RESUMO
5-Iodo-2'-deoxyuridine (IUdR) is an effective radiosensitiser but its clinical development has been limited by toxicity. Prolonged intravenous infusions of IUdR are necessary for optimal tumour uptake but cause dose-limiting myelosuppression. The lack of selective tumour uptake can lead to radiosensitisation of adjacent normal tissues and enhanced local radiation toxicity. Liposomal IUdR delivery offers selective targeting of tumour tissues and avoidance of local and systemic toxicity. In these studies, we report the development of a pegylated liposome containing a lipophilic IUdR derivative (3', 5'-O-dipalmitoyl-5-iodo-2'-deoxyuridine) for use in a head and neck cancer xenograft model. Initial studies confirmed the ability of IUdR to sensitise two head and neck cancer cell lines to single fractions of radiotherapy (SFRT) and this effect was seen to correlate with the thymidine replacement index in KB cells. In vivo delivery of single doses of either unencapsulated IUdR or pegylated liposomal IUdR (PLIUdR) to nude mice bearing KB xenograft tumours did not enhance the effect of SFRT delivered 16 h later. When PLIUdR was delivered by a protracted administration schedule to a dose of 48 mg kg(-1) over 7 days, it enhanced the effect of both 4.5 Gy SFRT and fractionated radiotherapy. PLIUdR was at least as effective as unencapsulated IUdR delivered by multiple intravenous injections or continuous subcutaneous infusion. Immunohistochemistry with a specific anti-IUdR monoclonal antibody confirmed greater levels of tumour staining in tumours from animals treated with PLIUdR compared with those treated with unencapsulated IUdR.
Assuntos
Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/radioterapia , Idoxuridina/administração & dosagem , Polietilenoglicóis/administração & dosagem , Animais , Carcinoma de Células Escamosas/patologia , Relação Dose-Resposta à Radiação , Portadores de Fármacos , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Idoxuridina/análogos & derivados , Injeções Intravenosas , Lipossomos , Camundongos , Camundongos Nus , Taxa de Sobrevida , Timidina/metabolismo , Células Tumorais Cultivadas/transplanteRESUMO
PURPOSE: The effect of total-body irradiation (TBI) on the biodistribution and pharmacokinetics of (111)In-DTPA-labeled pegylated liposomes (IDLPL) was evaluated in tumor-bearing nude mice as part of an ongoing effort to develop liposome-targeted radiosensitizers. METHODS AND MATERIALS: Mice received TBI (2 Gy or 5 Gy) according to two protocols: (1) to test the effect of radiation delivered 30 min before liposome injection on the time course of IDLPL biodistribution to tumor and normal tissues over 96 h; (2) to test the effect of radiation at times ranging from 72 h to 1 h before liposome injection on tumor and normal tissue uptake of IDLPL at 24 h. Tumor and tissue/organ levels of liposome uptake were measured by dissection and quantitation in a gamma counter. RESULTS: For most tissues (tumor, liver, kidney, lung, skin, heart, and central nervous system), irradiation did not alter IDLPL biodistribution. Splenic uptake appeared to be increased by TBI, but further analysis revealed that this effect was due to reduced splenic weight in irradiated mice. IDLPL uptake was increased in the small intestine, stomach, musculoskeletal system, female reproductive tract, and adrenal glands in irradiated mice. CONCLUSION: These findings suggest that concomitant administration of liposomal radiosensitizers during radical radiotherapy is likely to be safe. However, caution should be exercised in situations in which significant volumes of small intestine or hemopoietic tissue will be irradiated.
Assuntos
Lipossomos/efeitos da radiação , Ácido Pentético/farmacocinética , Polietilenoglicóis/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Irradiação Corporal Total , Animais , Relação Dose-Resposta à Radiação , Feminino , Humanos , Radioisótopos de Índio , Células KB , Lipossomos/farmacocinética , Masculino , Camundongos , Camundongos Nus , Ácido Pentético/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Fatores de Tempo , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: These studies were performed with the intention of examining the effect of single-fraction doses of radiotherapy (RT) on the tumor deposition of radiolabeled pegylated liposomes in an animal xenograft tumor model. METHODS AND MATERIALS: Human KB head-and-neck xenograft tumors were established in female nude mice. The effect of single fraction tumor RT doses (5, 10, 15, and 20 Gy) on the tumor uptake of intravenously administered (111)In-DTPA-labeled pegylated liposomes (IDLPL) was examined using two protocols: (1) to test the effect of RT delivered 30 min before liposome injection on the time course of tumor uptake over a 96-h period; (2) to test the effect of RT at times ranging from 72-h to 1-h before liposome injection on the levels of liposome uptake at 24 h. Tumor and normal tissue/organ (blood, liver, spleen, lung, and kidney) liposome uptake was determined by dissection and quantitation in a gamma counter. RESULTS: There was no demonstrable effect of RT on tumor uptake of IDLPL (p > 0.1 for all comparisons). Reassuringly, neither was there an effect of RT on the pharmacokinetics and biodistribution of radiolabeled liposomes to normal tissues. CONCLUSIONS: Single fraction doses of RT appear to have no effect on tumor or normal tissue biodistribution and pharmacokinetics of radiolabeled pegylated liposomes in this animal model.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/radioterapia , Excipientes/efeitos da radiação , Lipossomos/efeitos da radiação , Polietilenoglicóis/efeitos da radiação , Animais , Carcinoma de Células Escamosas/sangue , Excipientes/farmacocinética , Feminino , Humanos , Radioisótopos de Índio/sangue , Radioisótopos de Índio/farmacocinética , Lipossomos/química , Lipossomos/farmacocinética , Camundongos , Camundongos Nus , Ácido Pentético/sangue , Ácido Pentético/farmacocinética , Polietilenoglicóis/farmacocinética , Radiobiologia , Dosagem Radioterapêutica , Distribuição Tecidual , Transplante HeterólogoRESUMO
The biodistribution and pharmacokinetics of (111)In-DTPA-labeled pegylated liposomes (IDLPL) were studied in 17 patients with locally advanced cancers. The patients received 65-107 MBq of IDLPL, and nuclear medicine whole body gamma camera imaging was used to study liposome biodistribution. The t(1/2beta) of IDLPL was 76.1 h. Positive tumor images were obtained in 15 of 17 studies (4 of 5 breast, 5 of 5 head and neck, 3 of 4 bronchus, 2 of 2 glioma, and 1 of 1 cervix cancer). The levels of tumor liposome uptake estimated from regions of interest on gamma camera images were approximately 0.5-3.5% of the injected dose at 72 h. The greatest levels of uptake were seen in the patients with head and neck cancers [33.0 +/- 15.8% ID/kg (percentage of injected dose/kg)]. The uptake in the lung tumors was at an intermediate level (18.3 +/- 5.7% ID/kg), and the breast cancers showed relatively low levels of uptake (5.3 +/- 2.6% ID/kg). These liposome uptake values mirrored the estimated tumor volumes of the various tumor types (36.2 +/- 18.0 cm3 for squamous cell cancer of the head and neck, 114.5 +/- 42.0 cm3 for lung tumors, and 234.7 +/- 101.4 cm3 for breast tumors). In addition, significant localization of the liposomes was seen in the tissues of the reticuloendothelial system (liver, spleen, and bone marrow). One patient with extensive mucocutaneous AIDS-related Kaposi sarcoma was also studied according to a modified protocol, and prominent deposition of the radiolabeled liposomes was demonstrated in these lesions. An additional two patients with resectable head and neck cancer received 26 MBq of IDLPL 48 h before undergoing surgical excision of their tumors. Samples of the tumor, adjacent normal mucosa, muscle, fat, skin, and salivary tissue were obtained at operation. The levels of tumor uptake were 8.8 and 15.9% ID/kg, respectively, with tumor uptake exceeding that in normal mucosa by a mean ratio of 2.3:1, in skin by 3.6:1, in salivary gland by 5.6:1, in muscle by 8.3:1, and in fat by 10.8:1. These data strongly support the development of pegylated liposomal agents for the treatment of solid tumors, particularly those of the head and neck.
Assuntos
Neoplasias/metabolismo , Ácido Pentético/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Adulto , Idoso , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Feminino , Humanos , Radioisótopos de Índio/farmacocinética , Lipossomos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Urina/químicaRESUMO
The relationship between tumour size and uptake of(111)In-DTPA-labelled pegylated liposomes has been examined in a human head and neck cancer xenograft model in nude mice. The mean tumour uptake of(111)In-labelled pegylated liposomes at 24 hours was 7.2 +/- 6.6% ID/g. Liposome uptake for tumours < 0.1 g, 0.1-1.0 g and > 1.0 g was 15.1 +/- 10.8, 5.9 +/- 2.2 and 3.0 +/- 1.3% ID/g, respectively. An inverse correlation between tumour weight and liposome uptake was observed by both Spearman's rank correlation test (r(s)= - 0.573, P< 0.001) and Pearson's correlation coefficient (r(s)= - 0.555, P< 0.001). For 18 tumours with macroscopic central necrosis, the ratio of uptake in the tumour rim relative to the necrotic tumour core was 11.2 +/- 6.4. Measurement of tumour vascular volume for tumours of various sizes revealed an inverse correlation between tumour weight and tumour vascular volume (Spearman's rank correlation test, r(s)= - 0.598, P< 0.001), consistent with poor or heterogeneous vascularization of larger tumours. These data have important implications for the clinical application of pegylated liposome targeted strategies for solid cancers which are discussed in detail.
Assuntos
Quelantes/farmacocinética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Radioisótopos de Índio/farmacocinética , Ácido Pentético/farmacocinética , Animais , Feminino , Neoplasias de Cabeça e Pescoço/irrigação sanguínea , Humanos , Lipossomos/metabolismo , Lipossomos/farmacocinética , Camundongos , Camundongos Nus , Necrose , Transplante de Neoplasias , Polietilenoglicóis/metabolismo , Células Tumorais CultivadasRESUMO
PURPOSE: To evaluate the in vitro and in vivo activity of unencapsulated doxorubicin (DOX) and cisplatin (CDDP) and their pegylated liposome encapsulated counterparts (PLED and PLEC) in a subcutaneous model of human squamous cell cancer of the head and neck. METHODS: In vitro cytotoxicity was determined by means of the sulphorhodamine B assay and in vivo activity was assessed in terms of tumour growth delay following single intravenous doses of the various agents. Treatment-related toxicity was evaluated by means of serial weight measurement. RESULTS: The IC(50) values for DOX (12.1-fold) and CDDP (21.5-fold) were lower than for their liposome-encapsulated counterparts. When the two unencapsulated agents were compared, the IC(50) value for DOX was 16-fold lower than that for CDDP. In the in vivo studies, liposomes containing DTPA (PLEDTPA) exerted no effect on KB xenograft tumours when compared to untreated controls (P > 0.1). PLED was significantly more effective than DOX at doses of 2 mg/kg, 4 mg/kg and 8 mg/kg (P < 0.001 for all comparisons). At the 8 mg/kg dose, 7/13 animals treated with PLED were free of disease at 60 days, compared to 0/12 treated with DOX. PLEC displayed superior activity in comparison to CDDP at the 4 mg/kg dose level (P < 0.001), although at doses of 2 mg/kg and 10 mg/kg this comparison only reached borderline statistical significance (0.1 > P > 0.05). The highest dose level of 20 mg/kg was fatal to all animals in the CDDP group but well-tolerated by the animals in the PLEC group. On the basis of serial weight measurements, both PLED and PLEC were shown to be tolerated better than DOX and CDDP. CONCLUSION: Both PLED and PLEC were shown to exert significant activity against head and neck xenograft tumours, with PLED showing particular efficacy.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/uso terapêutico , Relação Dose-Resposta a Droga , Doxorrubicina/uso terapêutico , Feminino , Humanos , Lipossomos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Polietilenoglicóis , Transplante HeterólogoRESUMO
The biodistribution and pharmacokinetics of 111In-DTPA-labelled pegylated liposomes in tumour-bearing nude mice was studied to examine possible applications of pegylated liposome-targeted anti-cancer therapies. Nude mice received an intravenous injection of 100 microl of 111In-DTPA-labelled pegylated liposomes, containing 0.37-0.74 MBq of activity. The t1/2alpha and t1/2beta of 111In-DTPA-labelled pegylated liposomes were 1.1 and 10.3 h, respectively. Tumour uptake was maximal at 24 h at 5.5 +/- 3.0% ID g(-1). Significant reticuloendothelial system uptake was demonstrated with 19.3 +/- 2.8 and 18.8 +/- 4.2% ID g(-1) at 24 h in the liver and spleen, respectively. Other sites of appreciable deposition were the kidney, skin, female reproductive tract and to a lesser extent the gastrointestinal tract. There was no indication of cumulative deposition of pegylated liposomes in the lung, central nervous system, musculoskeletal system, heart or adrenal glands. In contrast, the t1/2alpha and t1/2beta of unencapsulated 111In-DTPA were 5 min and 1.1 h, respectively, with no evidence of accumulation in tumour or normal tissues. Incubation of 111In-DTPA-labelled pegylated liposomes in human serum for up to 10 days confirmed that they are very stable, with only minor leakage of their contents. The potential applications of pegylated liposomes in the arena of targeted therapy of solid cancers are discussed.
Assuntos
Neoplasias de Cabeça e Pescoço/metabolismo , Lipossomos/farmacocinética , Ácido Pentético/farmacocinética , Animais , Quelantes/farmacocinética , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Feminino , Humanos , Radioisótopos de Índio/farmacocinética , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fatores de Tempo , Distribuição Tecidual , Transplante HeterólogoRESUMO
The potential value of intratumoral or s.c. injections of pegylated liposomes as locoregionally targeted therapy of tumors and their draining lymph nodes was assessed in nude mice as part of an ongoing program aimed at developing pegylated liposomal radiosensitizers for the treatment of head and neck cancers. Animals received (111)In-labeled diethylenetriaminepentaacetic acid (DTPA), either encapsulated in pegylated liposomes (IDLPL) or in the unencapsulated form ((111)In-DTPA), as intratumoral or s.c. injections, and the local retention, locoregional nodal drainage, and systemic biodistribution were measured. After intratumoral injections, IDLPL were effectively retained in the tumor with an area under the curve (AUC) between 1 and 96 h of 2,574.4% injected dose per gram hours (%ID/g x h). The corresponding value for (111)In-DTPA was 204.4%ID/g x h. Accumulation of IDLPL was seen in ipsilateral lymph nodes. The maximal ipsilateral:contralateral node ratios were 8:1 (2.2 versus 0.27%ID/g) for inguinal nodes at 24 h and 19:1 (2.5 versus 0.13%ID/g) for axillary nodes at 48 h. Unencapsulated (111)In-DTPA showed no evidence of accumulation in locoregional nodes. After s.c. injection, IDLPL were cleared slowly from the injection site with an AUC between 1 and 192 h of 24,051.1%ID/g x h. Unencapsulated (111)In-DTPA was cleared rapidly with an AUC between 1 and 192 h of 46.4%ID/g x h. Again, significant levels of IDLPL were detected in the ipsilateral locoregional nodes, with ipsilateral:contralateral ratios of 121:1 (57.9 versus 0.48%ID/g) at 24 h (inguinal nodes) and 17:1 (5.2 versus 0.3%ID/g) at 72 h (axillary nodes). There was no retention of unencapsulated (111)In-DTPA in the draining nodes. Locoregional administration of pegylated liposomal radiosensitizers may be a useful approach for targeted therapy of head and neck tumors and their nodal metastases.
Assuntos
Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Lipossomos/química , Polietilenoglicóis/química , Animais , Área Sob a Curva , Quelantes/administração & dosagem , Feminino , Injeções Subcutâneas , Lipossomos/farmacocinética , Linfonodos/metabolismo , Camundongos , Camundongos Nus , Ácido Pentético/administração & dosagem , Radiossensibilizantes/administração & dosagem , Fatores de Tempo , Distribuição TecidualRESUMO
Concomitant chemotherapy and radiotherapy (CCRT) has recently been shown to improve treatment outcome in a range of solid tumors. Pegylated liposomes have the potential to target drugs directly to tumors and may increase the efficacy and reduce the toxicity of CCRT by selectively delivering radiosensitizing agents to tumor, as opposed to normal, tissues. In these studies, we have assessed CCRT using pegylated liposome encapsulated doxorubicin (PLED) and pegylated liposome encapsulated cisplatin (PLEC) against KB head and neck cancer xenograft tumors in nude mice. The addition of low-dose (2 mg/kg) PLED (P < 0.001) and PLEC (P < 0.001) significantly increased the effect of 4.5 Gy, but not 9 Gy, single-fraction radiotherapy (SFRT). Both PLED and PLEC were significantly more effective than their unencapsulated counterparts in increasing the effect of SFRT. In addition, PLED (P < 0.001) and PLEC (P < 0.05) significantly increased the effect of fractionated radiotherapy (9 Gy in 3 fractions) in two different dosing schedules (2 mg/kg single dose or three sequential doses of 0.67 mg/kg). Unencapsulated diethylenetriaminepentaacetic acid and pegylated liposomal diethylenetriaminepentaacetic acid were used as controls to test the effect of the liposome vehicle and showed no interaction with 4.5 Gy or 9 Gy SFRT (P > 0.1). CCRT was well-tolerated, with no evidence of increased local or systemic toxicity, as compared with radiotherapy alone. This study is the first to demonstrate the value of pegylated liposomes as vehicles for the delivery of radiosensitizing drugs in CCRT strategies.
Assuntos
Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Lipossomos/química , Polietilenoglicóis/química , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/administração & dosagem , Animais , Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Terapia Combinada , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Doxorrubicina/uso terapêutico , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Radiossensibilizantes/uso terapêutico , Fatores de Tempo , Células Tumorais CultivadasRESUMO
PURPOSE: This study examined the pharmacokinetics and tissue distribution of an antisense oligonucleotide ISIS 2503, formulated in stealth (pegylated) liposomes (encapsulated) or in phosphate-buffered saline (unencapsulated). METHODS: Encapsulated or unencapsulated ISIS 2503 was administered to rhesus monkeys by intravenous infusion. The concentrations of ISIS 2503 and metabolites in blood, plasma, and tissue samples were determined by capillary gel electrophoresis. RESULTS: Plasma concentrations of encapsulated ISIS 2503 decreased mono-exponentially after infusion with a mean half-life of 57.8 hours. In contrast, the concentration of unencapsulated ISIS 2503 in plasma decreased rapidly with a mean half-life of 1.07 hours. Both encapsulated and unencapsulated ISIS 2503 distributed widely into tissues. Encapsulated ISIS 2503 distributed primarily to the reticulo-endothelial system and there were few metabolites observed. In contrast, unencapsulated ISIS 2503 distributed rapidly to tissue with highest concentration seen in kidney and liver. Nuclease-mediated metabolism was extensive for unencapsulated oligonucleotide in plasma and tissues. CONCLUSIONS: The data suggest that stealth liposomes protect ISIS 2503 from nucleases in blood and tissues, slow tissue uptake, and slow the rate of clearance from the systemic circulation. These attributes may make these formulations attractive for delivering oligonucleotides to sites with increased vasculature permeability such as tumors or sites of inflammation.
Assuntos
Oligonucleotídeos Antissenso/farmacocinética , Proteínas ras/antagonistas & inibidores , Animais , Proteínas Sanguíneas/metabolismo , Cápsulas/farmacocinética , Sistemas de Liberação de Medicamentos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Meia-Vida , Cinética , Lipossomos , Macaca mulatta , Masculino , Taxa de Depuração Metabólica , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/síntese química , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Fosforotioatos , Distribuição Tecidual , Proteínas ras/genéticaRESUMO
We compared the therapeutic effects of low doses of cisplatin and doxorubicin hydrochloride encapsulated in long-circulating liposomes composed of cholesterol/hydrogenated soy phosphatidylcholine-polyethylene glycol-distearoyl-phosphatidyl-ethanolamine. The encapsulation of cisplatin and doxorubicin in these liposomes made ineffectively low doses of the free drugs able to inhibit the growth of and affect cures of a human colonic carcinoma growing in nude mice. Liposome-encapsulated cisplatin had minor systemic toxic side effects indicated by an average 9% weight loss which was recovered 3-4 weeks after the last treatment. Toxicity was not observed in mice treated with liposome-encapsulated doxorubicin.
Assuntos
Cisplatino/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Doxorrubicina/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias do Colo/patologia , Doxorrubicina/uso terapêutico , Portadores de Fármacos , Feminino , Humanos , Lipossomos , Camundongos , Camundongos Nus , Podofilina/administração & dosagem , Podofilina/análogos & derivados , Podofilina/uso terapêutico , Podofilotoxina/análogos & derivados , Polietilenoglicóis , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
The topoisomerase I inhibitor GL147211C [7-[(4-methylpiperazino)methyl]-10,11-(ethylenedioxy)-(20S)-campto thecin trifluoroacetate], a camptothecin analogue, has significant activity in tumor cell cytotoxicity assays in vitro and antitumor activity in both animal tumor models and human patients. Its toxicity is significant, however, effectively limiting the amount of drug that can be administered and its clinical utility. To determine whether the therapeutic index of GL147211C could be improved, the drug was encapsulated in long-circulating, pegylated (STEALTH) liposomes (SPI-355). The pharmacokinetics and antitumor activity of SPI-355 were compared to those of nonliposomal GL147211C. The plasma pharmacokinetics of SPI-355 in rats were typical of those of other pegylated liposomal formulations, with significantly increased blood circulation time; the dose-corrected area under the curve and Cmax of SPI-355 (10 mg/kg) were 1250- and 35-fold higher, respectively, than those of nonliposomal GL14711C (8.72 mg/kg). The comparative antitumor activity of SPI-355 and nonliposomal GL1472211C was evaluated in nude mice implanted with HT29 colon carcinoma xenografts. SPI-355 was 20-fold more effective than GL147211C in inhibiting tumor growth (1 mg/kg SPI-355 and 20 mg/kg GL147211C) and produced durable complete remissions of tumors at well-tolerated dose levels that were >5-fold lower than the maximally tolerated dose of GL147211C, which induced no durable complete responses. Signs of toxicity were similar between the two drugs, but liposome encapsulation increased the toxicity of drug approximately 4-fold, with increased weight loss and several deaths with SPI-355 (5 mg/kg SPI-355 versus 20 mg/kg GL147211C). Despite the increased toxicity seen with SPI-355, the therapeutic index of the liposomal formulation was increased approximately 5-fold over that of nonliposomal GL147211C, suggesting that such a pegylated liposomal formulation could demonstrate increased therapeutic index in human patients.
Assuntos
Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias do Colo/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Inibidores da Topoisomerase I , Animais , Antineoplásicos/farmacocinética , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Neoplasias do Colo/metabolismo , Portadores de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Humanos , Lipossomos , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Ratos , Ratos Sprague-Dawley , Transplante Heterólogo , Resultado do TratamentoRESUMO
Monthly treatments with intravenous doxorubicin encapsulated in long circulating, sterically stabilized liposomes delayed the appearance of primary mammary carcinomas and reduced the final incidence from 49 in 50 untreated mice to 46 in 87 treated mice. No toxic side effects of the treatments were observed.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Neoplasias Mamárias Experimentais/prevenção & controle , Animais , Esquema de Medicação , Portadores de Fármacos , Feminino , Lipossomos , Camundongos , Camundongos Endogâmicos C3HRESUMO
This study tested the therapeutic efficacy of doxorubicin hydrochloride in two formulations: free in saline suspension and encapsulated in polyethylene glycol-coated, long-circulating liposomes. The drug formulations at a dose level of 3 mg doxorubicin per kg body weight were injected intravenously to treat the human pancreatic carcinoma AsPC-1, implanted s.c. into nude Swiss mice. Liposome-encapsulated doxorubicin was significantly more effective in inhibiting tumour growth and in effecting cures, and had only minor systemic toxic side-effects, indicated by a transient weight loss. Confocal laser scanning microscopy was used to determine the tumour uptake and the clearance of doxorubicin in the free and in the liposomal forms. The liposome-encapsulated doxorubicin entered the tumour in greater quantity, and remained in the tumour longer, than the free drug. The liposome formulation produced a sixfold or greater increase in doxorubicin at the disease site. It is probable that increased penetration into the tumour, and long presence with slow drug release from liposomes in the tumour, account for the enhanced therapeutic effect when the drug was encapsulated in polyethylene glycol-coated liposomes.
Assuntos
Adenocarcinoma/metabolismo , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Portadores de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lipossomos , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/tratamento farmacológico , Transplante HeterólogoRESUMO
Transfer of MPEG(1900)-DSPE from micellar phase to pre-formed liposomes imparts long in vivo circulation half-life to an otherwise rapidly cleared lipid composition. MPEG(1900)-DSPE transfers efficiently and quickly in a time and temperature dependent manner. There is negligible content leakage and a strong correlation between assayed mol% MPEG(1900)-DSPE, liposome diameter increase, and pharmacokinetic parameters such as distribution phase half-life. Since a biological attribute (liposome clearance rate) can be modified by the insertion process, it suggests a simple and economical way to impart site-specific targeting to a variety of liposome delivery systems. This method is also a convenient way to measure the 'brush' thickness of such conjugates directly.
Assuntos
Lipossomos/farmacocinética , Fosfatidiletanolaminas/farmacocinética , Polietilenoglicóis/farmacocinética , Animais , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-Dawley , SolubilidadeRESUMO
Poly(ethylene glycol) (PEG)-derivatized liposome vehicles improve antitumor effectiveness of entrapped anthracyclines and vinca alkaloids. However, the plasma clearance of entrapped vincristine is substantially faster than the lipid phase or other entrapped aqueous markers, suggesting leakage out of the liposome during transit in the blood compartment. We tested the effect of altering the drug's in vivo leakage rate on pharmacokinetics, toxicity, and antitumor activity of entrapped drug in rodent models. Suramin, heparin, and dextran sulfate were tested for their ability to produce a precipitable complex in vitro. PEG-derivatized liposomes were prepared with the complexing agent inside, and vincristine was driven inside using an ammonium gradient. The resulting preparations were found to have plasma distribution half-lives significantly longer than the formulation without a complex-forming agent. There was no increase in acute lethality, and in the case of the suramin-vincristine complex, the acute lethality was significantly reduced at the highest does level. Anti-tumor activity against the mouse mammary carcinoma MC2 was tested in a multiple-dose study. Free vincristine did not affect the tumor growth rate significantly, but at the same dose level all PEG-coated liposome formulations inhibited tumor growth markedly. The suramin containing formulation was as effective as the formulation lacking polyanion, but the heparin and dextran sulfate containing formulations were less effective. Thus, compounds which form insoluble complexes with vincristine alter in vivo plasma distribution phase pharmacokinetics without increasing acute lethality, but without a corresponding increase in anti-tumor activity.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/toxicidade , Neoplasias Mamárias Experimentais/metabolismo , Vincristina/farmacocinética , Vincristina/toxicidade , Animais , Ânions , Anticoagulantes , Antineoplásicos , Antineoplásicos Fitogênicos/sangue , Sulfato de Dextrana , Portadores de Fármacos , Feminino , Heparina , Injeções Intravenosas , Lipossomos , Masculino , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Camundongos Endogâmicos ICR , Polietilenoglicóis , Ratos , Ratos Sprague-Dawley , Suramina , Vincristina/sangueRESUMO
Vincristine is used clinically for the treatment of various types of cancer. Recent significant therapeutic improvements obtained by entrapping anthracyclines in sterically stabilized liposomes raised the question whether the therapeutic index of vincristine can be similarly increased by formulation into such long-circulating liposomes. Encapsulation of vincristine in sterically stabilized liposomes (SL-VCR) prolonged the drug's distribution phase plasma half-life in rats from 0.22 to 10.5 hr. There was no significant difference in LD50 (> < or = 2.5 mg/kg, i.v.), but mice given sublethal doses of SL-VCR experienced significantly less weight loss than those given the same dose of free drug. Compared to free drug, SL-VCR was most effective against i.p. or s.c. implanted tumors. However, i.v. tumor inoculation nullified the therapeutic advantage of encapsulation. A single i.v. 2 mg/kg dose of SL-VCR increased the life span of mice bearing i.v. implanted P388 cells by only 44%, while the life span of i.p. P388 implanted mice was increased by 199%. In an s.c. implanted murine colon carcinoma, multiple doses of free drug did little to slow the growth of the tumors, but SL-VCR was able to produce long-term survivors in several dose regimens. These results indicate that prolonged circulation time increases the therapeutic index of VCR entrapped in liposomes against s.c. or i.p. implanted tumors, but does not improve the drug's activity against rapidly growing i.v. disseminated leukemias.
Assuntos
Vincristina/farmacocinética , Animais , Neoplasias do Colo/tratamento farmacológico , Feminino , Leucemia L1210/tratamento farmacológico , Leucemia P388/tratamento farmacológico , Lipossomos , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Análise de Sobrevida , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
This report characterizes a procedure for rapidly and accurately determining the entrapment of vincristine or other water-soluble drugs in polyethylene glycol-derivatized liposomes. Rapid liposome aggregation with poly(methacrylic acid) and pelleting by mild centrifugation separates liposome-associated vincristine from unentrapped drug. After collecting the supernatant fraction, the pellet is resuspended and solubilized in isopropyl alcohol. Quantitative uv spectrophotometry determines vincristine mass in both fractions. The mean accuracy (recovery) is 100.6% over an entrapped drug range from 70 to 99%. Within and between day precision of the method has a relative standard deviation of 0.76% for a single measurement.
Assuntos
Lipossomos/química , Ácidos Polimetacrílicos , Centrifugação , Estudos de Avaliação como Assunto , Polietilenoglicóis , Reprodutibilidade dos Testes , Espectrofotometria Ultravioleta , Vincristina/análiseRESUMO
This study tested the prophylactic efficacies of doxorubicin hydrochloride and vincristine sulphate, encapsulated in sterically stabilised long circulating liposomes, against the spontaneous development of mammary carcinomas in C3H/He mice. Monthly prophylactic intravenous (i.v.) injections of 6 mg/kg doses of liposome-encapsulated doxorubicin (DOX-SL) or 1 mg/kg doses of liposome-encapsulated vincristine (VIN-SL) were begun when retired breeding mice were 26 weeks old. Mice that developed a mammary carcinoma while on the monthly prophylactic protocols were then given weekly i.v. injections of 6 mg/kg DOX-SL or 1 mg/kg VIN-SL to test the therapeutic efficacies of the drugs, and to determine whether the tumours were susceptible or resistant to therapy. The monthly prophylactic injections reduced the incidence of first mammary carcinomas from 87/88 (99%) in untreated mice to 24/42 (57%) in DOX-SL-treated mice and to 26/32 (81%) in VIN-SL-treated mice. Of the mice that developed a mammary tumour while on the prophylactic protocols, 12 of 30 mice were cured by the weekly therapeutic use of DOX-SL, and the growth of 18 tumours was inhibited. The weekly therapeutic use of VIN-SL cured 3 of 8 mice, and inhibited the growth of five tumours. Weekly DOX-SL therapy cured 7 of 22 previously untreated mice. The mean survival of tumour-bearing mice was extended from 24 days in untreated mice to 87 days in DOX-SL-treated mice, which had not received prophylactic treatment. Metastases were found in 29 of 54 untreated mice, and in 3 of 72 mice treated with DOX-SL and VIN-SL. Toxic side effects were limited to a transient weight loss during the weekly treatments. Drug resistance as a result of treatments was not observed.
Assuntos
Doxorrubicina/administração & dosagem , Neoplasias Mamárias Animais/tratamento farmacológico , Vincristina/administração & dosagem , Animais , Progressão da Doença , Doxorrubicina/efeitos adversos , Portadores de Fármacos , Resistência a Medicamentos , Feminino , Lipossomos , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Animais/patologia , Neoplasias Mamárias Animais/prevenção & controle , Camundongos , Camundongos Endogâmicos C3H , Vincristina/efeitos adversosRESUMO
This study tested the therapeutic effects of vincristine sulfate and doxorubicin hydrochloride, each drug in 2 different formulations: (i) as a solution in saline, and (ii) encapsulated in sterically stabilized, long-circulating liposomes composed of hydrogenated soy-phosphatidylcholine/cholesterol/polyethylene-glycerol-disteroyl++ +- phosphatidylethanolamine. The 4 drug preparations were used to treat s.c. implants of the mouse mammary carcinoma MC2. The drugs were given by i.v. injection over 15 to 18 days, starting 3 days after tumor implantation. The single-drug therapeutic effects of vincristine (S-VCR) and doxorubicin (Doxil) in liposomes were compared, and the 2 preparations were also tested in alternate and in simultaneous combinations. These new liposome formulations of vincristine and doxorubicin were significantly more effective than the free drugs in curing the mice. Alternate, semi-weekly injection of both drugs gave the best therapeutic effect. Prolonged circulation time with increased accumulation in tumors are considered likely reasons for the improved therapeutic efficacy of both drugs when encapsulated in these liposomes.