micelles not only preserve the basic functions of micelles such as DTX solubilization, enhanced accumulation in tumor tissue, and improved bioavailability and biocompatibility of DTX, but also possess other new properties, for instance, tumor-specific DTX delivery and series of responses to endogenous or exogenous stimulations. In this paper, basic theories and action mechanism of intelligent polymeric micelles are discussed in detail, especially the related theories of DTX-loaded stimuli-responsive micelles. The relevant examples of stimuli-responsive DTX-loaded micelles are also provided in this paper to sufficiently illustrate the advantages of relevant technology for the clinical application of anticancer drug, especially for the medical application of DTX.

Folate-modified pluronic-polyethylenimine and cholic acid polyion complex micelles as targeted drug delivery system for paclitaxel.

The aim of the present study is to construct a type of polyion complex micelles made of PF127-PEI copolymer and cholic acid (CA) and to evaluate the potential of this type of micelles as a targeted drug delivery system for paclitaxel (PTX). To further improve the targeting capability of micelles, folate was also incorporated into micelles. The characteristics and anti-tumour activity in vitro were investigated. Enhanced solubility of PTX was achieved by incorporating into the micelles. The capability of the polyion complex micelles containing rhodamine 123 to increase the level of intracellular delivery was also observed using fluorescence microscopy. The cytotoxicity of PTX-loaded micelles against cancer cell in vitro was remarkably higher than that of free drug and was better when folate was incorporated into the micelles. These properties such as specificity towards the folate receptor and the low toxicity render folate-modified polyion complex micelles promising candidate for targeted PTX delivery.

Stable phosphatidylcholine-bile salt mixed micelles enhance oral absorption of paclitaxel: preparation and mechanism in rats.

The aim of this study is to prepare a stable phosphatidylcholine/bile salt micelles with Pluronic F127-polyethylenimine conjugates (F127-PEI), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), soybean phosphatidylcholine (SPC) and sodium cholate (NaC) and to elucidate the effects and possible mechanism of micelle components on the intestinal absorption of paclitaxel (PTX) in rats. The results of intestinal absorption revealed that the PTX in SPC/NaC micelles displayed superior permeability across intestinal barrier than free drug and PTX in TPGS/SPC/NaC and F127-PEI/TPGS/SPC/NaC mixed micelles exhibited the strongest permeability across intestinal barrier. These results were also proved by the studies on cell uptake tests. The mechanism was demonstrated in connection with inhibition of the efflux mediated by intestinal P-gp and enhancement of the drug transportation across the unstirred water layer to the endothelial lining, thereby promoting the permeation across the intestinal wall. Pharmacokinetic study demonstrated that the area under the plasma concentration-time curve (AUC0→∞) of paclitaxel in F127-PEI/TPGS/SPC/NaC micelles was much greater than that in TPGS/SPC/NaC micelles. This phenomenon deviated from the results of uptake studies by cells and permeability experiments through rat intestine and revealed that the micelle stability had a great effect on intestinal absorption of paclitaxel.

Enhancement on oral absorption of paclitaxel by multifunctional pluronic micelles.

The aim of the present study is to synthesize Pluronic F127-polyethylenimine-folate (PF127-PEI-FA) copolymer, construct a mixed micelle system with PF127-PEI-FA copolymer and Pluronic P123 (PP123) and to evaluate the potential of these mixed micelles as an oral drug delivery system for paclitaxel (PTX). The results of intestinal absorption revealed that the PTX-loaded micelles displayed superior permeability across intestinal barrier than free drug and PF127-PEI-FA/PP123 mixed micelles exhibited the strongest permeability across intestinal barrier. These results were also proved by the studies on cytotoxicity and cell uptake tests. The mechanism was demonstrated in connection with inhibition of the efflux mediated by intestinal P-glycoprotein (P-gp) and enhancement of the electrostatic interaction of positive micelles with the negative intestinal epithelial cells, thereby promoting the permeation across the intestinal wall. The presence of verapamil and Pluronic both improved the intestinal absorption of PTX, which further certified the effect of Pluronic on P-gp inhibition. Pharmacokinetic study demonstrated that the area under the plasma concentration-time curve (AUC(0→36 h)) of PTX-loaded micelles was three times greater than the PTX solution (dissolved in a 50/50 (vol/vol) mixture of Cremophore EL/dehydrated ethanol) (p < 0.05). In general PF127-PEI-FA/PP123 mixed micelles were proved to be potential oral drug delivery system for PTX.

Pharmacokinetic analysis and optimization of hydroxycamptothecin-loaded nanoparticles for liver targeting.

In this paper, a pharmacokinetic model to describe the tissue distribution process of nanoparticles was established. To test the possibility of the model, nanoparticles composed of poly(butylcyanoacrylate) and hydroxypropyl-ß-cyclodextrins (HP-ß-CD) was prepared with a poorly soluble anticancer drug, hydroxycamptothecin (HCPT). Characteristics were determined including particle's size, morphology and in vitro release. The tissue distribution of nanoparticles was also studied. Further, mathematical equation was fitted to the curve of drug concentration-time in liver of hydroxycamptothecin-loaded nanoparticles and the pharmacokinetic parameters of liver were obtained. The effectiveness of hydroxycamptothecin-loaded nanoparticles for liver targeting was evaluated. The results showed that nanoparticles composed of poly(butylcyanoacrylate) and hydroxypropyl-ß-cyclodextrins (HP-ß-CD) exhibited enhanced liver targeting in rats after i.v. injection. More importantly, the pharmacokinetic parameters (transport constant from blood to target organ KT, drug release rate from nanoparticles Kr and drug elimination constant in target organ Ke) provided some quantitative measure of liver distribution and were useful guidelines for development of targeted drug delivery systems.