Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies

Pegylated liposomal doxorubicin (doxorubicin HCl liposome injection; Doxil or Caelyx) is a liposomal formulation of doxorubicin, reducing uptake by the reticulo-endothelial system due to the attachment of polyethylene glycol polymers to a lipid anchor and stably retaining drug as a result of liposomal entrapment via an ammonium sulfate chemical gradient. These features result in a pharmacokinetic profile characterised by an extended circulation time and a reduced volume of distribution, thereby promoting tumour uptake. Preclinical studies demonstrated one- or two-phase plasma concentration-time profiles. Most of the drug is cleared with an elimination half-life of 20-30 hours. The volume of distribution is close to the blood volume, and the area under the concentration-time curve (AUC) is increased at least 60-fold compared with free doxorubicin. Studies of tissue distribution indicated preferential accumulation into various implanted tumours and human tumour xenografts, with an enhancement of drug concentrations in the tumour when compared with free drug. Clinical studies of pegylated liposomal doxorubicin in humans have included patients with AIDS-related Kaposi's sarcoma (ARKS) and with a variety of solid tumours, including ovarian, breast and prostate carcinomas. The pharmacokinetic profile in humans at doses between 10 and 80 mg/m(2) is similar to that in animals, with one or two distribution phases: an initial phase with a half-life of 1-3 hours and a second phase with a half-life of 30-90 hours. The AUC after a dose of 50 mg/m(2) is approximately 300-fold greater than that with free drug. Clearance and volume of distribution are drastically reduced (at least 250-fold and 60-fold, respectively). Preliminary observations indicate that utilising the distinct pharmacokinetic parameters of pegylated liposomal doxorubicin in dose scheduling is an attractive possibility. In agreement with the preclinical findings, the ability of pegylated liposomes to extravasate through the leaky vasculature of tumours, as well as their extended circulation time, results in enhanced delivery of liposomal drug and/or radiotracers to the tumour site in cancer patients. There is evidence of selective tumour uptake in malignant effusions, ARKS skin lesions and a variety of solid tumours. The toxicity profile of pegylated liposomal doxorubicin is characterised by dose-limiting mucosal and cutaneous toxicities, mild myelosuppression, decreased cardiotoxicity compared with free doxorubicin and minimal alopecia. The mucocutaneous toxicities are dose-limiting per injection; however, the reduced cardiotoxicity allows a larger cumulative dose than that acceptable for free doxorubicin. Thus, pegylated liposomal doxorubicin represents a new class of chemotherapy delivery system that may significantly improve the therapeutic index of doxorubicin.     

Liposome encapsulation reduces cantharidin toxicity

Several reports have demonstrated that cantharidin is a strong anticancer compound in vitro; however, its in vivo usefulness is often limited due to its high systemic toxicity. In this study, we encapsulated cantharidin into pegylated liposomes and studied its activity against human breast cancer MCF-7 cells in vitro and its systemic toxicity in mice. Another two methods were also used to reduce the dosage of cantharidin, including labeling liposomal cantharidin with octreotide and exposing cells to hyperbaric oxygen. The cytotoxic activity of pegylated liposomal cantharidin was drastically reduced compared with free cantharidin in vitro. Octreotide-labeled pegylated liposomal cantharidin induced cell death by specifically targeting somatostatin receptors in MCF-7 cells. Cell death was augmented with a low dose of cantharidin under hyperbaric oxygen. Liposomal cantharidin had significantly less systemic toxicity than free cantharidin in vivo and also exhibited a high efficacy against antitumor growth in nude mice. These results suggest that the systemic toxicity of cantharidin can be mitigated by liposome encapsulation; however, that did not decrease its antitumor activity.     

Investigation of the Discriminatory Ability of Pharmacokinetic Metrics for the Bioequivalence Assessment of PEGylated Liposomal Doxorubicin

Purpose

The purpose of the study was to construct a population pharmacokinetic model for pegylated liposomal doxorubicin and use the final model to investigate the discrimination performance of pharmacokinetic metrics (e.g., C_max, AUC and partial AUC) of various analytes (e.g., liposome encapsulated doxorubicin, free doxorubicin and total doxorubicin) for the identification of formulation differences by means of Monte Carlo simulations.

Methods

A model was simultaneously built to characterize the concentration time profiles of liposome-encapsulated doxorubicin and free doxorubicin using NONMEM. The different scenarios associated with changes in release rate (Rel) were simulated based on the final parameters. 500 simulated virtual bioequivalence (BE) studies were performed for each scenario, and power curves for the probability of declaring BE were also computed.

Results

The concentration time profiles of liposome-encapsulated doxorubicin and free doxorubicin were well described by a one- and two-compartment model, respectively. pAUC_0-24 h and pAUC_0-48 h of free doxorubicin was most responsive to changes in the Rel when the Rel (test)/Rel (reference) ratios decreased. In contrast, when the Rel (test) increased, AUC_0-t of liposome-encapsulated doxorubicin was the most responsive metric.

Conclusions

In addition to the traditional metrics, partial AUC should be included for the BE assessment of pegylated liposomal doxorubicin.

     

Pegylated liposomal doxorubicin in the treatment of cancers of the breast and ovary

Peglyated liposomal doxorubicin was developed to maintain or enhance the demonstrated antineoplastic effects of doxorubicin, while improving the toxicity profile associated with this important cytotoxic agent. Accumulating clinical data have confirmed the activity of pegylated liposomal doxorubicin in cancers of the breast and ovary. Furthermore, Phase II and III trial experience has revealed that the drug produces objective responses comparable in rate and duration to doxorubicin and other single agents employed in metastatic breast cancer. In recurrent and platinum-resistant ovarian cancer, single-agent pegylated liposomal doxorubicin has assumed an important role in routine patient management.     

Pegylated liposomal doxorubicin in the treatment of cancers of the breast and ovary

Peglyated liposomal doxorubicin was developed to maintain or enhance the demonstrated antineoplastic effects of doxorubicin, while improving the toxicity profile associated with this important cytotoxic agent. Accumulating clinical data have confirmed the activity of pegylated liposomal doxorubicin in cancers of the breast and ovary. Furthermore, Phase II and III trial experience has revealed that the drug produces objective responses comparable in rate and duration to doxorubicin and other single agents employed in metastatic breast cancer. In recurrent and platinum-resistant ovarian cancer, single-agent pegylated liposomal doxorubicin has assumed an important role in routine patient management.     

Doxorubicin liposomal pegylated: new preparation. Breast cancer: not just a question of short-term cardiac effects

(1) There is no reference first-line chemotherapy regimen for metastatic breast cancer. Anthracycline-based combinations are generally used. One of the main problems with anthracyclines is the risk of heart failure, both during and some time after treatment. (2) A liposomal pegylated doxorubicin, an anthracycline, is now available in Europe. The aim of pegylation is supposedly to reduce the cardiotoxicity relative to standard doxorubicin. The marketing licence specifies that liposomal pegylated doxorubicin must not be used in combination with other drugs in people with metastatic breast cancer. This is the second liposomal doxorubicin preparation to be authorised for this use in France; we concluded that the first product, a non-pegylated form, offered no therapeutic advance. (3) According to the only available comparative trial, liposomal pegylated doxorubicin is no more effective than standard doxorubicin in terms of the duration or quality of survival. (4) In this trial, liposomal pegylated doxorubicin was associated with slightly fewer cardioechographic abnormalities than standard doxorubicin. (5) Other adverse events were also less common (hair loss, nausea and vomiting, and neutropenia), while some were more common (palmoplantar erythrodysesthesia, stomatitis and mucitis). Overall, 24% of patients stopped using liposomal pegylated doxorubicin because of adverse events, compared with 11% of patients receiving standard doxorubicin. (6) Unlike liposomal non-pegylated doxorubicin, the liposomal pegylated form is no more difficult than standard doxorubicin to prepare for injection. (7) In practice, when the decision is made to use doxorubicin, the standard form, at an appropriate dose, is suitable for most patients, as long as cardiac function is closely monitored. Differences in the adverse effect profile (especially hair loss) may make liposomal pegylated doxorubicin more attractive to some patients (it costs 20 times more than standard doxorubicin in France).     

In vivo evaluation of doxorubicin carried with long circulating and remote loading proliposome

Long circulating and remote loading proliposome (LRP-L) was a kind of transparent solution and composed of soybean phosphatidylcholine (SPC), cholesterol, polyethylene glycol derivative of distearoylphosphatidyl ethanolamine (PEG-DSPE) and oleic acid sodium salt. When LRP-L was mixed with 0.9% NaCl aqueous solution containing doxorubicin (DXR), liposomes formed and automatically loaded DXR, in which sonication and extruders were not needed. The average diameter of the liposomal DXR in saline was 129.0+/-1.9 nm and the encapsulation efficiency was 98.1+/-0.6%. The pharmacokinetics, biodistribution, acute toxicity and anticancer effect of DXR carried with LRP-L (LRP-L-DXR) were studied. The plasma concentration-time curves of DXR were best fitted to the triexponential decay curves. The area under the plasma concentration-time curve (AUC) of LRP-L-DXR was 22 and five times of free DXR (F-DXR) and conventional cardiolipin liposomal DXR (CL-DXR), respectively. Following i.v. administration, the biodistribution of LRP-L-DXR in the heart and the liver, unlike that of CL-DXR, was not greater than that of F-DXR. However, the biodistribution of LRP-L-DXR in the spleen was less than that of CL-DXR and greater than that of F-DXR. The acute toxicity of LRP-L-DXR was decreased compared with that of F-DXR. The anticancer effect of LRP-L-DXR was significantly increased compared with that of F-DXR in the ascitic M5076 tumor model of C57BL/6 mice and had no significant difference compared with that of doxorubicin HCl liposome injection (Doxil).     

Pegylated liposomal doxorubicin: a review of its use in metastatic breast cancer, ovarian cancer, multiple myeloma and AIDS-related Kaposi's sarcoma

Pegylated liposomal doxorubicin (Caelyx?, Doxil?) represents an improved formulation of conventional doxorubicin, with reduced cardiotoxicity and an improved pharmacokinetic profile. This article reviews the efficacy and tolerability of pegylated liposomal doxorubicin in metastatic breast cancer, progressive ovarian cancer, relapsed or refractory multiple myeloma and AIDS-related Kaposi's sarcoma, as well as summarizing its pharmacological properties. In three randomized, open-label, multicentre trials, monotherapy with pegylated liposomal doxorubicin was as effective as doxorubicin or capecitabine in the first-line treatment of metastatic breast cancer, and as effective as vinorelbine or combination mitomycin plus vinblastine in taxane-refractory metastatic breast cancer. Pegylated liposomal doxorubicin alone was as effective as topotecan or gemcitabine alone in patients with progressive ovarian cancer resistant or refractory to platinum- or paclitaxel-based therapy, according to the results of three randomized multicentre trials. In addition, in patients with progressive ovarian cancer who had received prior platinum-based therapy, progression-free survival was significantly longer with pegylated liposomal doxorubicin plus carboplatin than with paclitaxel plus carboplatin, according to the results of a randomized, open-label multicentre trial. Combination therapy with pegylated liposomal doxorubicin plus bortezomib was more effective than bortezomib alone in patients with relapsed or refractory multiple myeloma, according to the results of a randomized, open-label, multinational trial. Randomized multinational trials also demonstrated the efficacy of pegylated liposomal doxorubicin in patients with advanced AIDS-related Kaposi's sarcoma. Pegylated liposomal doxorubicin exhibited a relatively favourable safety profile compared with conventional doxorubicin and other available chemotherapy agents. The most common treatment-related adverse events included myelosuppression, palmar-plantar erythrodysesthesia and stomatitis, although these are manageable with appropriate supportive measures. To conclude, pegylated liposomal doxorubicin is a useful option in the treatment of various malignancies, including metastatic breast cancer, ovarian cancer, multiple myeloma and AIDS-related Kaposi's sarcoma.     

聚乙二醇多柔比星脂质体联合化疗治疗晚期恶性肿瘤临床观察

目的探讨以聚乙二醇多柔比星脂质体为主联合化疗治疗晚期恶性肿瘤的临床疗效和不良反应。方法收集2007年1月—2009年11月以聚乙二醇多柔比星脂质体为主的联合化疗治疗晚期恶性肿瘤患者的治疗信息、临床情况,并对患者进行跟踪随访至2010年4月30日。结果 33例恶性肿瘤患者共计完成化疗106周期,中位3周期（1~8周期）,可评价疗效28例,其中完全缓解4例,占14.3%;部分缓解11例,占39.3%;稳定11例,占39.3%;进展2例,占7.1%;客观有效率为53.6%,临床受益率为92.9%。随访周期6~39个月,中位随访时间16个月,总生存时间4~39个月,中位生存时间16个月,无疾病进展时间2~39个月,中位无疾病进展时间为10个月,1和2年生存率分别为69.2%和34.2%,3例生存3年以上。不良反应主要为骨髓抑制、脱发和胃肠道反应,另外乏力、手足综合症常见,心脏毒性轻微。结论以聚乙二醇多柔比星脂质体为主联合化疗治疗晚期恶性肿瘤是有效的,患者可以良好耐受。     

Reduced hepatic toxicity, enhanced cellular uptake and altered pharmacokinetics of stavudine loaded galactosylated liposomes.

The aim of the present investigation was to reduce the hepatic toxicity, enhance the cellular uptake and alter the pharmacokinetics of stavudine using galactosylated liposomes. beta-D-1-Thiogalactopyranoside residues were covalently coupled with dimyristoyl phosphatidylethanolamine, which was then used to form liposomes. The galactosylated liposomal system was assessed for in vitro ligand-specific activity. The drug release from liposomes was studied by dialysis method. Ex vivo cellular uptake study was performed using liver parenchymal cells harvested from male albino rats. Changes in hematological parameters, hepatic enzymes, hepatomegaly, plasma and tissue distribution of the formulations (free stavudine solution, uncoated liposomal and galactosylated liposomes) were determined using albino rats. Percent cumulative drug release in 24h was low (34.8+/-2.6%). Enhanced hepatic cellular d4T uptake (27.96+/-2.41pg d4T/million cells) was seen in case of galactosylated liposomal d4T. Galactosylated liposomes maintained a significant level of d4T in tissues rich in galactose specific receptors and had a prolonged residence (11.44+/-1.25h) in the body resulting in enhanced half-life of d4T (23.07+/-1.25h). This formulation did not show either hematological or hepatic toxicity. Galactosylation of liposomes alter the biodistribution of encapsulated drug thereby delivering the drug to cells bearing galactose specific receptors.     

Antitumor activity of doxorubicin encapsulated in hexadecylphosphocholine (HePC) liposomes against human xenografts on Scid mice

Doxorubicin was encapsulated into liposomes composed of hexadecylphosphocholine:egg yolk phosphatidylcholine:stearylamine (HePC.EPC:SA) 10:10.0.1 (molar ratio) (1) and EPC:SA 10:0.1 (molar ratio) (2). Liposomal formulations 1 and 2, as well as free doxorubicin and free HePC, were tested in vitro against HCT116 human colon cancer cell lines and peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, using the sulphorodamine B assay. The activity of doxorubicin was retained or slightly improved when entrapped into liposomes 1 and 2, while liposomal formulation 1 incorporating doxorubicin was found to be less toxic against normal cells. The liposomes were tested in vivo against human colon cancer xenografts in scid mice. The antitumor activities of liposomes 1 and 2 were statistically similar to that of free doxorubicin, but their toxicity was significantly lower. Based on these results, the combination of HePC and doxorubicin in one liposomal formulation may be justified for further evaluation.     

阿霉素的不同盐型对其脂质体体外药物泄漏和体内长循环的影响

目的探讨阿霉素不同盐型对脂质体体内外稳定性的影响。方法以薄膜分散-挤压法制备含有不同缓冲对的空白脂质体，用pH梯度和化学梯度法包载阿霉素，对其在脂质体内状态进行观察，测定了阿霉素脂质体理化性质；用透析法检测阿霉素脂质体在不同介质中的药物泄漏；用HPLC法研究不同盐型阿霉素脂质体在大鼠体内药代动力学行为。结果甘氨酸盐缓冲液、柠檬酸盐缓冲液和硫酸铵溶液作内水相制得的空白脂质体的平均粒径分别为(103±8)，(102±12)和(97±8) nm，zeta电位分别为(-21.3±0.5)，(-21.7±0.4)和(-20.9±0.7) mV，对阿霉素的包封率分别为47.8%，96.7%和98.6%。甘氨酸盐制得的脂质体体外泄漏最快，硫酸铵制得的脂质体泄漏最慢；甘氨酸盐缓冲液、柠檬酸盐缓冲液和硫酸铵溶液作内水相制得的阿霉素脂质体大鼠体内平均滞留时间分别为12.13，23.31和29.79 h。结论阿霉素在脂质体内水相中不同盐型影响其脂质体的体内外稳定性，以硫酸铵为内水相制得的阿霉素脂质体最稳定，其稳定次序与内水相中酸的强度有关，酸性越弱其脂质体稳定性越高。     

Trastuzumab and Liposomal Doxorubicin in the Treatment of MCF-7 Xenograft Tumor-Bearing Mice: Combination Does Not Affect Drug Serum Levels

Purpose We assessed the combination of doxorubicin or liposomal doxorubicin with trastuzumab for alterations in peak serum drug levels, as these agents are increasingly being paired in the treatment of aggressive breast cancer. We hypothesized that trastuzumab would exhibit a slower rate of elimination from the serum when in combination with liposomal doxorubicin based on the known effects of liposomal doxorubicin on phagocytic cells of the mononuclear phagocyte system (MPS), which are responsible in part for the uptake and degradation of antibodies.Methods Doxorubicin and trastuzumab serum levels were assessed following injection of free doxorubicin, liposomal doxorubicin, or trastuzumab into female RAG2-M mice bearing subcutaneous MCF-7^HER-2 tumors. The effects of combination drug treatment on tumor growth were compared to single-agent treatment.Results Peak serum trastuzumab levels were not altered as a result of addition of doxorubicin therapy, nor were doxorubicin levels altered over 24 h as a result of coadministration of trastuzumab. Liposomal doxorubicin administration did result in serum doxorubicin levels 200- to 1000-fold higher than with injection of free doxorubicin.Conclusions For the specific combination of trastuzumab with doxorubicin, either in free or liposomal form, coadministered in mice, there was no impact of one drug on the other in terms of peak serum drug levels or efficacy.     

抗癌复方硫酸长春新碱脂质体的体外释药特性及小鼠体内的组织分布

目的研究复方硫酸长春新碱脂质体的制备方法并考察其体外释放规律以及在小鼠体内的组织分布。方法采用pH梯度法合并逆相蒸发制备同时包载硫酸长春新碱(VCR)和盐酸米托蒽醌(MTO)的复方脂质体，实验考察脂质体的体外释药特性；采用反相高效液相法测定小鼠组织中的VCR和MTO浓度。结果体外释放结果表明，复方脂质体中VCR在24 h释放完全，对照溶液中VCR在6 h释放完全，脂质体中MTO在288 h仅释放了0.05%，对照溶液中MTO在12 h释放完全；体内药动学结果表明复方脂质体在血浆中VCR的AUC是对照溶液的1.70倍，T_1/2(Ke)为对照溶液的1.14倍；MTO的AUC是对照溶液的40.62倍，T_1/2(Ke)为对照溶液的432倍。结论 与对照液比较，体外释放实验证实复方脂质体具有缓释特性，体内实验结果表明复方脂质体可延长药物在血液中的循环时间并且提高了药物在血液中浓度，改善了原药的体内分布特性。     

Repeated injection of pegylated liposomal antitumour drugs induces the disappearance of the rapid distribution phase

Upon repeated administration, empty pegylated liposomes lose their long‐circulating characteristics, referred to as the accelerated blood clearance (ABC) phenomenon. To investigate whether cytotoxic drug‐containing pegylated liposomes could also elicit a similar phenomenon, two pegylated liposomal antitumour drugs (doxorubicin and mitoxantrone) were prepared, and they were administrated twice in the same animals with a 10‐day interval at a dose level of 8 mg kg^?1 (pegylated liposomal doxorubicin) and 4 mg kg^?1 (pegylated liposomal mitoxantrone). By comparing the overall pharmacokinetics after a single‐dose injection with that in animals treated with two doses, it was surprising to find that repeated administration of pegylated liposomal antitumour drugs caused the disappearance of rapid distribution phase instead of the ABC phenomenon, resulting in the conversion of a two‐compartment model to a one‐compartment model. Further investigation revealed that repeated injection induced the decreased uptake of liposomal antitumour drugs by the spleen at the early time point of 0.5–8 h after injection. In contrast, the deposition of liposomal antitumour drugs into liver was not affected. Therefore, the disappearance of the rapid distribution phase might be related to the reduced spleen uptake at the early time point.     

Lecithinized copper,zinc-superoxide dismutase as a protector against doxorubicin-induced cardiotoxicity in mice

Production of superoxide radicals from doxorubicin is widely accepted to be the cause of the cardiotoxicity induced by this antitumor agent. Pretreatment with superoxide dismutase could improve the therapeutic application. Aim of the present study was to determine whether lecithinized superoxide dismutase (PC-SOD) can serve as a cardioprotective drug during doxorubicin treatment. The protective potential of PC-SOD on doxorubicin-induced cardiotoxicity was investigated in BALB/c mice. The possible influence of PC-SOD on the antitumor activity of doxorubicin was investigated in vitro as well as in vivo. Mice were treated intravenously with doxorubicin (4 mg x kg(-1)) or doxorubicin and PC-SOD (5000, 20000 or 80000 U x kg(-1)) weekly x 6 and appropriate controls were included. Cardiotoxicity was monitored for 8 weeks by ECG measurement. The influence of PC-SOD on the antitumor activity of doxorubicin was evaluated in three human malignant cell lines. Nude mice bearing OVCAR-3 human ovarian cancer xenografts were treated intravenously with doxorubicin (8 mg x kg(-1)) alone or preceded by PC-SOD 20000 or 80000 U x kg(-1) weekly x 2 and appropriate controls were included. PC-SOD prevented doxorubicin-induced cardiotoxicity already at 5000 U x kg(-1) whereas 20000 and 80000 U x kg(-1) were equally protective. No toxicity was observed in mice treated with PC-SOD. PC-SOD did not interfere with the antiproliferative effects of doxorubicin in vitro. In vivo, PC-SOD had no negative effect on the inhibition of xenograft growth induced by doxorubicin.It can be concluded that PC-SOD protects the heart, but not the tumor against doxorubicin. These data suggest that PC-SOD may be a suitable cardioprotector during doxorubicin treatment.     

Monohydroxyethylrutoside as protector against chronic doxorubicin-induced cardiotoxicity.

1. The clinical use of the antitumour agent, doxorubicin, is largely limited by the development of a cumulative dose-related cardiotoxicity. This toxicity is generally believed to be caused by the formation of oxygen free radicals. In earlier studies it was established that flavonoids, naturally occurring antioxidants, can provide some degree of protection. In this study we investigated whether 7-monohydroxyethylrutoside (monoHER), a powerful antioxidative flavonoid with extremely low toxicity, can provide protection to an extent comparable to the clinically successful Cardioxane (ICRF-187). 2. Balb/c mice of 20-25 g were equipped i.p. with a telemeter to measure ECG. They were given 6 i.v. doses of doxorubicin (4 mg kg-1) at weekly intervals. ICRF-187 (50 mg kg-1) or monoHER (500 mg kg-1) were administered i.p. 1 h before doxorubicin administration. In the 2 monoHER groups the treatment continued with either 1 or 4 additional injections per week. A saline and monoHER treated group served as controls. After these 6 weeks, they were observed for another 2 weeks. 3. At the end of this study (week 8) the ST interval had increased by 16.7 +/- 2.7 ms (mean +/- s.e. mean) in doxorubicin-treated mice. At that time, the ST interval had increased by only 1.8 +/- 0.9 ms in ICRF-187 co-mediated mice and in monoHER co-medicated mice by only 1.7 +/- 0.8 and 5.1 +/- 1.7 ms (5- and 2-day schedule, respectively, all P < 0.001 relative to doxorubicin and not significantly different from control). The ECG of the control animals did not change during the entire study.(ABSTRACT TRUNCATED AT 250 WORDS)     

Liposomal doxorubicin and weekly paclitaxel in the treatment of metastatic breast cancer

The combination of paclitaxel and doxorubicin or epirubicin is highly active against metastatic breast cancer, yet may produce congestive heart failure. Liposome-encapsulated doxorubicin is a new formulation of doxorubicin with no dose-limiting cardiac toxicity. Twenty-one patients with metastatic breast cancer were treated with pegylated liposomal doxorubicin (20 mg/m2, day 1) and paclitaxel (100 mg/m2, days 1 and 8) for six cycles every 2 weeks. All patients had had relapse or progression on one to five previous chemotherapies. We observed two patients with complete and eight patients with partial remissions (48% response rate). Eight of the 10 responders had had previous therapy with epirubicin, doxorubicin or mitoxantrone. The mean remission duration was 5 months. Disease progression due to brain metastasis occurred in five cases. Severe side effects (grade 3 WHO) were alopecia (100%), skin toxicity in 29%, neuropathy in 24% and mucositis in 13%. Leukopenia (grade 4 WHO) was observed in 48%, but there was no cardiac toxicity, no death and no hospitalization. The combination of weekly paclitaxel and liposomal doxorubicin every 2 weeks is highly effective in previously treated patients. Based on the doses we administered, we recommend 15 mg/m2 liposomal doxorubicin every 2 weeks and 80 mg/m2 paclitaxel weekly.     

PEGylated elastic liposomal formulation for lymphatic targeting of zidovudine

The present study was aimed at in vitro and in vivo evaluation of PEGylated elastic liposomal formulation for lymphatic targeting of zidovudine (AZT). PEGylated elastic liposomal formulation was prepared and characterized for characteristic in vitro, ex-vivo and in vivo parameters. The plain and PEGylated elastic liposomal formulation showed transdermal flux of 99.8+/-5.8 and 119.5+/-5.2 microg/cm(2)/hr, respectively across the rat skin. Results of biodistribution study indicated 27-fold higher accumulation of AZT in lymphoid tissues after application of PEGylated elastic liposomes as compared to free drug. The efficient localization of elastic liposomal formulation in lymphatic system is of particular interest for HIV therapy, taking in account that replication of HIV mainly takes place in the lymphoid system. The Cellular uptake studies showed significantly higher cellular uptake in lymphoid cells (MT-2 cell line) from PEGylated elastic liposomal formulation (88.9+/-8.7%) in comparison to phosphate buffer saline (PBS, pH 7.4) solution of drug (27.1+/-2.8%). The entrapment of AZT into PEGylated elastic liposomes represents a potential approach for overcoming the toxicity by its selective uptake in lymphoid organs. This represents attractive approach for sustained and targeted delivery of AZT.