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Objective. This study aims to study the preparation method of arsenic trioxide (As2O3) polylactic-co-glyconlic acid (PLGA) microspheres and 10-hydroxycamptothecin (HCPT) PLGA microspheres and explore their therapeutic effects as embolic agents for VX2 hepatocellular carcinoma in rabbits. Methods. As2O3 and HCPT PLGA microspheres were prepared by multiple emulsion solvent evaporation method. Scanning electron microscopy (SEM) and particle size distribution were used to analyze the morphology, the drug sustained release ability was observed by the release of microspheres in vitro. The rabbit model of VX2 hepatocellular carcinoma was established and the hepatocellular carcinoma was treated with combined microspheres. The therapeutic effects were detected by qPCR, western blotting, HE staining and immunohistochemical methods. Results. The PLGA microspheres loaded with As2O3 and HCPT were successfully prepared by optimizing the ratio. The particle size was between 30 and 50 μm. In vitro release results showed that PLGA microspheres loaded with As2O3 released completely in 10 days and PLGA microspheres loaded with HCPT released completely in 12 days. Western blotting and qPCR results showed that the expression of ALDH1A1 and Nanog decreased significantly in treatment group. HE staining and immunohistochemical analysis showed that the expression of CD31, HIF and VEGF decreased significantly and the apoptosis of tissues was obvious. Conclusion. The combination of As2O3 and HCPT PLGA microspheres as embolization for VX2 hepatocellular carcinoma in rabbits has significant therapeutic effect.

Yue Yuan,1,2 Jian Wen,3 Jie Tang,2 Qiming Kan,1 Rose Ackermann,2 Karl Olsen,2 Anna Schwendeman2 1Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China; 2Department of Pharmaceutical Sciences, Biointerfaces Institute, College of Pharmacy, University of Michigan, 3Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan Medical School, Ann Arbor, MI, USA Abstract: The purpose of this study was to develop a novel synthetic high-density lipoprotein (sHDL) nanoparticle delivery system for 10-hydroxycamptothecin (HCPT) for treatment of colon carcinoma. HDL is recognized by scavenger receptor B-I (SR-BI) over-expressed in colon carcinomas 5- to 35-fold relative to the human fibroblasts. The sHDL nanoparticles were composed of apolipoprotein A-I mimic peptide (5A) and contained 0.5%–1.5% (w/w) of HCPT. An optimized HCPT-sHDL formulation exhibited 0.7% HCPT loading with 70% efficiency with an average size of 10–12 nm. Partitioning of HCPT in the sHDL lipid membrane enhanced drug stability in its active lactone form, increased solubilization, and enabled slow release. Cytotoxicity studies in HT29 colon carcinoma cells revealed that the IC50 of HCPT-sHDL was approximately 3-fold lower than that of free HCPT. Pharmacokinetics in rats following intravenous administration showed that the area under the serum concentration-time curve (AUC0–t) and Cmax of HCPT-HDL were 2.7- and 6.5-fold higher relative to the values for the free HCPT, respectively. These results suggest that sHDL-based formulations of hydrophobic drugs are useful for future evaluation in treatment of SR-BI-positive tumors. Keywords: apolipoprotein A-I mimic peptide, phospholipids, SR-BI receptor, colon carcinoma, camptothecin, nanoparticle, nanodisc

Abstract: In the realm of drug delivery, carbon nanotubes (CNTs) have gained tremendous attention as promising nanocarriers, owing to their distinct characteristics, such as high surface area, enhanced cellular uptake and the possibility to be easily conjugated with many therapeutics, including both small molecules and biologics, displaying superior efficacy, enhanced specificity and diminished side effects. While most CNT-based drug delivery system (DDS) had been engineered to combat cancers, there are also emerging reports that employ CNTs as either the main carrier or adjunct material for the delivery of various non-anticancer drugs. In this review, the delivery of small molecule drugs is expounded, with special attention paid to the current progress of in vitro and in vivo research involving CNT-based DDSs, before finally concluding with some consideration on inevitable complications that hamper successful disease intervention with CNTs. [Copyright &y& Elsevier]

Abstract: 10-Hydroxycamptothecin (HCPT) is a well-established topoisomerase I inhibitor of a broad spectrum of cancers. However, poor aqueous solubility, low instability, and toxicity to normal tissues have limited its clinical development. A novel HCPT-containing drug carrier system was developed to overcome these disadvantages. The response surface methodology was used to optimize the process of preparing HCPT–chitosan nanoparticles (HCPT–CSNPs) by the SAS-ionic crosslink (supercritical antisolvent SAS) combination method; the resulting HCPT–CSNPs were then conjugated with folate for specific targeting. A central composite design, composed of four independent variables, namely, chitosan concentration, TPP concentration, HCPT nanoparticle concentration, and crosslink time, was applied in the modeling process. The mean particle size and drug entrapment efficiency (DEE) of HCPT–CSNPs were chosen as response variables. The interactive effects of the four independent variables on the response variables were also studied. Nanoparticle characteristics such as morphology, DEE, and mean particle size were investigated. The optimum conditions for preparing HCPT–CSNPs were determined as follows: folate-coupled chitosan concentration 2.46mg/ml, TPP concentration 7.73mg/ml, HCPT nanoparticle concentration 0.48mg/ml, and crosslinking time 47.4min. Optimum conditions for preparing desired HCPT–CSNPs with a mean particle size of 173.5nm and entrapment efficiency of 77.3% were obtained. The resulting folate-conjugated HCPT–CSNPs (FA–HCPT–CSNPs) reveal that the amount of folate conjugation was 197.64mg/g CS. FA–HCPT–CSNPs used in drug carrier systems could have potential value in HCPT-sensitive tumors. [Copyright &y& Elsevier]

Levels of camptothecin (CPT) and 10-hydroxycamptothecin (HCPT) were determined in different cultures of Camptotheca acuminata grown either in a Temporary Immersion System (TIS) or on solid medium. CPT was also detected in liquid culture medium. HPLC analysis showed significant differences in CPT contents in all tissues analysed and the highest CPT contents were found in shoots grown on solid medium and in TIS with a mean of 2.2 and 2.5 mg g DW, respectively. The highest content of CPT detected in seedlings was 1.96 mg g DW; while that of somatic embryos at cotyledonary stage and regenerated plants were 0.87 and 1.23 mg g DW, respectively. It was also shown that shoots cultured in TIS secreted substantial amount of CPT into the liquid medium. After 4 weeks in culture a mean of 6, 05 and 12, 6 μg g FW were determined at 4 and 8 immersion cycles daily (IC d), respectively. This aspect opens new possibilities regarding the isolation of CTP using TIS culture systems. [ABSTRACT FROM AUTHOR]

Abstract: 10-Hydroxycamptothecin (HCPT) is insoluble in both water and physiological acceptable organic solvents and tends to change into its carboxylate form, which shows minimal anticancer activity and several unpredictable side effects. The goal of this study is to exploit an appropriate delivery system for HCPT to improve the stability of its lactone form. Bovine serum albumin (BSA) nanoparticles entrapping HCPT were prepared by reformative emulsion-heat stabilization technique. During this process, HCPT transformed from lactone to carboxylate and finally back to lactone form successfully. A simple reversed-phased HPLC method was developed to analyze both lactone and carboxylate forms of HCPT synchronously. Mean particle size and the ratio of lactone and carboxylate forms of HCPT were evaluated to investigate the effects of the formulations and preparation conditions. It was indicated the percentage of lactone form of HCPT in resultant BSA nanoparticles could be improved over 95% through adjusting the concentration of NaOH solution and the stirring time after high-speed emulsification. This drug delivery system was also characterized by dynamic light scattering (DLS) and light microscopy. The investigations on drug loading, in vitro release and body distribution in rats after intravenous (i.v.) administration were also carried out. It was found that the obtained nanoparticles showed spherical shape with the mean particle size of around 600nm, and drug loading content, encapsulation efficiency and yield achieved 2.21%, 57.5% and 90.5% with the optimal preparation conditions, respectively. The in vitro release behavior exhibited a sustaining release manner and was affected by the trypsin in medium. HCPT could release more than 90% within 20h in the medium of pH 7.4 PBS containing 750U/ml trypsin, but only 25% within 40h in the pure pH 7.4 PBS. The results of body distribution study in rats showed the liver targeting potential of HCPT–BSA nanoparticles that 59.6%, 52.9% and 55.3% of the examined amount of lactone HCPT accumulated in livers at 1, 4 and 24h after injection, respectively. These results suggest that the HCPT–BSA nanoparticles seem to be a stable delivery system for poorly soluble HCPT or its derivatives. [Copyright &y& Elsevier]

We report a sensitive and convenient voltammetric method for the direct determination of 10-hydroxycamptothecin (HCPT). At a multi-wall carbon nanotube (MWNT)-modified electrode, HCPT yields a very sensitive and well-shaped oxidation peak, which can be used as analytical signal for HCPT determination. Compared with the poor electrochemical signal at the unmodified GCE, the electrochemical response of HCPT at the MWNT-modified GCE was greatly improved, as confirmed by the significant peak current enhancement. This result indicates that the MWNT-modified GCE has great potential in the sensitive determination of HCPT. Based on this, a very sensitive and simple electrochemical method was proposed for HCPT determination after all the experimental parameters were optimized. The newly-proposed method possesses very low detection limit (2 × 10−9 mol L−1) and wider linear range (from 1 × 10−8 to 4 × 10−6 mol L−1). Rapid and simple sample analysis is another advantage. Finally, this method was successfully demonstrated using HCPT drugs. [ABSTRACT FROM AUTHOR]