RGD-modified liposomes enhance efficiency of aclacinomycin A delivery: evaluation of their effect in lung cancer.

In this study, long-circulating Arg-Gly-Asp (RGD)-modified aclacinomycin A (ACM) liposomes were prepared by thin film hydration method. Their morphology, particle size, encapsulation efficiency, and in vitro release were investigated. The RGD-ACM liposomes was about 160 nm in size and had the visual appearance of a yellowish suspension. The zeta potential was -22.2 mV and the encapsulation efficiency was more than 93%. The drug-release behavior of the RGD-ACM liposomes showed a biphasic pattern, with an initial burst release and followed by sustained release at a constant rate. After being dissolved in phosphate-buffered saline (pH 7.4) and kept at 4°C for one month, the liposomes did not aggregate and still had the appearance of a milky white colloidal solution. In a pharmacokinetic study, rats treated with RGD-ACM liposomes showed slightly higher plasma concentrations than those treated with ACM liposomes. Maximum plasma concentrations of RGD-ACM liposomes and ACM liposomes were 4,532 and 3,425 ng/mL, respectively. RGD-ACM liposomes had a higher AUC0-∞ (1.54-fold), mean residence time (2.09-fold), and elimination half-life (1.2-fold) when compared with ACM liposomes. In an in vivo study in mice, both types of liposomes inhibited growth of human lung adenocarcinoma (A549) cells and markedly decreased tumor size when compared with the control group. There were no obvious pathological tissue changes in any of the treatment groups. Our results indicate that RGD-modified ACM liposomes have a better antitumor effect in vivo than their unmodified counterparts.

Pharmacokinetics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, after i.v. bolus multiple administration in rats.

We investigated the pharmacokinetics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, after intravenous (i.v.) bolus administration at a multiple dose every 24 h for 5 days in rats. To analyze ID-6105 levels in biological samples, we used an HPLC-based method which was validated in a pharmacokinetic study by suitable criteria. The concentrations of ID-6105 after the multiple administration for 5 days were not significantly different from the results after the single administration. The t1/2alpha, t1/2beta, Vdss, and CLt after the multiple administration were not significantly different from the values after the single administration. Moreover, the concentrations of ID-6105 1 min at day 1-5 after i.v. bolus multiple administration did not show the significant difference. Of the various tissues, ID-6105 mainly distributed to the kidney, lung, spleen, adrenal gland, and liver after i.v. bolus multiple administration. ID-6105 concentrations in the kidney or lung 2 h after i.v. bolus administration were comparable to the plasma concentration shortly after i.v. bolus administration. However, the ID-6105 concentrations in various tissues 48 h after i.v. bolus administration decreased to low levels. ID-6105 was excreted largely in the bile after i.v. bolus multiple administration at the dose of 3 mg/kg. The amounts of ID-6105 found in the bile by 12 h or in the urine by 48 h after the administration were calculated to be 14.1% or 4.55% of the initial dose, respectively, indicating that ID-6105 is mostly excreted in the bile. In conclusion, ID-6105 was rapidly cleared from the blood and transferred to tissues, suggesting that ID-6105 might not be accumulated in the blood following i.v. bolus multiple dosages of 3 mg/kg every 24 h for 5 days. By 48 h after i.v. bolus administration, ID-6105 concentrations in various tissues had decreased to very low levels. The majority of ID-6105 appears to be excreted in the bile.

Selective distribution of aclarubicin to regional lymph nodes with a new dosage form: aclarubicin adsorbed on activated carbon particles.

A new dosage form (ACR-CH) comprising aclarubicin adsorbed on activated carbon particles was designed to sustain release of aclarubicin. ACR-CH or aclarubicin aqueous solution (ACR-sol) was injected subcutaneously into the fore foot-pads of rats. ACR-CH distributed a statistically significantly higher level of aclarubicin to the axillary lymph nodes (detectable up to 7 days after injection) than aclarubicin distributed in an ACR-sol (not detectable after 48 h). To other tissues, ACR-CH distributed statistically significantly low levels of aclarubicin, as compared with ACR-sol.

[Adsorption and desorption of aclarubicin into and from activated carbon particles as drug carrier--an in vitro study].

A new dosage form (ACR-CH), aclarubicin(ACR) adsorbed on activated carbon particles (CH), was studied for adsorption and desorption onto and from CH. The adsorption isotherm at 37 degrees C in saline and phosphate buffer (pH 7.4-7.5) were shown as M = 175 Co.15 and M = 207 Co.24, respectively (M = ACR amount adsorbed on CH, microgram/mg; C = ACR concentration in a free state, microgram/ml). In both fluids, CH adsorbed more than 100-1,000 times more amount of ACR than ACR in a free state. ACR-CH was lavaged 7 times and the released ACR in a free state was measured. The results showed that ACR-CH desorbed constantly a small amount of ACR, namely, 1.5-8 percent of initial concentration of ACR in a free state in saline, 0.1-10% in phosphate buffer, and 0.5-4.0% in Ringer's solution. Under the same conditions, desorption of ACR-CH was measured in dog's blood plasma. The first lavage made ACR-CH desorb at 25.7 +/- 0.85 percent of ACR initial concentration in a free state, and two times' to 7 times' lavage made 1-3%. Overall, 43.3 +/- 0.99% of ACR were desorbed from the activated carbon. It was concluded that ACR-CH slowly released a constant amount of ACR for a long period.