RESUMO
We previously reported that hydroxylated oxime ether lipids (OELs) efficiently deliver functional Dicer substrate siRNAs (DsiRNAs) in cells. Here, we explored in vivo utility of these OELs, using OEL4 as a prototype and report that surface modification of the OEL4 formulations was essential for their in vivo applications. These surface-modified OEL4 formulations were developed by inclusion of various PEGylated lipids. The vesicle stability and gene knock-down were dependent on the PEG chain length. OEL4 containing DSPE-PEG350 and DSPE-PEG1000 (surprisingly not DSPE2000) promoted gene silencing in cells. In vivo studies demonstrated that OEL4 vesicles formulated using 3 mol% DSPE-PEG350 accumulate in human lung cancer (A549-luc2) xenografts in mice and exhibit a significant increase in tumor to liver ratios. These vesicles also showed a statistically significant reduction of luciferase signal in tumors compared to untreated mice. Taken together, the scalable OEL4:DSPE-PEG350 formulation serves as a novel candidate for delivery of RNAi therapeutics.
Assuntos
Éter , Neoplasias Pulmonares , Animais , Éteres , Xenoenxertos , Humanos , Lipídeos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Camundongos , Oximas , Polietilenoglicóis , RNA Interferente Pequeno/genéticaRESUMO
We previously reported the development of an amphiphilic brush-like block copolymer composed of polynorbornene-cholesterol/polyethylene glycol (P(NBCh9-b-NBPEG)) that self-assembles in aqueous media to form long circulating nanostructures capable of encapsulating doxorubicin (DOX-NPs). Biodistribution studies showed that this formulation preferentially accumulates in tumor tissue with markedly reduced accumulation in the heart and other major organs. The aim of the current study was to evaluate the in vivo efficacy and toxicity of DOX containing self-assembled polymer nanoparticles in a mouse xenograft tumor model and compare its effects with the hydrochloride non-encapsulated form (free DOX). DOX-NPs significantly reduced the growth of tumors without inducing any apparent toxicity. Conversely, mice treated with free DOX exhibited significant weight loss, early toxic cardiomyopathy, acute toxic hepatopathy, reduced hematopoiesis and fatal toxicity. The improved safety profile of the polymeric DOX-NPs can be explained by the low circulating concentration of non-nanoparticle-associated drug as well as the reduced accumulation of DOX in non-target organs. These findings support the use of P(NBCh9-b-NBPEG) nanoparticles as delivery platforms for hydrophobic anticancer drugs intended to reduce the toxicity of conventional treatments.
Assuntos
Antineoplásicos , Colesterol/química , Doxorrubicina , Nanopartículas , Células A549 , Alanina Transaminase/sangue , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos SCID , Miocárdio/patologia , Nanopartículas/efeitos adversos , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Baço/efeitos dos fármacos , Baço/patologia , Troponina I/sangue , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Mesoporous silica nanoparticles (MSNs) containing paclitaxel for intraperitoneal (i.p.) delivery were developed to exploit the tumor specific accumulation of these nanocarriers after i.p. injection and the slow release of paclitaxel from the MSNs. A 3.5-fold increase in tumor cellular drug uptake was observed for the paclitaxel-loaded MSNs compared with free paclitaxel. An in vivo study using xenograft mice bearing peritoneal human pancreatic carcinoma MIA PaCa-2 demonstrated that the MSN-paclitaxel formulation, compared to free paclitaxel, exhibited a 3.2-fold increase in peritoneal cavity residence time, slower absorption into the systemic circulation with one third systemic exposure, but a 6.5-fold increase in peritoneal tumor accumulation. Tissue distribution imaging showed significantly greater accumulation of fluorescent MSNs in tumor tissues compared to other peritoneal tissues. In conclusion, intraperitoneal administration of drug-containing MSNs was effective at reducing systemic exposure and increasing the peritoneal tumor accumulation of paclitaxel.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Nanopartículas , Paclitaxel/farmacocinética , Dióxido de Silício , Animais , Portadores de Fármacos/uso terapêutico , Humanos , Camundongos , Neoplasias/tratamento farmacológico , PorosidadeRESUMO
Amphiphilic brush-like block copolymers composed of polynorbonene-cholesterol/poly(ethylene glycol) (P(NBCh9-b-NBPEG)) self-assembled to form a long circulating nanostructure capable of encapsulating the anticancer drug doxorubicin (DOX) with high drug loading (22.1% w/w). The release of DOX from the DOX-loaded P(NBCh9-b-NBPEG) nanoparticles (DOX-NPs) was steady at less than 2% per day in PBS. DOX-NPs were effectively internalized by human cervical cancer cells (HeLa) and showed dose-dependent cytotoxicity, whereas blank nanoparticles were noncytotoxic. The DOX-NPs demonstrated a superior in vivo circulation time relative to that of free DOX. Tissue distribution and in vivo imaging studies showed that DOX-NPs preferentially accumulated in tumor tissue with markedly reduced accumulation in the heart and other vital organs. The DOX-NPs greatly improved survival and significantly inhibited tumor growth in tumor-bearing SCID mice compared to that for the untreated and free DOX-treated groups. The results indicated that self-assembled P(NBCh9-b-NBPEG) may be a useful carrier for improving tumor delivery of hydrophobic anticancer drugs.
Assuntos
Antineoplásicos/química , Colesterol/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Polímeros/química , Animais , Antineoplásicos/administração & dosagem , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos SCID , Nanopartículas/administração & dosagem , Polímeros/administração & dosagem , Distribuição Aleatória , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
The use of intraperitoneal administration of nanoparticles has been reported to facilitate higher concentrations of nanoparticles in metastatic peritoneal tumors. While this strategy is appealing for limiting systemic exposure of nanocarrier delivered toxic cargoes and increasing nanoparticle concentrations in avascular peritoneal tumors, little is known about the mechanism of nanoparticle accumulation on tumor tissues and currently, no nanoparticle-based product has been approved for intraperitoneal delivery. Here, we investigated the nanoparticle-specific characteristics that led to increased peritoneal tumor accumulation using MCM-41 type mesoporous silica nanoparticles as our model system. We also investigated the components of the peritoneal tumor stroma that facilitated nanoparticle-tumor interaction. The tumor extracellular matrix is the main factor driving these interactions, specifically the interaction of nanoparticles with collagen. Upon disruption of the collagen matrix, nanoparticle accumulation was reduced by 50%. It is also notable that the incorporation of targeting ligands did not increase overall tumor accumulation in vivo while it significantly increased nanoparticle accumulation in vitro. The use of other particle chemistries did not grossly affect the tumor targetability, but additional concerns arose when those tested particles exhibited significant systemic exposure. Mesoporous silica nanoparticles are advantageous for intraperitoneal administration for the treatment of peritoneal metastasis due to their physical stability, tumor targetability, strong interaction with the collagen matrix, and extended peritoneal residence time. Maximizing nanoparticle interaction with the tumor extracellular matrix is critical for developing strategies to deliver emerging therapeutics for peritoneal cancer treatment using nanocarriers.
Assuntos
Nanopartículas , Neoplasias Peritoneais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Injeções Intraperitoneais , Neoplasias Peritoneais/tratamento farmacológico , Porosidade , Dióxido de SilícioRESUMO
Intraperitoneal internal radiation therapy is a cancer treatment option that is employed in situations where surgical resection, systemic chemotherapy, and external beam radiotherapy are not amenable for patients. However, exposure of noncancerous tissues to radiation continues to be a hindrance to safe and effective treatment of patients. In addition, reducing prolonged radiation exposure of personnel during preparation of internal radiation therapy agents makes their manufacture complicated and hazardous. Developments in nanotechnology have provided a platform for targeted treatments that combine dual imaging and treatment capabilities all in one package, while also being robust enough to withstand the intense stresses faced during neutron activation. Here, we describe a method for synthesizing neutron activatable mesoporous silica nanoparticles for use in radiotherapy of metastatic peritoneal cancers while limiting personal exposure to radioactive materials, limiting the leakage of radioactive isotopes caused by nanoparticle degradation during neutron activation, and increasing cancer tissue specificity of radiation.
Assuntos
Nanopartículas , Neoplasias/radioterapia , Nêutrons , Hólmio/química , Hidroxibutiratos/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/ultraestrutura , Nêutrons/uso terapêutico , Pentanonas/química , Porosidade , Radioisótopos/administração & dosagem , Dióxido de Silício/químicaRESUMO
Because of its good biocompatibility and biodegradability, albumins such as bovine serum albumin (BSA) and human serum albumin (HSA) have found a wide range of biomedical applications. Herein, we report that glutaraldehyde cross-linked BSA (or HSA) forms a novel fluorescent biological hydrogel, exhibiting new green and red autofluorescence in vitro and in vivo without the use of any additional fluorescent labels. UV-vis spectra studies, in conjunction with the fluorescence spectra studies including emission, excitation and synchronous scans, indicated that three classes of fluorescent compounds are presumably formed during the gelation process. SEM, FTIR and mechanical tests were further employed to investigate the morphology, the specific chemical structures and the mechanical strength of the as-prepared autofluorescent hydrogel, respectively. Its biocompatibility and biodegradability were also demonstrated through extensive in vitro and in vivo studies. More interestingly, the strong red autofluorescence of the as-prepared hydrogel allows for conveniently and non-invasively tracking and modeling its in vivo degradation based on the time-dependent fluorescent images of mice. A mathematical model was proposed and was in good agreement with the experimental results. The developed facile strategy to prepare novel biocompatible and biodegradable autofluorescent protein hydrogels could significantly expand the scope of protein hydrogels in biomedical applications.
Assuntos
Materiais Biocompatíveis/química , Fluorescência , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Proteínas/química , Animais , Sobrevivência Celular , Reagentes de Ligações Cruzadas/química , Glutaral/química , Fenômenos Mecânicos , Camundongos , Soroalbumina Bovina/química , Espectroscopia de Infravermelho com Transformada de Fourier , Raios UltravioletaRESUMO
Bovine serum albumin (BSA) microspheres were prepared through a facile and low-cost route including a high-speed dispersion of BSA in cross-linking solution followed by spray drying. Interestingly the as-prepared BSA microspheres possess unique blue-green, green, green-yellow, and red fluorescence when excited by specific wavelengths of laser or LED light. The studies of UV-visible reflectance spectra and fluorescence emission spectra indicated that four classes of fluorescent compounds are presumably formed during the fabrication processes. The formation and the potential contributors for the unique green and red autofluorescence were also discussed and proposed though the exact structures of the fluorophores formed remain elusive due to the complexity of the protein system. The effect of spray-drying conditions on the morphology of spray-dried samples was investigated and optimized. FTIR was further employed to characterize the formation of the functional groups in the as-prepared autofluorescent microspheres. Good in vitro and in vivo biocompatibility was demonstrated by the cytotoxicity test on the A549 cancer cells and tissue histological analysis, respectively. The autofluorescent BSA microspheres themselves were then applied as a novel tracer for convenient tracking/modeling of the biodegradation of autofluorescent BSA microspheres injected into mouse model based on noninvasive, time-dependent fluorescence images of the mice, in which experimental data are in good agreement with the proposed mathematical model. All these studies indicate that the as-developed protein microspheres exhibiting good biocompatibility, biodegradability, and unique autofluorescence, can significantly broaden biomedical applications of fluorescent protein particles.