RESUMEN
Mucin, a glycosylated protein, is aberrantly overexpressed in a variety of tumor cells. The glycoprotein mesh decreases the rate of intracellular drug uptake and effectiveness. We investigated the influence of the mucin mesh on the cellular uptake of anti-MUC1 antibody and nanoparticles by fluorescence spectroscopy and microscopy. A glycosylation inhibitor (benzyl-α-GalNAc) was employed to regulate mucin glycosylation events. In our panel of pancreatic cell lines, only PANC-1 cells exhibited a significant increase in the uptake of liposomes following glycosylation inhibition, resulting in improved cytotoxicity of gemcitabine-loaded liposomes. Interestingly, areas devoid of liposome uptake were observed for pancreatic cancer cell lines PANC-1, Capan-1, and Capan-2; however, these restricted regions could be diminished for PANC1 cells only. In conclusion, investigating the reason(s) for differential cellular uptake of nanoparticles, in association with the production of mucin glycosylation mesh, should provide valuable leads to the future development of nanomedicine for cancer treatment.
Asunto(s)
Mucinas/fisiología , Nanopartículas , Neoplasias Pancreáticas/tratamiento farmacológico , Antígenos de Neoplasias/administración & dosificación , Humanos , Mucina-1RESUMEN
The ideal siRNA delivery system should selectively deliver the construct to the target cell, avoid enzymatic degradation, and evade uptake by phagocytes. In the present study, we evaluated the importance of polyethylene glycol (PEG) on lipid-based carrier systems for encapsulating, and delivering, siRNA to tumor vessels using cellular models. Lipid nanoparticles containing different percentage of PEG were evaluated based on their physical chemical properties, density compared to water, siRNA encapsulation, toxicity, targeting efficiency and gene silencing in vitro. siRNA can be efficiently loaded into lipid nanoparticles (LNPs) when DOTAP is included in the formulation mixture. However, the total amount encapsulated decreased with increase in PEG content. In the presence of siRNA, the final formulations contained a mixed population of particles based on density. The major population which contains the majority of siRNA exhibited a density of 4% glucose, and the minor fraction associated with a decreased amount of siRNA had a density less than PBS. The inclusion of 10 mol% PEG resulted in a greater amount of siRNA associated with the minor fraction. Finally, when kinesin spindle protein (KSP) siRNA was encapsulated in lipid nanoparticles containing a modest amount of PEG, the proliferation of endothelial cells was inhibited due to the efficient knock down of KSP mRNA. The presence of siRNA resulted in the formation of solid lipid nanoparticles when prepared using the thin film and hydration method. LNPs with a relatively modest amount of PEG can sufficiently encapsulate siRNA, improve cellular uptake and the efficiency of gene silencing.
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Células Endoteliales/fisiología , Marcación de Gen/métodos , Cinesinas/genética , Nanocápsulas/química , Fosfolípidos/química , ARN Interferente Pequeño/genética , Transfección/métodos , Animales , Línea Celular , Proliferación Celular , Humanos , Ratones , ARN Interferente Pequeño/administración & dosificaciónRESUMEN
Chronic myeloid leukemia (CML) is a blood cancer predominantly affecting older adult patients. According to the American Cancer Society, an estimated 8,860 people will be diagnosed with CML in 2022. Treatments for CML have evolved with a focus on CML phase severity or progression. Overall, there have been some breakthrough treatment options for a high percentage of patients with CML. This is largely due to the discovery of tyrosine kinase inhibitors (TKI); however, drug resistance continues to present a significant challenge in the management of CML disease. The use of interferon (IFN), antimetabolites, and bone marrow transplants provides alternative treatment options, but also presents limitations, including severe side effects, toxicity, and graft versus host disease. Nanomedicine has demonstrated benefits in terms of efficacy, often reducing or eliminating unwanted toxicities associated with the use of conventional drug agents. This review summarizes rational molecular targets of CML drugs and provides highlights of current FDA-approved agents for the treatment of CML. Additionally, this communication includes an overview of the limitations of conventional treatments and how nanomedicine has addressed challenges encountered during CML treatment.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Anciano , Sistemas de Liberación de Medicamentos , Resistencia a Antineoplásicos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
Acute lymphoblastic leukemia (ALL) is a common form of pediatric cancer affecting the lymphoblast, a type of white blood cell found in the bone marrow. In this disease, the normal lymphoblast cells transform into leukemic cells and subsequently enter the bloodstream. Leukemic cells found in patients with ALL have shown differences in cholesterol uptake and utilization. Current treatment consists of chemotherapy, chimeric antigen receptor (CAR) therapy, and hematopoietic stem cell transplantation (HSCT). In addition, minimal residual disease (MRD) has become an effective tool in measuring treatment efficacy and the potential for relapse. Chemotherapy resistance remains a significant barrier in the treatment of ALL. Biomarkers such as an upregulated Akt signaling pathway and an overexpressed VLA-4 integrin-protein have been associated with drug resistance. Nanoparticles have been used to favorably alter the pharmacokinetic profile of conventional drug agents. These drug-delivery systems are designed to selectively deliver their drug payloads to desired targets. Therefore, nanoparticles offer advantages such as improved efficacy and reduced toxicity. This review highlights conventional treatment options, distinctive characteristics of pediatric ALL, therapeutic challenges encountered during therapy, and the key role that nanotherapeutics play in the treatment of ALL.
RESUMEN
Acute lymphoblastic leukemia (ALL) is a common form of pediatric cancer affecting the lymphoblast, a type of white blood cell found in the bone marrow. In this disease, the normal lymphoblast cells transform into leukemic cells and subsequently enter the bloodstream. Leukemic cells found in patients with ALL have shown differences in cholesterol uptake and utilization. Current treatment consists of chemotherapy, chimeric antigen receptor (CAR) therapy, and hematopoietic stem cell transplantation (HSCT). In addition, minimal residual disease (MRD) has become an effective tool for measuring treatment efficacy and the potential for relapse. Chemotherapy resistance remains a significant barrier in the treatment of ALL. Biomarkers such as an upregulated Akt signaling pathway and an overexpressed VLA-4 integrin-protein have been associated with drug resistance. Nanoparticles have been used to favorably alter the pharmacokinetic profile of conventional drug agents. These drug-delivery systems are designed to selectively deliver their drug payloads to desired targets. Therefore, nanoparticles offer advantages such as improved efficacy and reduced toxicity. This review highlights conventional treatment options, distinctive characteristics of pediatric ALL, therapeutic challenges encountered during therapy, and the key role that nanotherapeutics play in the treatment of ALL.
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Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores Quiméricos de Antígenos , Niño , Colesterol/uso terapéutico , Humanos , Integrina alfa4beta1/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt , Receptores Quiméricos de Antígenos/uso terapéuticoRESUMEN
Transport parameters determine the access of drugs to tumors. However, technical difficulties preclude the measurement of these parameters deep inside living tissues. To this end, we adapted and further optimized two-photon fluorescence correlation microscopy (TPFCM) for in vivo measurement of transport parameters in tumors. TPFCM extends the detectable range of diffusion coefficients in tumors by one order of magnitude, and reveals both a fast and a slow component of diffusion. The ratio of these two components depends on molecular size and can be altered in vivo with hyaluronidase and collagenase. These studies indicate that TPFCM is a promising tool to dissect the barriers to drug delivery in tumors.
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Microscopía Fluorescente/métodos , Neoplasias/metabolismo , Animales , Transporte Biológico , Difusión , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Colorantes Fluorescentes/metabolismo , Humanos , Ratones , Neoplasias/patologíaRESUMEN
Evaporation of streams of liquid droplets in environments at vacuum pressures below the vapor pressure has not been widely studied. Here, experiments and simulations are reported that quantify the change in droplet diameter when a steady stream of ≈100 µm diameter drops is injected into a chamber initially evacuated to <10^{-8}bar. In experiments, droplets fall through the center of a 0.8 m long liquid nitrogen cooled shroud, simulating infinity radiation and vapor mass flux boundary conditions. Experimentally measured changes in drop diameters vary from ≈0 to 6 µm when the initial vapor pressure is increased from 10^{-6} to 10^{-3} bar by heating the liquid. Measured diameter changes are predicted by a model based on the Hertz-Knudsen equation. One uncertainty in the calculation is the "sticking coefficient" ß. Assuming a constant ß for all conditions studied here, predicted diameter changes best match measurements with ß≈0.3. This value falls within the range of ß reported in the literature for organic liquids. Finally, at the higher vapor pressure conditions considered here, the drop stream disperses transverse to the main flow direction. This spread is attributed to forces imparted by an absolute pressure gradient produced by the evaporating stream.
RESUMEN
The use of magnetic drug targeting (MDT) to selectively deliver chemotherapeutic drugs to tumor cells is a widely investigated approach; however, the notion of targeting tumor endothelial cells by this method is a fairly new concept. Positively-charged (cationic) liposomes have an extraordinarily high affinity for tumor vessels, but heterogeneous targeting is frequently observed. In order to improve on the overall efficiency of targeting tumor vessels, we investigated the use of an externally applied magnetic field together with magnetic cationic liposomes (MCLs) for cancer treatment. We examined the antitumor effect of the chemotherapeutic agent vinblastine loaded in MCLs, using a murine model of melanoma. Two hours following i.v. administration of MCLs, we observed significant tumor vascular uptake with use of an external magnet (15.9 +/- 6.3%) compared to no magnet (5 +/- 1.3%). The administration of vinblastine-loaded MCLs with the magnet produced a significant antitumor effect, reducing the presence of tumor nodules in preferential sites of metastasis compared to untreated and free drug control groups. CD31 immunostaining revealed a decrease in the general length of tumor blood vessels, altered vascular morphology and interruptions in the tumor vascular lining for the vinblastine-loaded MCL groups. Drug-loaded MCLs with magnetic fields may represent a promising combination approach for cancer treatment.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Magnetismo , Metástasis de la Neoplasia/prevención & control , Neovascularización Patológica/tratamiento farmacológico , Vinblastina/farmacología , Animales , Cationes/farmacología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos/métodos , Femenino , Inmunohistoquímica , Liposomas/farmacología , Melanoma Experimental/irrigación sanguínea , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Melanoma Experimental/ultraestructura , Ratones , Ratones SCID , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Neoplasias/ultraestructura , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Factores de Tiempo , Carga TumoralRESUMEN
Cationic liposomes preferentially target tumor vasculature compared to vessels in normal tissues. The distribution of cationic liposomes along vascular networks is, however, patchy and heterogeneous. To target vessels more uniformly we combined the electrostatic properties of cationic liposomes with the strength of an external magnet. We report part I of development. We evaluated bilayer physical properties of our preparations. We investigated interaction of liposomes with target cells including the role of PEG (polyethylene-glycol), and determined whether magnetic cationic liposomes can respond to an external magnetic field. The inclusion of relatively high concentration of MAG-C (magnetite) at 2.5 mg/ml significantly increased the size of cationic liposomes from 105+/-26.64 to 267+/-27.43 nm and reduced the zeta potential from 64.55+/-16.68 to 39.82+/-5.26 mv. The phase transition temperature of cationic liposomes (49.97+/-1.34 degrees C) reduced with inclusion of MAG-C (46.05+/-0.21 degrees C). MAG-C cationic liposomes were internalized by melanoma (B16-F10 and HTB-72) and dermal endothelial (HMVEC-d) cells. PEG partially shielded cationic charge potential of MAG-C cationic liposomes, reduced their ability to interact with target cells in vitro, and uptake by major RES organs. Finally, application of external magnet enhanced tumor retention of magnetic cationic liposomes.
Asunto(s)
Liposomas/farmacología , Magnetismo , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Animales , Cationes , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Fenómenos Químicos , Química Física , Dermis/citología , Relación Dosis-Respuesta a Droga , Endotelio Vascular/citología , Humanos , Inyecciones Subcutáneas , Membrana Dobles de Lípidos , Liposomas/farmacocinética , Masculino , Melanoma/patología , Melanoma Experimental/patología , Ratones , Ratones Desnudos , Polietilenglicoles/química , Distribución TisularRESUMEN
Chemotherapy is a popular treatment approach against cancer but significant uptake of drugs by normal tissues is still a major limitation. Magnetic drug targeting (MDT) has been used to improve localized drug delivery to interstitial tumor targets. MDT is now being developed to improve drug delivery to tumor vessels. We thus seek to understand the role of magnetite (MAG-C) in drug loading, influence on cytotoxicity and vascular targeting characteristics. The inclusion of MAG-C at lower concentrations (0.5 mg/ml) in cationic liposomes did not alter the efficiency of loading etoposide, but at higher concentrations (2.5 mg/ml) incorporation decreased from 80+/-3.4% to 44+/-4.26%. MAG-C reduced the incorporation of dacarbazine. The incorporation was significantly lower compared to liposomal etoposide, both in the presence and absence of MAG-C. The incorporation efficiency of vinblastine sulfate in cationic liposomes was similar for low and relatively high MAG-C content; values for incorporation were 21+/-0.11 and 23+/-2, respectively. Polyethylene-glycol improved the efficiency of loading chemotherapeutic agents regardless of drug type. Additionally, cytotoxicity and tumor vascular targeting characteristics of liposome therapeutics were not influenced by MAG-C. The components used to prepare magnetic liposomes for MDT should be optimized for maximum therapeutic benefit.
Asunto(s)
Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Etopósido/administración & dosificación , Etopósido/química , Óxido Ferrosoférrico/química , Melanoma/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Animales , Antineoplásicos/química , Línea Celular Tumoral , Química Farmacéutica/métodos , Difusión , Melanoma/patología , Ratones , Neovascularización Patológica/patologíaRESUMEN
Designing an effective nanoparticle for selective drug transport requires careful consideration of the complex biological barriers encountered in transit to the desired target. Here, we review several of these barriers, and provide possible methods for formulating liposomal nanoparticles to overcome them. The methods include the biotinylation of an antibody, and subsequent conjugation to a PEGylated cationic lipid nanoparticle. Additionally, the incorporation of drug, and other relevant characteristics of the nanoparticle are also discussed.
Asunto(s)
Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Nanopartículas , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/química , Portadores de Fármacos/química , Composición de Medicamentos , Liposomas , Nanopartículas/químicaRESUMEN
Tumor vessels possess unique physiological features that might be exploited for improving drug delivery. In the present study, we investigate the possibility of modifying polyethylene glycol-ylated liposome cationic charge of polyethylene glycol coated liposomes to optimize delivery to tumor vessels using biodistribution studies and intravital microscopy. The majority of liposomes accumulated in the liver, and increasing charge resulted in lower retention in the spleen and blood. Although overall tumor uptake was not affected by charge in the biodistribution studies, intravital microscopy showed that increasing the charge content from 10 to 50 mol % doubled the accumulation of liposomes in tumor vessels, suggesting a change in intratumor distribution; no significant effect of charge on interstitial accumulation could be detected, possibly attributable to spatial heterogeneity. Increased vascular accumulation of cationic liposomes was similar in two different tumor types and sites. Our results suggest that optimizing physicochemical properties of liposomes that exploit physiological features of tumors and control the intratumor distribution of these drug carriers should improve vascular-specific delivery.
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Adenocarcinoma/irrigación sanguínea , Neoplasias del Colon/irrigación sanguínea , Lípidos/farmacocinética , Liposomas/farmacocinética , Polietilenglicoles/farmacocinética , Adenocarcinoma/metabolismo , Animales , Cationes , Neoplasias del Colon/metabolismo , Endotelio Vascular/metabolismo , Humanos , Lípidos/química , Liposomas/química , Ratones , Ratones SCID , Microscopía Fluorescente , Polietilenglicoles/química , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The molecular site of anesthetic action remains an area of intense research interest. It is not clear whether general anesthetics act through direct binding to proteins or by perturbing the membrane properties of excitable tissues. Several studies indicate that anesthetics affect the properties of either membrane lipids or proteins. However, gaps remain in our understanding of the molecular mechanism of anesthetic action. Recent developments in membrane biology have led to the concept of small-scale domain structures in lipid and lipid--protein coupled systems. The role of such domain structures in anesthetic action has not been studied in detail. In the present study, we investigated the effect of anesthetics on lipid domain structures in model membranes using the fluorescent spectral properties of Laurdan (6-dodecanoyl-2-dimethylamino naphthalene). Propofol, a general anesthetic, promoted the formation of fluid domains in model membranes of dipalmitoyl phosphatidyl choline (DPPC) or mixtures of lipids of varying acyl chains (DPPC:DMPC dimyristoyl phosphatidyl choline 1:1). The estimated size of these domains is 20--50 A. Based on these studies, we speculate that the mechanism of anesthetic action may involve effects on protein--lipid coupled systems through alterations in small-scale lipid domain structures.
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2-Naftilamina/análogos & derivados , Anestésicos Generales/farmacología , Fluidez de la Membrana/efectos de los fármacos , Membranas Artificiales , Propofol/farmacología , 1,2-Dipalmitoilfosfatidilcolina , Dimiristoilfosfatidilcolina , Colorantes Fluorescentes , Lauratos , Liposomas , Microdominios de Membrana , Espectrometría de FluorescenciaRESUMEN
AIMS: Cationic liposomes have been shown to preferentially target the tumor vasculature, but not uniformly. Bevacizumab antibody selectively accumulates in tumors expressing VEGF. We thus developed bevacizumab-modified, pegylated cationic liposomes (PCLs) to improve the distribution of liposomes along tumor vessels, and to enhance tumor targeting. MATERIALS & METHODS: We evaluated the delivery vehicle both in the absence and presence of VEGF, using human pancreatic cancer (Capan-1, HPAF-II and PANC-1) and endothelial (MS1-VEGF and HMEC-1) cell lines. RESULTS: All cell lines except for HMEC-1 secreted VEGF. Modification of PCLs with bevacizumab did not alter zeta-potential, but increased overall liposome size. The toxicity profile for bevacizumab-modified PCLs was cell line dependent and, in general, bevacizumab improved cellular uptake and tumor targeting of PCLs. CONCLUSION: Bevacizumab-modified PCLs represent a potential improvement over the unmodified variety, supporting their future development for the treatment of cancer.
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Anticuerpos Monoclonales/farmacología , Liposomas/química , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Factor A de Crecimiento Endotelial Vascular/metabolismo , Inhibidores de la Angiogénesis/farmacología , Anticuerpos Monoclonales Humanizados , Bevacizumab , Cationes , Línea Celular Tumoral , Proliferación Celular , Separación Celular , Ensayos de Selección de Medicamentos Antitumorales , Ensayo de Inmunoadsorción Enzimática/métodos , Citometría de Flujo/métodos , Humanos , Polietilenglicoles/químicaRESUMEN
AIMS: The development of noninvasive imaging techniques for the assessment of cancer treatment is rapidly becoming highly important. The aim of the present study is to show that magnetic cationic liposomes (MCLs), incorporating superparamagnetic iron oxide nanoparticles (SPIONs), are a versatile theranostic nanoplatform for enhanced drug delivery and monitoring of cancer treatment. MATERIALS & METHODS: MCLs (with incorporated high SPION cargo) were administered to a severe combined immunodeficiency mouse with metastatic (B16-F10) melanoma grown in the right flank. Pre- and post-injection magnetic resonance (MR) images were used to assess response to magnetic targeting effects. Biodistribution studies were conducted by ¹¹¹In-labeled MCLs and the amount of radioactivity recovered was used to confirm the effect of targeting for intratumoral administrations. RESULTS: We have shown that tumor signal intensities in T2-weighted MR images decreased by an average of 20 ± 5% and T2* relaxation times decreased by 14 ± 7 ms 24 h after intravenous administration of our MCL formulation. This compares to an average decrease in tumor signal intensity of 57 ± 12% and a T2* relaxation time decrease of 27 ± 8 ms after the same time period with the aid of magnetic guidance. CONCLUSION: MR and biodistribution analysis clearly show the efficacy of MCLs as MRI contrast agents, prove the use of magnetic guidance, and demonstrate the potential of MCLs as agents for imaging, guidance and therapeutic delivery.
Asunto(s)
Imagen por Resonancia Magnética/métodos , Neoplasias/irrigación sanguínea , Neoplasias/patología , Animales , Medios de Contraste , Portadores de Fármacos , Ácidos Grasos Monoinsaturados/administración & dosificación , Compuestos Férricos , Colorantes Fluorescentes/administración & dosificación , Humanos , Inyecciones Intravenosas , Cinética , Liposomas/administración & dosificación , Liposomas/uso terapéutico , Magnetismo , Melanoma/irrigación sanguínea , Melanoma/tratamiento farmacológico , Melanoma/patología , Ratones , Ratones SCID , Nanopartículas , Metástasis de la Neoplasia , Compuestos de Amonio Cuaternario/administración & dosificación , Distribución TisularRESUMEN
The goal of this research was to evaluate the effectiveness of cationic liposomes for intranasal administration of proteins to the brain. Cationic liposomes were loaded with a model protein, ovalbumin (OVAL), and a 50 microg dose was administered intranasally to rats. In qualitative studies, liposomes were loaded with Alexa 488-OVAL and delivery was assessed by fluorescence microscopy. By 6 and 24 h after administration, Alexa 488-OVAL deposits were widely distributed throughout brain, with apparent cellular uptake in midbrain by 6 h after administration. In quantitative studies, liposomes were loaded with (111)In-OVAL, and distribution to brain and peripheral tissues was monitored by gamma counting at 1, 4, 6, and 24 h after administration. The highest brain concentrations were achieved at the shortest time point, 1 h, for both liposomal and aqueous OVAL. However, the liposomes yielded higher (111)In-OVAL concentrations in brain than (111)In-OVAL in PBS. Moreover, a 2 microg/microL form of liposomal OVAL yielded a higher percentage of dose in brain, and a lower percentage in stomach and intestines, than twice the volume of a 1 microg/microL preparation. Cationic liposomes may provide a novel, noninvasive strategy for delivery of neuroactive proteins to the brain for treatment of central nervous system disorders.
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Encéfalo/metabolismo , Liposomas/química , Ovalbúmina/administración & dosificación , Ovalbúmina/farmacocinética , Administración Intranasal , Animales , Cationes/química , Permeabilidad de la Membrana Celular , Masculino , Nanopartículas/química , Ratas , Ratas Sprague-DawleyRESUMEN
Current treatments for pancreatic cancer have failed to effectively manage the disease, and hence, more effective treatment approaches are urgently needed. Studies suggest that mucin O-glycosylation limits the cytotoxic effect of fluorouracil (5-FU) against the growth of human pancreatic cancer cells in vitro. In the present study, we investigated the relationship between the levels of mucin O-glycosylation expressed in pancreatic tumours and the antitumour effect of 5-FU. The inhibition of O-glycosylation was achieved by intratumoural (IT) injections of benzyl-alpha-GalNAc. Immunohistochemical staining of human pancreatic tumours revealed relatively high (Capan-1) and moderate (HPAF-II) expression levels of MUC1 mucin compared to MUC1 negative control (U-87 MG human glioblastoma) tumours. The antitumour effects of 5-FU (given systemically) against Capan-1 tumours improved significantly following IT injections of benzyl-alpha-GalNAc. Histochemical staining of tumour sections revealed a reduced number of neoplastic cells in tumours exposed to benzyl-alpha-GalNAc prior to 5-FU treatment compared to 5-FU alone. Furthermore, intracellular uptake of 5-FU by Capan-1 cells was significantly greater following injections of benzyl-alpha-GalNAc; however, no such effect was observed with U-87 MG cells. Mucin overexpression reduces intracellular drug uptake, antineoplastic and antitumour drug effects, which may have important clinical implications in treatment.
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Antineoplásicos/uso terapéutico , Fluorouracilo/uso terapéutico , Mucina-1/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Acetilgalactosamina/análogos & derivados , Acetilgalactosamina/farmacología , Animales , Antineoplásicos/análisis , Antineoplásicos/farmacocinética , Compuestos de Bencilo/farmacología , Línea Celular Tumoral , Femenino , Fluorouracilo/análisis , Fluorouracilo/farmacocinética , Glicosilación/efectos de los fármacos , Ratones , Mucina-1/análisis , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/metabolismo , Insuficiencia del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The use of second generation cationic liposomes to deliver cytotoxic drugs to solid tumors is a rational and promising therapeutic approach, given the natural affinity of cationic carrier molecules for the tumor microvasculature. Cationic liposomal therapeutics are effective in the treatment of cancers that are resistant to conventional chemotherapy and other treatment modalities. Researchers are now exploring novel ways to combine cationic nanosystems with other treatment approaches. For example, strategies for using cationic liposomes with hyperthermia or magnetic fields have been evaluated. Drug-loaded cationic liposomes have been documented to induce tumor vascular defects, alter vascular function and limit the growth of the primary tumors and metastasis. In this review, we discuss general features of the endothelium as a function of its tissue environment. We discuss the rationale for targeting tumor vessels over the tumor interstitial matrix, and for the development of second generation cationic lipids and liposomes for tumor vascular targeting. We evaluate the benefits of incorporating the polymer polyethylene-glycol (PEG) in conventional and cationic liposomes for nonspecific and relatively vascular-specific tumor targeting, respectively. Finally, we review preclinical and clinical investigations evaluating drug-loaded cationic liposomes in cancer treatment.
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Antineoplásicos/administración & dosificación , Endotelio Vascular/efectos de los fármacos , Lípidos/química , Liposomas , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Cationes , Química Farmacéutica , Composición de Medicamentos , Diseño de Fármacos , Endotelio Vascular/metabolismo , Terapia Genética/métodos , Humanos , Ratones , Neoplasias/irrigación sanguínea , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias Experimentales/terapia , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Transfección , Resultado del TratamientoRESUMEN
Using cationic liposomes to deliver cytotoxic molecules to the tumor microvasculature is currently being developed for the treatment of cancer and other angiogenesis-related diseases. To improve on their beneficial properties, the authors have examined whether the particular cationic lipid type and lipid content employed are important factors influencing cellular interactions and formulation effects. The authors prepared different PEG (polyethylene glycol)-modified cationic liposomes (PCLs) with varying percent cationic lipid content and lipid type, and evaluated liposome size, surface charge (zeta) potential, and cellular properties in vitro. The cell lines used were human umbilical vein (HUVEC), lung microvascular (HMVEC-L and HPVE-26), coronary microvascular (HMVEC-C), dermal microvascular (HMVEC-D), and immortalized dermal microvascular (HMEC-1) endothelial cells. In vitro experiments consisted of cellular uptake and cytotoxicity studies, fluorescence-activated cell sorting (FACS) analysis, fluorescence, and transmission electron microscopic analysis. Liposome size and zeta potential analysis of five different PCLs revealed significant differences in their physicochemical properties. Some cationic lipids formed relatively toxic liposomes compared to others. The efficiency of loading chemotherapeutic drugs (doxorubicin hydrochloride, etoposide), affinity of PCLs for endothelial cells, and formulation effects varied according to cationic lipid content and the lipid type. Cellular uptake was observed in lung, dermal, and coronary endothelial cells. Heparan sulfate proteoglycans were found present on HMEC-1 cells, which may have enabled PCL uptake. In conclusion, physicochemical properties of cationic liposomes and their ability to interact with endothelial cells are important factors to consider during the early stages of formulation development for the treatment of cancer and other angiogenesis-dependent diseases.
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Endotelio Vascular/fisiología , Lípidos/fisiología , Liposomas/metabolismo , Línea Celular , Línea Celular Transformada/citología , Línea Celular Transformada/efectos de los fármacos , Línea Celular Transformada/fisiología , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/farmacología , Doxorrubicina/toxicidad , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Etopósido/farmacología , Etopósido/toxicidad , Humanos , Fosfatidilcolinas/metabolismo , Circulación PulmonarRESUMEN
Over the past few decades significant advances have been made in the development of nanopharmaceuticals (including phospholipid and polymer-based therapeutics) against cancer. There is still, however, room for improvement. Today, many researchers are focusing on the development of innovative approaches to selectively deliver drugs to solid tumors, while minimizing insult to healthy tissues. Unfortunately, the majority of these efforts are confronted by physiological barriers that reduce the clinical dose required to effectively manage the disease state. In an effort to develop promising nanopharmaceutical products of the future, we review the most important problems facing drug delivery experts today. We discuss here, the physiological role of solid tumors in delivery and transport of nanopharmaceutical products. The nature of tumors in terms of their unique anatomical structure and functions is also discussed. Finally, an overview of ways to overcome physiological barrier functions and exploit tumor pathogenesis for therapeutic gain is provided.