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1.
Drug Deliv ; 27(1): 542-555, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32241176

RESUMEN

Nanoparticles (NPs), such as liposomes, effectively evade the severe toxicity of unexpected accumulation and passively shuttle drugs into tumor tissues by enhanced permeability and retention. In the case of non-small cell lung cancer and pancreatic ductal adenocarcinoma, cancer-associated fibroblasts promote the aggregation of a gel-like extracellular matrix that forms a physical barrier in the desmoplastic stroma of the tumor. These stroma are composed of protein networks and glycosaminoglycans (GAGs) that greatly compromise tumor-penetrating performance, leading to insufficient extravasation and tissue penetration of NPs. Moreover, the presence of heparan sulfate (HS) and related proteoglycans on the cell surface and tumor extracellular matrix may serve as molecular targets for NP-mediated drug delivery. Here, a GAG-binding peptide (GBP) with high affinity for HS and high cell-penetrating activity was used to develop an HS-targeting delivery system. Specifically, liposomal doxorubicin (L-DOX) was modified by post-insertion with the GBP. We show that the in vitro uptake of L-DOX in A549 lung adenocarcinoma cells increased by GBP modification. Cellular uptake of GBP-modified L-DOX (L-DOX-GBP) was diminished in the presence of extracellular HS but not in the presence of other GAGs, indicating that the interaction with HS is critical for the cell surface binding of L-DOX-GBP. The cytotoxicity of doxorubicin positively correlated with the molecular composition of GBP. Moreover, GBP modification improved the in vivo distribution and anticancer efficiency of L-DOX, with enhanced desmoplastic targeting and extensive distribution. Taken together, GBP modification may greatly improve the tissue distribution and delivery efficiency of NPs against HS-abundant desmoplastic stroma-associated neoplasm.


Asunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/análogos & derivados , Heparitina Sulfato/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Células A549 , Adenocarcinoma del Pulmón/metabolismo , Animales , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Doxorrubicina/farmacocinética , Sistemas de Liberación de Medicamentos , Femenino , Glicosaminoglicanos/metabolismo , Humanos , Liposomas/administración & dosificación , Liposomas/síntesis química , Liposomas/química , Liposomas/farmacocinética , Neoplasias Pulmonares/metabolismo , Ratones , Células 3T3 NIH , Nanopartículas/administración & dosificación , Nanopartículas/química , Nanopartículas/metabolismo , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Distribución Tisular/efectos de los fármacos , Microambiente Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Biomaterials ; 35(37): 9930-9940, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25212525

RESUMEN

Methoxy PEGylated nanoparticles (mPEG-NPs) are increasingly used for cancer imaging and therapy. Here we describe a general and simple approach to confer tumor tropism to any mPEG-NP. We demonstrate this approach with humanized bispecific antibodies (BsAbs) that can bind to both mPEG molecules on mPEG-NPs and to EGFR or HER2 molecules overexpressed on the surface of cancer cells. Simple mixing of BsAbs with mPEG-NPs can mediate preferential binding of diverse mPEG-NPs to cancer cells that overexpress EGFR or HER2 under physiological conditions and significantly increase cancer cell killing by liposomal doxorubicin to EGFR(+) and HER2(+) cancer cells. BsAbs modification also enhanced accumulation of fluorescence-labeled NPs and significantly increased the anticancer activity of drug-loaded NPs to antigen-positive human tumors in a mouse model. Anti-mPEG BsAbs offer a simple one-step method to confer tumor specificity to mPEG-NPs for enhanced tumor accumulation and improved therapeutic efficacy.


Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Anticuerpos Biespecíficos , Anticuerpos Monoclonales Humanizados , Doxorrubicina/análogos & derivados , Nanopartículas , Polietilenglicoles , Animales , Antibióticos Antineoplásicos/uso terapéutico , Anticuerpos Biespecíficos/química , Anticuerpos Monoclonales Humanizados/química , Células 3T3 BALB , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Receptores ErbB/análisis , Femenino , Humanos , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Imagen Óptica , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Polietilenglicoles/uso terapéutico , Receptor ErbB-2/análisis
3.
Nucl Med Biol ; 40(8): 1035-42, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23969084

RESUMEN

OBJECTIVE: Previous studies have shown that the accumulation level of FMAU in tumor is proportional to its proliferation rate. This study demonstrated that 2'-deoxy-2'-[(18)F]fluoro-ß-d-arabinofuranosyluracil ([(18)F]FMAU) is a promising PET probe for noninvasively monitoring the therapeutic efficacy of 6% PEGylated liposomal vinorelbine (lipo-VNB) in a subcutaneous murine NG4TL4 sarcoma mouse model. METHODS: Female syngenic FVB/N mice were inoculated with NG4TL4 cells in the right flank. After tumor size reached 150 ± 50 mm(3) (day 0), lipo-VNB (5mg/kg) was intravenously administered on days 0, 3 and 6. To monitor the therapeutic efficacy of lipo-VNB, [(18)F]FMAU PET was employed to evaluate the proliferation rate of tumor, and it was compared with that observed from [(18)F]FDG/[(18)F]fluoroacetate PET. The expression of proliferating cell nuclear antigen (PCNA) in tumor during treatment was determined by semiquantitative analysis of immunohistochemical staining. RESULTS: A significant inhibition (p<0.001) in tumor growth was observed on day 3 after a single dose treatment. The tumor-to-muscle ratio (T/M) derived from [(18)F]FMAU-PET images of lipo-VNB-treated group declined from 2.33 ± 0.16 to 1.26 ± 0.03 after three doses of treatment, while that of the control remained steady. The retarded proliferation rate of lipo-VNB-treated sarcoma was confirmed by PCNA immunohistochemistry staining. However, both [(18)F]FDG and [(18)F]fluoroacetate microPET imaging did not show significant difference in T/M between the therapeutic and the control groups throughout the entire experimental period. CONCLUSION: Lipo-VNB can effectively impede the growth of NG4TL4 sarcoma. [(18)F]FMAU PET is an appropriate modality for early monitoring of the tumor response during the treatment course of lipo-VNB.


Asunto(s)
Arabinofuranosil Uracilo/análogos & derivados , Radioisótopos de Flúor , Sarcoma/diagnóstico por imagen , Sarcoma/tratamiento farmacológico , Vinblastina/análogos & derivados , Animales , Arabinofuranosil Uracilo/metabolismo , Arabinofuranosil Uracilo/farmacocinética , Transporte Biológico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Humanos , Liposomas , Ratones , Tomografía de Emisión de Positrones , Antígeno Nuclear de Célula en Proliferación/metabolismo , Sarcoma/metabolismo , Sarcoma/patología , Tomografía Computarizada de Emisión de Fotón Único , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vinblastina/farmacología , Vinblastina/uso terapéutico , Vinorelbina , Ensayos Antitumor por Modelo de Xenoinjerto
4.
PLoS One ; 8(5): e63078, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23675454

RESUMEN

PURPOSE: PEGylated liposomes are important drug carriers that can passively target tumor by enhanced permeability and retention (EPR) effect in neoplasm lesions. This study demonstrated that tumor burden determines the tumor uptake, and also the tumor response, in cancer treatment with PEGylated liposomal drugs in a C26/tk-luc colon carcinoma-bearing mouse model. METHODS: Empty PEGylated liposomes (NanoX) and those encapsulated with VNB (NanoVNB) were labeled with In-111 to obtain InNanoX and InVNBL in high labeling yield and radiochemical purity (all >90%). BALB/c mice bearing either small (58.4±8.0 mm(3)) or large (102.4±22.0 mm(3)) C26/tk-luc tumors in the right dorsal flank were intravenously administered with NanoVNB, InNanoX, InVNBL, or NanoX as a control, every 7 days for 3 times. The therapeutic efficacy was evaluated by body weight loss, tumor growth inhibition (using calipers and bioluminescence imaging) and survival fraction. The scintigraphic imaging of tumor mouse was performed during and after treatment. RESULTS: The biodistribution study of InVNBL revealed a clear inverse correlation (r (2) = 0.9336) between the tumor uptake and the tumor mass ranged from 27.6 to 623.9 mg. All three liposomal drugs showed better therapeutic efficacy in small-tumor mice than in large-tumor mice. Tumor-bearing mice treated with InVNBL (a combination drug) showed the highest tumor growth inhibition rate and survival fraction compared to those treated with NanoVNB (chemodrug only) and InNanoX (radionuclide only). Specific tumor targeting and significantly increased tumor uptake after periodical treatment with InVNBL were evidenced by scintigraphic imaging, especially in mice bearing small tumors. CONCLUSION: The significant differences in the outcomes of cancer treatment and molecular imaging between animals bearing small and large tumors revealed that tumor burden is a critical and discriminative factor in cancer therapy using PEGylated liposomal drugs.


Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Carga Tumoral/efectos de los fármacos , Vinblastina/análogos & derivados , Animales , Antineoplásicos Fitogénicos/farmacocinética , Peso Corporal , Línea Celular Tumoral , Neoplasias del Colon/mortalidad , Diagnóstico por Imagen , Modelos Animales de Enfermedad , Esquema de Medicación , Liposomas/química , Mediciones Luminiscentes , Masculino , Ratones , Polietilenglicoles/química , Tomografía Computarizada de Emisión , Vinblastina/administración & dosificación , Vinblastina/farmacocinética , Vinorelbina
5.
Invest New Drugs ; 30(1): 282-9, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20809205

RESUMEN

PURPOSE: This phase I study was performed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of an untargeted liposomal formulation of vinorelbine (NanoVNB®) and to characterize its plasma pharmacokinetics in patients with advanced solid tumors which were refractory to conventional treatment or without an effective treatment. PATIENTS & METHODS: The study incorporated an accelerated titration design. Twenty-two patients with various solid tumors were enrolled. NanoVNB(®) was administered intravenously at doses of 2.2-23 mg/m(2) once every 14 days. Pharmacokinetic endpoints were evaluated in the first cycle. The safety profiles and anti-tumor effects of NanoVNB® were also determined. RESULTS: Skin rash was the DLT and the most common non-hematological toxicity. The MTD was 18.5 mg/m(2). Drug-related grade 3-4 hematological toxicities were infrequent. Compared with intravenous free vinorelbine, NanoVNB® showed a high C(max) and low plasma clearance. Of the 11 patients completing at least 1 post-treatment tumor assessment, 5 had stable disease. No responders were noted. CONCLUSION: NanoVNB® was well tolerated and exhibited more favorable pharmacokinetic profiles than free vinorelbine. Based on dose-limiting skin toxicity, further evaluation of NanoVNB® starting from 18.5 mg/m(2) as a single agent or in combination with other chemotherapeutic agents for vinorelbine-active malignancies is warranted.


Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Neoplasias/tratamiento farmacológico , Vinblastina/análogos & derivados , Adulto , Anciano , Análisis de Varianza , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/sangre , Área Bajo la Curva , Femenino , Semivida , Humanos , Infusiones Intravenosas , Liposomas , Masculino , Dosis Máxima Tolerada , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neoplasias/patología , Taiwán , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vinblastina/efectos adversos , Vinblastina/sangre , Vinblastina/farmacocinética , Vinorelbina
6.
Cancer Biother Radiopharm ; 26(3): 373-80, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21711113

RESUMEN

PEGylated liposomes are important drug carriers for nanomedicine cancer therapy. PEGylated liposomes can encapsulate radio- and chemo-drugs and passively target tumor sites via enhanced permeability and retention effect. This study estimated the pharmacokinetics and dosimetry after administration of radio-chemotherapeutics ((111)In-labeled vinorelbine [VNB]-encapsulated liposomes, InVNBL, and (188)Re-labeled doxorubicin [DXR]-encapsulated liposomes, ReDXRL) for radionuclide therapy in two colon carcinoma-bearing mouse models. A C26 colon carcinoma tumor/ascites mouse model and a subcutaneous solid tumor-bearing mouse model were employed. Biodistribution studies of InVNBL and ReDXRL after intraperitoneal administration in tumor/ascites-bearing mice (protocol A) and intravenous administration in subcutaneous solid tumor-bearing mice (protocol B) were performed. The radiation dose to normal tissues and tumors were calculated based on the results of distribution studies in mice, using the OLINDA/EXM program. The cumulated activities in most organs after administration of InVNBL in either the tumor/ascites-bearing mice (protocol A) or the subcutaneous solid tumor-bearing mice (protocol B) were higher than those of ReDXRL. Higher tumor-to-normal-tissues absorption dose ratios (T/NTs) were observed after administration of InVNBL than those of ReDXRL for protocol A. The T/NTs for the liver, spleen, and red marrow after injection of InVNBL for protocol B were similar to those of ReDXRL. The critical organ was found to be red marrow, and thus the red marrow absorption dose defined the recommended maximum administration activity of these liposomal drugs. Characterization of pharmacokinetics and dosimetry is needed to select the appropriate radiotherapeutics for specific tumor treatment applications. The results suggest that InVNBL is a promising therapeutic agent, which is as good as ReDXRL, in two mouse tumor models.


Asunto(s)
Neoplasias del Colon/radioterapia , Radioisótopos de Indio/farmacología , Polietilenglicoles/química , Radioisótopos/farmacología , Radiometría/métodos , Renio/farmacología , Animales , Línea Celular Tumoral , Humanos , Infusiones Parenterales , Masculino , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Distribución Tisular
7.
J Nucl Med ; 50(12): 2073-81, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19949027

RESUMEN

UNLABELLED: In our previous studies using combined radioisotopes with chemotherapeutic liposomal drugs (i.e., (111)In-labeled polyethylene glycol (PEG)ylated liposomal vinorelbine) we have reported possible therapeutic efficiency in tumor growth suppression. Nevertheless, the challenge remains as to whether this chemotherapy has a therapeutic effect as good as that of combination therapy. The goal of this study was to investigate the real therapeutic effectiveness of 6 mol% PEG (111)In-vinorelbine liposomes via the elevation of the radiation dosage and reduction in the concentration of chemotherapeutic agents. METHODS: Murine colon carcinoma cells transfected with dual-reporter genes (CT-26/tk-luc) were xenografted into BALB/c mice. The biodistribution was estimated to determine the drug profile and targeting efficiency of (111)In-vinorelbine liposomes. Bioluminescence imaging and (18)F-FDG small-animal PET were applied to monitor the therapeutic response after drug administration. The survival in vivo was estimated and linked with the toxicologic and histopathologic analyses to determine the preclinical safety and feasibility of the nanomedicine. RESULTS: Effective long-term circulation of radioactivity in the plasma was achieved by 6 mol% PEG (111)In-vinorelbine liposomes, and this dose showed significantly lower uptake in the reticuloendothelial system than that of 0.9 mol% PEG (111)In-vinorelbine liposomes. Selective tumor uptake was represented by cumulative deposition, and the maximum accumulation was at 48 h after injection. The combination therapy exhibited an additive effect for tumor growth suppression as tracked by caliper measurement, bioluminescence imaging, and small-animal PET. Furthermore, an improved survival rate and reduced tissue toxicity were closely correlated with the toxicologic and histopathologic results. CONCLUSION: The results demonstrated that the use of 6 mol% PEG (111)In-vinorelbine liposomes for passively targeted tumor therapy displayed an additive effect with combined therapy, not only by prolonging the circulation rate because of a reduction in the phagocytic effect of the reticuloendothelial system but also by enhancing tumor uptake. Thus, this preclinical study suggests that 6 mol% PEG (111)In-vinorelbine liposomes have the potential to increase the therapeutic index and reduce the toxicity of the passively nanotargeted chemoradiotherapies.


Asunto(s)
Neoplasias del Colon/radioterapia , Radioisótopos de Indio/química , Polietilenglicoles/química , Vinblastina/análogos & derivados , Animales , Peso Corporal/efectos de los fármacos , Línea Celular Tumoral , Neoplasias del Colon/diagnóstico por imagen , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Relación Dosis-Respuesta a Droga , Fluorodesoxiglucosa F18 , Marcaje Isotópico , Liposomas , Mediciones Luminiscentes , Ratones , Ratones Endogámicos BALB C , Imagen Molecular , Tomografía de Emisión de Positrones , Dosis de Radiación , Tasa de Supervivencia , Distribución Tisular , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vinblastina/farmacología , Vinblastina/uso terapéutico , Vinorelbina
8.
Cancer Biother Radiopharm ; 24(4): 453-60, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19694580

RESUMEN

Nanoliposomes are important drug carriers that can passively target tumor sites by the enhanced permeability and retention (EPR) effect in neoplasm lesions. This study evaluated the biodistribution and pharmacokinetics of 111In-labeled vinorelbine (VNB)-encapsulated PEGylated liposomes (IVNBPL) after intraperitoneal (i.p.) and intravenous (i.v.) administration in a C26/tk-luc colon carcinoma ascites mouse model. IVNBPL was prepared by labeling VNB-encapsulated PEGylated liposomes with 111In-oxine. BALB/c mice were i.p. inoculated with 2 x 10(5) C26/tk-luc cells in 500 muL of phosphate-buffered saline. Peritoneal tumor lesions were confirmed by 124I-FIAU/micro-PET (positron emission tomography) and bioluminescence imaging. Ascites production was examined by ultrasound imaging on day 10 after tumor cell inoculation. The pharmacokinetics and biodistribution studies of IVNBPL in a tumor/ascites mouse model were conducted. The labeling efficiency was more than 90%. The in vitro stability in human plasma at 37 degrees C for 72 hours was 83% +/- 3.5%. For i.p. administration, the areas under curves (AUCs) of ascites and tumor were 6.78- and 1.70-fold higher, whereas the AUCs of normal tissues were lower than those via the i.v. route. This study demonstrates that i.p. administration is a better approach than i.v. injection for IVNBPL, when applied to the treatment of i.p. malignant disease in a tumor/ascites mouse model.


Asunto(s)
Neoplasias del Colon/diagnóstico por imagen , Neoplasias del Colon/metabolismo , Radioisótopos de Indio , Vinblastina/análogos & derivados , Animales , Ascitis/diagnóstico por imagen , Ascitis/metabolismo , Neoplasias del Colon/patología , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos , Humanos , Radioisótopos de Indio/farmacocinética , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Liposomas/administración & dosificación , Liposomas/farmacocinética , Masculino , Ratones , Ratones Endogámicos BALB C , Nanopartículas/administración & dosificación , Neoplasias Peritoneales/diagnóstico por imagen , Neoplasias Peritoneales/metabolismo , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , Tomografía de Emisión de Positrones , Distribución Tisular , Vinblastina/administración & dosificación , Vinblastina/farmacocinética , Vinorelbina
9.
Anticancer Res ; 29(6): 2111-20, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19528471

RESUMEN

Liposomes modified with a high concentration of polyethylene glycol (PEG) could significantly prolong the retention time of the carried drug in the circulation, thus improving the drug accumulation in the tumor. In this study, 6 mol% rather than 0.9 mol% PEGylated liposomes (100 nm in diameter) encapsulated with indium-111 were used in a human colorectal carcinoma HT-29/luc tumor-bearing mouse model for comparing the PEGylation effect. Pharmacokinetics, biodistribution, passive-targeted assay, bioluminescence imaging (BLI) and tumor growth measurements were used for the spatial and temporal distribution, tumor localization and therapeutic evaluation of the drug. Pharmacokinetic studies indicated that the terminal half-life (T((1/2))lambdaz) and C(max) of 6 mol% PEG (111)In liposomes were similar to those of 0.9 mol% PEG (111)In liposomes. In the blood, the total body clearance (Cl) of 6 mol% PEG (111)In liposomes was about 1.7-fold lower and the area under the curve (AUC) was 1.7-fold higher than those of 0.9 mol% PEG (111)In liposomes. These results showed that the long-term circulation and localization of 6 mol% PEGylated liposomes was more appropriate for use in the tumor-bearing animal model. In addition, the biodistribution of 6 mol% PEG (111)In liposomes showed significantly lower uptake in the liver, spleen, kidneys, small intestine and bone marrow than those of 0.9 mol% PEG (111)In liposomes. The clearance rate of both drugs from the blood decreased with time, with the maximum at 24 h post intravenous (i.v.) injection. Prominent tumor uptake and the highest tumor/muscle ratios were found at 48 h post injection. Both AUC and relative ratio of the AUCs (RR-AUC) also showed that 6 mol% PEGylated liposomes significantly reduced the uptake of drugs in the reticuloendothelial system (RES), yet enhanced the uptake in the tumor. Gamma scintigraphy at 48 h post injection also demonstrated more distinct tumor uptake with 6 mol% PEG (111)In liposomes as compared to that of 0.9 mol% PEGylated liposomes (p<0.01). BLI and in vivo tumor growth tracing showed that growth in tumor volume could largely be inhibited by 6 mol% PEG (111)In liposomes. The results suggest that 6 mol% PEGylated liposomes might be a more suitable liposomal carrier for drug delivery than 0.9 mol% PEGylated liposomes, not only by reducing the drug accumulation in the RES or its related organs, but by prolonging drug circulation and eventually enhancing the targeting efficiency in the tumor to reach a better therapeutic index.


Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Neoplasias Colorrectales/tratamiento farmacológico , Modelos Animales de Enfermedad , Luciferasas/metabolismo , Polietilenglicoles/farmacocinética , Vinblastina/análogos & derivados , Animales , Antineoplásicos Fitogénicos/farmacología , Humanos , Radioisótopos de Indio , Liposomas , Luciferasas/genética , Luminiscencia , Ratones , Ratones Endogámicos NOD , Ratones SCID , Radiofármacos , Distribución Tisular , Células Tumorales Cultivadas/trasplante , Vinblastina/farmacocinética , Vinblastina/farmacología , Vinorelbina
10.
J Pharmacol Exp Ther ; 328(1): 321-30, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18948499

RESUMEN

Effective liposomal formulations of vinorelbine (5' nor-anhydro-vinblastine; VRL) have been elusive due to vinorelbine's hydrophobic structure and resulting difficulty in stabilizing the drug inside the nanocarrier. Triethylammonium salts of several polyanionic trapping agents were used initially to prepare minimally pegylated nanoliposomal vinorelbine formulations with a wide range of drug release rates. Sulfate, poly(phosphate), and sucrose octasulfate were used to stabilize vinorelbine intraliposomally while in circulation, with varying degrees of effectiveness. The release rate of vinorelbine from the liposomal carrier was affected by both the chemical nature of the trapping agent and the resulting drug-to-lipid ratio, with liposomes prepared using sucrose octasulfate displaying the longest half-life in circulation (9.4 h) and in vivo retention in the nanoparticle (t(1/2) = 27.2 h). Efficacy was considerably improved in both a human colon carcinoma (HT-29) and a murine (C-26) colon carcinoma model when vinorelbine was stably encapsulated in liposomes using triethylammonium sucrose octasulfate. Early difficulties in preparing highly pegylated formulations were later overcome by substituting a neutral distearoylglycerol anchor for the more commonly used anionic distearoylphosphatidylethanolamine anchor. The new pegylated nanoliposomal vinorelbine displayed high encapsulation efficiency and in vivo drug retention, and it was highly active against human breast and lung tumor xenografts. Acute toxicity of the drug in immunocompetent mice slightly decreased upon encapsulation in liposomes, with a maximum tolerated dose of 17.5 mg VRL/kg for free vinorelbine and 23.8 mg VRL/kg for nanoliposomal vinorelbine. Our results demonstrate that a highly active, stable, and long-circulating liposomal vinorelbine can be prepared and warrants further study in the treatment of cancer.


Asunto(s)
Vinblastina/análogos & derivados , Portadores de Fármacos , Estabilidad de Medicamentos , Humanos , Liposomas , Nanopartículas , Fosfolípidos/sangre , Tritio , Vinblastina/química , Vinblastina/farmacocinética , Vinorelbina
11.
Nucl Med Biol ; 35(5): 623-34, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18589307

RESUMEN

Colorectal carcinoma is a highly prevalent and common cause of cancer in Taiwan. There is still no available cure for this malignant disease. To address this issue, we applied the multimodality of molecular imaging to explore the efficacy of diagnostic and therapeutic nanoradiopharmaceuticals in an animal model of human colorectal adenocarcinoma [colorectal cancer (CRC)] that stably expresses luciferase (luc) as a reporter. In this study, an in vivo therapeutic efficacy evaluation of dual-nanoliposome (100 nm in diameter) encaged vinorelbine (VNB) and (111)In-oxine on HT-29/luc mouse xenografts was carried out. HT-29/luc tumor cells were transplanted subcutaneously into male SCID mice. Multimodality of molecular imaging approaches including bioluminescence imaging (BLI), gamma scintigraphy, whole-body autoradiography (WBAR) and in vivo tumor growth tracing, histopathology and biochemistry/hematology analyses were applied on xenografted SCID mice to study the treatments with 6% polyethylene glycol (PEG) of (111)In-NanoX/VNB-liposomes. In vivo tumor growth tracing and BLI showed that tumor volume could be completely inhibited by the combination therapy with (111)In-VNB-liposomes and by chemotherapy with NanoX/VNB-liposomes (i.e., without Indium-111) (P<.01). The nuclear medicine images of gamma scintigraphy and WBAR also revealed the conspicuous inhibition of tumor growth by the combination therapy with (111)In-VNB-liposomes. Animal body weights, histopathology and biochemistry/hematology analyses were used to confirm the safety and feasibility of radiopharmaceuticals. A synergistic therapeutic effect on CRC xenografted SCID mice was proven by combining an Auger electron-emitting radioisotope (Indium-111) with an anticancer drug (VNB). This study further demonstrates the beneficial potential applications of multimodality molecular imaging as part of the diagnostic and therapeutic approaches available for the evaluation of new drugs and other strategic approaches to disease treatment.


Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Radiofármacos/uso terapéutico , Vinblastina/análogos & derivados , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Autorradiografía , Proliferación Celular/efectos de los fármacos , Composición de Medicamentos , Genes Reporteros , Células HT29 , Humanos , Radioisótopos de Indio/administración & dosificación , Radioisótopos de Indio/uso terapéutico , Liposomas , Luciferasas/genética , Luminiscencia , Masculino , Ratones , Ratones SCID , Trasplante de Neoplasias , Fotones , Radiofármacos/administración & dosificación , Distribución Tisular , Vinblastina/administración & dosificación , Vinblastina/uso terapéutico , Vinorelbina
12.
Cancer Res ; 64(21): 8002-8, 2004 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-15520208

RESUMEN

Nasopharyngeal carcinoma (NPC) is a common cancer among Chinese living in southern China, Taiwan, and Singapore. The 5-year survival rate in the early stage of NPC has been reported as high as 90 to 95% with the use of radiotherapy, but in the advanced cases, even with the use of both chemotherapy and radiotherapy, the survival rate is still <50%. To improve the survival rate, we identify a 12-mer peptide (L-peptide) specifically binding to NPC cells with a phage displayed random peptide library. The L-phage and synthetic L-peptide bound to the tumor cell surfaces of most NPC cell lines and biopsy specimens, but not normal nasal mucosal cells, and the L-peptide-linked liposomes containing fluorescent substance (L-peptide-Lipo-HPTS) were capable of binding to and translocating across plasma membranes. L-Peptide-linked liposomes that carried doxorubicin (L-peptide-Lipo-Dox) caused marked cytotoxicity in NPC cells. In SCID mice bearing NPC xenografts, the L-phages specifically bound to the tumor mass, an effect that was inhibited by competition with synthetic L-peptide. In addition, the L-peptide-Lipo-Dox suppressed tumor growth better than Lipo-Dox. These results indicate that the novel L-peptide specifically binds NPC cells and is a good candidate for targeted drug delivery to NPC solid tumors.


Asunto(s)
Doxorrubicina/administración & dosificación , Neoplasias Nasofaríngeas/tratamiento farmacológico , Péptidos/administración & dosificación , Animales , Sitios de Unión , Endocitosis , Liposomas , Ratones , Ratones SCID , Trasplante de Neoplasias , Biblioteca de Péptidos , Péptidos/metabolismo , Trasplante Heterólogo
13.
Cancer Chemother Pharmacol ; 51(5): 433-8, 2003 May.
Artículo en Inglés | MEDLINE | ID: mdl-12736762

RESUMEN

PURPOSE: Chemotherapy of advanced hepatocellular carcinoma (HCC) is frequently limited by unacceptable toxicity. Long-circulating polyethylene glycol-coated (PEGylated) liposomal doxorubicin (PLD) has low systemic toxicity. Its safety and efficacy in patients with advanced HCC and the relationship between hepatic function and pharmacokinetics were investigated in this phase II study. METHODS: Patients were given 30 mg/m(2) PLD every 3 weeks and the dose was escalated to 45 mg/m(2) from the third course if the toxicity was deemed tolerable. The plasma level of doxorubicin was determined with fluorometry. RESULTS: A total of 40 patients were recruited into this phase II study. The toxicities were usually mild but unexpectedly, three cirrhotic patients died of infection without neutropenia. Four had a partial response (response rate 10%, confidence interval 0-20%). The median duration of response was 5.6 months. The median time to tumor progression and the median survival of all patients was only 2 and 3 months, respectively. Patients with advanced HCC had lower initial serum concentration, larger volume of distribution and more rapid clearance than patients with other malignancies and normal liver function. However, the pharmacokinetic parameters correlated with neither toxicity nor response. CONCLUSIONS: The disposition of PLD in patients with liver dysfunction was not hampered, but it did not exhibit higher activity compared with free drug, and the risk of infection must be watched closely especially in patients with liver cirrhosis.


Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/tratamiento farmacológico , Doxorrubicina/farmacología , Doxorrubicina/farmacocinética , Neoplasias Hepáticas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/patología , Doxorrubicina/administración & dosificación , Femenino , Humanos , Infusiones Intravenosas , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Sobrevida , Distribución Tisular , Resultado del Tratamiento
14.
J Biomed Sci ; 10(3): 337-44, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12711861

RESUMEN

Cationic liposome-mediated gene delivery to tumors has met with only limited success due to the low transfection efficiency and lack of target specificity. We developed a gene delivery system for HER-2-overexpressing cells by adding modified anti-HER-2 Fab' fragments to liposome/DNA complexes (lipoplexes). The modified anti-HER-2-Fab' was conjugated to liposomes containing cationic lipids such as 1,2-dioleoyl-3-(trimethylammonium) propane and cholesterol (1:1 w/w) using a maleimido-polyethyleneglycol-3400-1,2-dioleoyl-3-sn-phosphatidylethanolamine linker. The specific modification constricted the sizes of these immunolipoplexes to a range of 0.3- 0.7 microm, and they remained stable for a longer duration of time compared to the lipoplex controls (0.8-3.2 microm at 4 h). In addition, a 10-fold increase in luciferase activity was achieved after transfecting human breast cancer SK-BR3 cells with immunolipoplexes as compared to the control lipoplexes. Flow cytometry analysis demonstrated that 80% of SK-BR3 cells expressed the green fluorescent protein (GFP) 48 h after being transfected with immunolipoplexes, while only 40% of those with control lipoplexes and 3% of those with naked DNA alone expressed GFP. Furthermore, the anti-HER-2 immunolipoplexes showed specific enhancement of transfection efficiency in HER-2-overexpressing SK-BR3 cells (a 6-fold increase in luciferase activity) but not in HER-2-negative MCF-7 breast cancer cells. The enhancement of gene delivery by anti-HER-2 immunoliposomes was not affected by the presence of serum. These results demonstrate the feasibility of improving target-specific gene delivery to HER-2-overexpressing cells by insertion of lipid-modified anti-HER-2-Fab' into the preformed liposomes.


Asunto(s)
Anticuerpos Antineoplásicos/genética , Marcación de Gen/métodos , Receptor ErbB-2/genética , Receptor ErbB-2/fisiología , Línea Celular Tumoral , Citometría de Flujo , Humanos , Liposomas , Transfección
15.
Mol Pharmacol ; 62(4): 864-72, 2002 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12237333

RESUMEN

Unlike conventional liposomes, sterically stabilized liposomes, with their smaller volume of distribution and reduced clearance, preferentially convey encapsulated drugs into tumor sites. Despite these improvements, intracellular delivery is hampered by the stable drug retention of the liposomes, which diminishes the efficacy of the liposomal drug. To facilitate uptake of liposomal drugs into cells, two cell-penetrating peptides, penetratin (PEN) and TAT, derived from the HIV-1 TAT protein, were studied. In contrast to control peptides, both TAT and PEN enhanced the translocation efficiency of liposomes in proportion to the number of peptides attached to the liposomal surface. A peptide number of as few as five could enhance the intracellular delivery of liposomes. The kinetics of uptake was peptide- and cell-type dependent. Intracellular accumulation of TAT-liposomes increased with incubation time, but PEN-liposomes peaked at 1 h and then declined gradually. After treatment with 1 microg/ml doxorubicin equivalents of liposome for 2 h, TAT increased the doxorubicin uptake of A431 cells by 12-fold. However, the improvement of uptake of liposomal doxorubicin was not reflected by cytotoxicity in vitro or tumor control in vivo. Our results demonstrated that merely adding CPP to a liposome encapsulating anticancer drug was inadequate in improving its antitumor activity. An additional approach to enhance the intracellular release of the encapsulated drug is obviously necessary.


Asunto(s)
Proteínas Portadoras/administración & dosificación , Transformación Celular Neoplásica/efectos de los fármacos , Productos del Gen tat/administración & dosificación , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacología , Transporte Biológico , Proteínas Portadoras/farmacología , Péptidos de Penetración Celular , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Portadores de Fármacos , Endocitosis/fisiología , Productos del Gen tat/farmacología , Humanos , Cinética , Liposomas , Masculino , Ratones , Ratones Endogámicos BALB C , Células Tumorales Cultivadas
16.
Anticancer Drugs ; 13(7): 709-17, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12187327

RESUMEN

Topotecan (TPT), a topoisomerase I inhibitor, is presently undergoing clinical evaluation worldwide. Previous studies have shown that entrapping TPT within multi-lamellar vesicle liposome can stabilize the lactone moiety, which is structurally important for biological activity. However, low drug:lipid ratios due to the amphipathic character and small entrapment volume in the unilamellar vesicle limits the development of pharmaceutically acceptable liposomal formulation. With an aim to improve on this drawback, we herein describe a method that utilizes the ammonium sulfate gradient to entrap TPT into liposomes. By this method, the encapsulation efficiency was over 90% and a drug:lipid molar ratio as high as 1:5.4 was reached. In comparison with free drug, liposome-encapsulated TPT is more stable in physiological conditions and shows higher in vitro cytotoxicity. Because of increased blood circulation time, the initial plasma concentration and area under the plasma concentration of liposomal drugs were 14 and 40 times, respectively, of those of free drug. Furthermore, liposome encapsulation enhanced the antitumor activity of TPT in syngeneic murine C-26 and human HTB-9 xenograft models in vivo. At a dose of 5 mg/kg, the tumor growth delay of liposomal formulation was significantly than that of free TPT. Based on these results, we believe that this liposomal TPT formulation is worthy of further clinical study.


Asunto(s)
Antineoplásicos/administración & dosificación , Composición de Medicamentos/métodos , Topotecan/administración & dosificación , Algoritmos , Sulfato de Amonio/química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Portadores de Fármacos , Estabilidad de Medicamentos , Humanos , Indicadores y Reactivos , Lactonas/química , Liposomas , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Topotecan/farmacocinética , Topotecan/uso terapéutico , Células Tumorales Cultivadas
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