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1.
Biomacromolecules ; 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32687312

RESUMO

In light of research reporting abnormal pharmacokinetic behavior for therapeutics and formulations containing poly(ethylene glycol) (PEG), a renewed emphasis has been placed on exploring alternative surrogate materials and tailoring specific materials to distinct nanomedicine applications. Poly(2-oxazolines) (POx) have shown great promise in this regard; however, a comparison of POx and PEG interactions with components of the immune system is needed to inform on their distinct suitability. Herein, the interaction of isolated immune cells following injection of hyperbranched polymers comprised of PEG or hydrophilic POx macromonomers was determined via flow cytometry. All materials showed similar association with all of the splenic immune cells analyzed. Interestingly, splenic CD68hi and CD11bhi macrophages showed similar levels of polymer association, despite CD11bhi being a smaller population, suggesting CD68 is linked to increased recognition and phagocytosis of these nanomaterials. This is of interest given that CD68 is a scavenger receptor and directly facilitates the clearance of cellular debris and promotion of phagocytosis, as opposed to CD11b, which is associated with the mediating inflammation via the production of cytokines as well as complement-mediated uptake of foreign particles. In the liver, PEG and poly(2-methyl oxazoline) hyperbranched polymers showed no discernible differences in their cellular association, while hyperbranched poly(2-ethyl oxazoline) showed increased association with dendrocytes and CD68hi macrophages, suggesting that this material exhibited a greater propensity to interact with components of the immune system. This work highlights the importance of how subtle changes in chemical structure can influence the immune response.

2.
Analyst ; 145(13): 4504-4511, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32409797

RESUMO

Dabrafenib is one of the most widely used of the new generation of targeted anti-cancer drugs. However, its therapeutic window varies for different patients and so there is an unmet need for methods to monitor the dose of drug which the patient receives and at the specific site where it acts. In the case of cancers, it is critical to measure the concentration of drug not just in the bloodstream overall, but in or near tumours, as these will not be the same over multiple time periods. A novel sensor based on an optical fibre long period grating (LPG) modified with a molecular imprinted polymer (MIP) has been developed with the ultimate aim of achieving minimally invasive measurements of Dabrafenib at the tumour site. A molecularly imprinted polymer specific for Dabrafenib was coated on a methacryloylalkoxysilane-functionalised optical fibre long period grating. In vitro experimental results demonstrate that the Dabrafenib sensitivity is 15.2 pm (µg mL-1)-1 (R2 = 0.993) with a limit of detection (LoD) of 74.4 µg mL-1 in serum solution. Moreover, the proposed sensor shows selective response to Dabrafenib over structurally similar 2-Aminoquinoline.

3.
Biomacromolecules ; 21(6): 2320-2333, 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32343128

RESUMO

Phosphorylcholine is known to repel the absorption of proteins onto surfaces, which can prevent the formation of a protein corona on the surface of nanoparticles. This can influence the fate of nanoparticles used for drug delivery. This material could therefore serve as an alternative to poly(ethylene glycol) (PEG). Herein, the synthesis of different particles prepared by polymerization-induced self-assembly (PISA) coated with either poly(ethylene glycol) (PEG) or zwitterionic 2-methacryloyloxyethyl phosphorylcholine (MPC) and 4-(N-(S-penicillaminylacetyl)amino) phenylarsenonous acid (PENAO) was reported. The anticancer drug 4-(N-(S-penicillaminylacetyl)amino) phenylarsenonous acid (PENAO) was conjugated to the shell-forming block. Interactions of the different coated nanoparticles, which present comparable sizes and size distributions (76-85 nm, PDI = 0.067-0.094), with two-dimensional (2D) and three-dimensional (3D) cultured cells were studied, and their cytotoxicities, cellular uptakes, spheroid penetration, and cell localization profiles were analyzed. While only a minimal difference in behaviour was observed for nanoparticles assessed using in vitro experiment (with PEG-co- PENAO-coated micelles showing slightly higher cytotoxicity and better spheroid penetration and cell localization ability), the effect of the different physicochemical properties between nanoparticles had a more dramatic effect on in vivo biodistribution. After 1 h of injection, the majority of the MPC-co-PENAO-coated nanoparticles were found to accumulate in the liver, making this particle system unfeasible for future biological studies.

4.
Polymers (Basel) ; 11(9)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480780

RESUMO

Nanomedicine has generated significant interest as an alternative to conventional cancertherapy due to the ability for nanoparticles to tune cargo release. However, while nanoparticletechnology has promised significant benefit, there are still limited examples of nanoparticles inclinical practice. The low translational success of nanoparticle research is due to the series ofbiological roadblocks that nanoparticles must migrate to be effective, including blood and plasmainteractions, clearance, extravasation, and tumor penetration, through to cellular targeting,internalization, and endosomal escape. It is important to consider these roadblocks holistically inorder to design more effective delivery systems. This perspective will discuss how nanoparticlescan be designed to migrate each of these biological challenges and thus improve nanoparticledelivery systems in the future. In this review, we have limited the literature discussed to studiesinvestigating the impact of polymer nanoparticle structure or composition on therapeutic deliveryand associated advancements. The focus of this review is to highlight the impact of nanoparticlecharacteristics on the interaction with different biological barriers. More specific studies/reviewshave been referenced where possible.

5.
ACS Appl Mater Interfaces ; 11(32): 28720-28731, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31369234

RESUMO

In the present study, a capsule system that consists of a stealth carrier based on poly(ethylene glycol) (PEG) and functionalized with bispecific antibodies (BsAbs) is introduced to examine the influence of the capsule shape and size on cellular targeting. Hollow spherical and rod-shaped PEG capsules with tunable aspect ratios (ARs) of 1, 7, and 18 were synthesized and subsequently functionalized with BsAbs that exhibit dual specificities to PEG and epidermal growth factor receptor (EGFR). Dosimetry (variation between the concentrations of capsules present and capsules that reach the cell surface) was controlled through "dynamic" incubation (i.e., continuously mixing the incubation medium). The results obtained were compared with those obtained from the "static" incubation experiments. Regardless of the incubation method and the capsule shape and size studied, BsAb-functionalized PEG capsules showed >90% specific cellular association to EGFR-positive human breast cancer cells MDA-MB-468 and negligible association with both control cell lines (EGFR negative Chinese hamster ovary cells CHO-K1 and murine macrophages RAW 264.7) after incubation for 5 h. When dosimetry was controlled and the dose concentration was normalized to the capsule surface area, the size or shape had a minimal influence on the cell association behavior of the capsules. However, different cellular internalization behaviors were observed, and the capsules with ARs 7 and 18 were, respectively, the least and most optimal shape for achieving high cell internalization under both dynamic and static conditions. Dynamic incubation showed a greater impact on the internalization of rod-shaped capsules (∼58-67% change) than on the spherical capsules (∼24-29% change). The BsAb-functionalized PEG capsules reported provide a versatile particle platform for the evaluation and comparison of cellular targeting performance of capsules with different sizes and shapes in vitro.


Assuntos
Anticorpos Biespecíficos , Antineoplásicos Imunológicos , Sistemas de Liberação de Medicamentos , Polietilenoglicóis , Animais , Anticorpos Biespecíficos/química , Anticorpos Biespecíficos/farmacologia , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Células CHO , Cápsulas , Cricetulus , Humanos , Camundongos , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Células RAW 264.7
6.
Biomater Sci ; 7(11): 4661-4674, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31469127

RESUMO

As polymeric nanomedicines grow increasingly complex in design, an effective therapeutic release is often inherently tied to localisation to specific intracellular compartments or microenvironments. The inclusion of environmentally-sensitive moieties links the functionality of such materials to the trafficking behaviours exhibited once materials have obtained access to the cellular milieu. In order to perform their designed function, such materials often need to encounter specific biological cues or stimuli. As such, there is an increased need to improve our understanding of how the physicochemical properties of nanomaterials influence post-internalisation behaviours. Amongst the unknown factors that may contribute to the trafficking behaviours and distribution of polymers within the cellular environment, is the influence of the components selected in the development of such materials. To examine whether composition and arrangement of components within small polymeric nanomaterials contribute to their ability to navigate the intracellular space, here we utilise fluorophores to model component selection, varying the fluorescent handle selected and its method of incorporation. We explore the intracellular behaviours of well-characterised hyperbranched polymers in live MDA-MB-468 breast cancer cells in vitro. Changes in distribution as a function of both fluorophore selection and placement are reported, and our data suggest that the individual components used to produce potential nanomedicines are critical to their overall functioning and efficacy. Further to this, through the use of a novel non-conjugated targeting ligand, we demonstrate that there is inherent competition between component-directing factors and cellular influences on the ultimate fate of the polymers. The behaviours reported here suggest that not only does component selection contribute to intracellular processing, but these factors could potentially be harnessed when designing polymers to ensure improved functionality of future materials for therapeutic delivery.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Polietilenoglicóis/farmacocinética , Neoplasias da Mama/diagnóstico por imagem , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Feminino , Citometria de Fluxo , Humanos , Microscopia Confocal , Imagem Óptica , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Distribuição Tecidual , Células Tumorais Cultivadas
7.
Biomaterials ; 216: 119232, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31195300

RESUMO

Combined and targeted therapy have been extensively employed to achieve more effective elimination of tumor tissues. In this study, biocompatible multifunctional lipid-coated calcium phosphate nanoparticles (LCP NPs) were designed and constructed as an efficient targeted delivery system for combined gene/photothermal therapy to inhibit growth of the triple negative breast tumor (MDA-MB-468) in vitro and in vivo. LCP NPs were functionalized with a bispecific antibody (BsAb) via non-covalent bond specific for methoxy group of PEG (mPEG) on the particle surface. This BsAb is also able to target epidermal growth factor receptor (EGFR) expressed on MDA-MB-468 cells. Such LCP-BsAb NPs loaded with Cell Death (CD)-siRNA and indocyanine green (ICG) were efficiently taken up by MDA-MB-468 cells, significantly inducing cell apoptosis and synergistically suppressing cell proliferation upon irradiation of 808 nm near-infrared laser. These targeted multifunctional LCP NPs more efficiently accumulated in the tumor tissue. The combined RNAi (CD-siRNA) and photothermal (ICG) therapy using the targeted LCP NPs nearly eliminated both small tumors (∼100 mm3) and large tumors (∼500 mm3) in the mouse model. Thus, the well-devised multifunctional LCP NPs are one of the most promising delivery systems for combined and targeted cancer therapy.

8.
Appl Spectrosc ; 73(12): 1428-1435, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31124368

RESUMO

Plasmonic nanoassemblies with amplified optical responses are attractive as chemo/bio sensors and diagnostic tracking agents. For real-life implementation, such nanostructures require a well-designed and controlled formation for maximizing the optical amplification. Forming these nanoassemblies typically requires numerous steps; however, the importance of the sequence of the steps is typically not discussed. Thus, here we have investigated the role of the sequence of tagging (or labeling, barcoding) of such plasmonic nanoassemblies with Raman active molecules in a quest to maximize the surface-enhanced Raman scattering (SERS) enhancement that could be achieved from the nanoassemblies. We have chosen the core-satellite nanoassembly arrangement to study the role of tagging sequence because it allows us to keep structural parameters constant that would otherwise influence the SERS amplification. We demonstrate that incorporating the tag molecule at an assembly point before formation of the nanojunctions leads to more tag molecules being positioned at the core-satellite nanojunctions, thereby resulting in higher SERS signal enhancement. This will thus prove to be a useful tool in fully utilizing the nanoassembly morphology generated hot-spot and maximizing its SERS performance.

9.
Int J Pharm ; 563: 174-183, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30940503

RESUMO

Liposomes are promising delivery vehicles and offer the added drawcard of being able to be made functional to target tissues such as cardiac muscle and cancerous cells. Current methods to manufacture liposomes need to be improved and supercritical fluid (SCF) technologies may offer a solution. Herein, the dispersibility of six different phospholipids (PLs) was determined in supercritical carbon dioxide (scCO2). 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) showed the highest post-processing dispersibility, while 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) showed no dispersibility in scCO2 at the assessed experimental conditions. The zetasizer results showed that the SCF conditions at 37 °C, 250 bar and 200 RPM for 60 min provided nanoparticles with the narrowest polydispersity index (PDI) and a spherical shape as shown by cryo-transmission electron microscopy (Cryo-TEM). The mean diameter of liposomes using the SCF method for DSPC-PEGylated and DOPC-PEGylated liposomes was 98.3 ±â€¯3.3 nm and 124.5 ±â€¯4.1 nm, while using the thin film method it was 153.6 ±â€¯4.5 nm and 131.3 ±â€¯3.4 nm, respectively. A size-based stability evaluation of the scCO2-prepared liposomes stored at different temperatures (25 °C, 4 °C and -20 °C) was compared to that of the thin film method over a period of 3 months. The current study provides a possible green alternative SCF method to preparing liposomes that is less laborious, time saving, and a low energy process.


Assuntos
Composição de Medicamentos/métodos , Lipossomos/química , Fosfolipídeos/química , Dióxido de Carbono/química , Nanopartículas/química , Tamanho da Partícula , Polietilenoglicóis/química , Sonicação
10.
Int J Mol Sci ; 20(6)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875730

RESUMO

Brain metastases are the most prevalent of intracranial malignancies. They are associated with a very poor prognosis and near 100% mortality. This has been the case for decades, largely because we lack effective therapeutics to augment surgery and radiotherapy. Notwithstanding improvements in the precision and efficacy of these life-prolonging treatments, with no reliable options for adjunct systemic therapy, brain recurrences are virtually inevitable. The factors limiting intracranial efficacy of existing agents are both physiological and molecular in nature. For example, heterogeneous permeability, abnormal perfusion and high interstitial pressure oppose the conventional convective delivery of circulating drugs, thus new delivery strategies are needed to achieve uniform drug uptake at therapeutic concentrations. Brain metastases are also highly adapted to their microenvironment, with complex cross-talk between the tumor, the stroma and the neural compartments driving speciation and drug resistance. New strategies must account for resistance mechanisms that are frequently engaged in this milieu, such as HER3 and other receptor tyrosine kinases that become induced and activated in the brain microenvironment. Here, we discuss molecular and physiological factors that contribute to the recalcitrance of these tumors, and review emerging therapeutic strategies, including agents targeting the PI3K axis, immunotherapies, nanomedicines and MRI-guided focused ultrasound for externally controlling drug delivery.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antineoplásicos/farmacologia , Encéfalo/cirurgia , Neoplasias Encefálicas/imunologia , Quimiorradioterapia Adjuvante , Sistemas de Liberação de Medicamentos , Humanos , Imunoterapia , Terapia de Alvo Molecular , Nanomedicina , Nanopartículas , Resultado do Tratamento , Microambiente Tumoral
11.
Adv Healthc Mater ; 8(9): e1801607, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30868751

RESUMO

Low-fouling or "stealth" particles composed of poly(ethylene glycol) (PEG) display a striking ability to evade phagocytic cell uptake. However, functionalizing them for specific targeting is challenging. To address this challenge, stealth PEG particles prepared by a mesoporous silica templating method are functionalized with bispecific antibodies (BsAbs) to obtain PEG-BsAb particles via a one-step binding strategy for cell and tumor targeting. The dual specificity of the BsAbs-one arm binds to the PEG particles while the other targets a cell antigen (epidermal growth factor receptor, EGFR)-is exploited to modulate the number of targeting ligands per particle. Increasing the BsAb incubation concentration increases the amount of BsAb tethered to the PEG particles and enhances targeting and internalization into breast cancer cells overexpressing EGFR. The degree of BsAb functionalization does not significantly reduce the stealth properties of the PEG particles ex vivo, as assessed by their interactions with primary human blood granulocytes and monocytes. Although increasing the BsAb amount on PEG particles does not lead to the expected improvement in tumor accumulation in vivo, BsAb functionalization facilitates tumor cell uptake of PEG particles. This work highlights strategies to balance evading nonspecific clearance pathways, while improving tumor targeting and accumulation.

12.
Sci Rep ; 9(1): 1716, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30737457

RESUMO

The aims of this study are to investigate the selective cytotoxic activity of supercritical carbon dioxide (scCO2)-extracted freeze-dried leaf juice (FDLJ) of Carica papaya on squamous cell carcinoma (SCC25) cells, and to delineate the best small scale extraction parameters allowing maximal extract activity. Using scCO2 as a solvent, six operating parameters were studied and the supercritical fluid extraction (SFE) process investigated using a factorial design 26-2. The processing values promoting cytotoxic activity towards SCC-25 are: high pressure (250 bar), low temperature (35 °C), extended processing time (180 minutes), as well as a large amount of starting material (5 g). The factorial experimental design successfully identified the key parameters controlling the SFE of molecules cytotoxic to SCC cells from C. papaya juice. This study also validated the extraction method and showed that the SFE yield was reproducible. The chromatographic and mass spectrometric profiles of the scCO2 extract acquired with high-resolution quadrupole time-of-flight mass spectrometry (LC-QToF-MS) were used to tentatively identify the bioactive compounds using comparative analysis. The principal compounds were likely to be mainly vitamins and phytosterols, some of which are documented to be cytotoxic to cancer cells.

13.
Eur J Pharm Biopharm ; 136: 102-107, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30660691

RESUMO

The intravitreal route faces many challenges in rapidly and effectively reaching posterior eye pathology, with administered therapeutics experiencing non-specific distribution around and premature clearance from ocular tissues. Nanobubbles and ultrasound may improve outcomes of intravitreally administered drugs by influencing the directionality of drug-containing particle migration. In this study, we assessed the impact of trans-scleral or corneal ultrasound application on the distribution of intravitreally-injected nanobubbles. Rhodamine-tagged gas entrapped nanobubble formulations were prepared and injected into ex vivo bovine and porcine eyes and subjected to ultrasound (1 MHz, 0-2.5 W/cm2, 50-100% duty, 60 s). Bovine eyes were partially dissected to visualize the vitreous humor and particle migration was evaluated via optical fluorescence spectroscopy. Directional migration in porcine eyes was evaluated using a snap freezing protocol complemented by quantification of regional fluorescence. The impact on nanobubble migration following pars-plana injection and sequential ultrasound cycle application from scleral or corneal-surface positions was also assessed. Administration of ultrasound significantly enhanced the directional migration of nanobubbles in both ex vivo models, with multiple corneal ultrasound cycles promoting greater migration of dye-filled nanobubbles to posterior regions of the vitreous. Moreover, particles moved in a directional manner away from the ultrasound wave source demonstrating an ability to effectively control the rate and path of nanobubble migration. These findings establish an encouraging new and safe modality enabling rapid distribution of intravitreally-injected therapeutics where expeditious therapeutic intervention is warranted.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Corantes Fluorescentes/análise , Injeções Intravítreas/métodos , Nanocápsulas/análise , Ondas Ultrassônicas , Corpo Vítreo/química , Animais , Bovinos , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/metabolismo , Nanocápsulas/administração & dosagem , Espectrometria de Fluorescência/métodos , Suínos , Corpo Vítreo/efeitos dos fármacos , Corpo Vítreo/metabolismo
14.
Cancers (Basel) ; 10(12)2018 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-30562956

RESUMO

The EphA3 receptor has recently emerged as a functional tumour-specific therapeutic target in glioblastoma (GBM). EphA3 is significantly elevated in recurrent disease, is most highly expressed on glioma stem cells (GSCs), and has a functional role in maintaining self-renewal and tumourigenesis. An unlabelled EphA3-targeting therapeutic antibody is currently under clinical assessment in recurrent GBM patients. In this study, we assessed the efficacy of EphA3 antibody drug conjugate (ADC) and radioimmunotherapy (RIT) approaches using orthotopic animal xenograft models. Brain uptake studies, using positron emission tomography/computed tomography (PET/CT) imaging, show EphA3 antibodies are effectively delivered across the blood-tumour barrier and accumulate at the tumour site with no observed normal brain reactivity. A robust anti-tumour response, with no toxicity, was observed using EphA3, ADC, and RIT approaches, leading to a significant increase in overall survival. Our current research provides evidence that GBM patients may benefit from pay-loaded EphA3 antibody therapies.

15.
Nanotheranostics ; 2(4): 360-370, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30324082

RESUMO

Targeted nanomedicines offer many advantages over macromolecular therapeutics that rely only on passive accumulation within the tumour environment. The aim of this work was to investigate the in vivo anticancer efficiency of polymeric nanomedicines that were conjugated with peptide aptamers that show high affinity for receptors on many cancer cells. In order to assess the ability for the nanomedicine to treat cancer and investigate how structure affected the behavior of the nanomedicine, three imaging modalities were utilized, including in vivo optical imaging, multispectral optoacoustic tomography (MSOT) and ex vivo confocal microscopy. An 8-mer (A8) or 13-mer (A13) peptide aptamer that have been shown to exhibit high affinity for heat shock protein 70 (HSP70) was covalently-bound to hyperbranched polymer (HBP) nanoparticles with the purpose of both cellular targeting, as well as the potential to impart some level of chemo-sensitization to the cells. Furthermore, doxorubicin was bound to the polymeric carrier as the anticancer drug, and Cyanine-5.5 (Cy5.5) was incorporated into the polymer as a monomeric fluorophore to aid in monitoring the behavior of the nanomedicine. Enhanced tumour regression was observed in nude mice bearing MDA-MB-468 xenografts when the nanocarriers were targeted using the peptide ligands, compared to control groups treated with free DOX or HBP without aptamer. The accumulated DOX level in solid tumours was 5.5 times higher in mice treated with the targeted therapeutic, than mice treated with free DOX, and 2.6 times higher than the untargeted nanomedicine that relied only on passive accumulation. The results suggest that aptamer-targeted therapeutics have great potential for improving accumulation of nanomedicines in tumours for therapy.

16.
Nat Nanotechnol ; 13(9): 777-785, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30190620

RESUMO

Studying the interactions between nanoengineered materials and biological systems plays a vital role in the development of biological applications of nanotechnology and the improvement of our fundamental understanding of the bio-nano interface. A significant barrier to progress in this multidisciplinary area is the variability of published literature with regards to characterizations performed and experimental details reported. Here, we suggest a 'minimum information standard' for experimental literature investigating bio-nano interactions. This standard consists of specific components to be reported, divided into three categories: material characterization, biological characterization and details of experimental protocols. Our intention is for these proposed standards to improve reproducibility, increase quantitative comparisons of bio-nano materials, and facilitate meta analyses and in silico modelling.


Assuntos
Biotecnologia/métodos , Simulação por Computador , Modelos Biológicos , Nanoestruturas , Nanotecnologia/métodos , Animais , Humanos , Reprodutibilidade dos Testes
17.
ACS Cent Sci ; 4(6): 718-723, 2018 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-29974067

RESUMO

Covalent PEGylation of biologics has been widely employed to reduce immunogenicity, while improving stability and half-life in vivo. This approach requires covalent protein modification, creating a new entity. An alternative approach is stabilization by encapsulation into polymersomes; however this typically requires multiple steps, and the segregation requires the vesicles to be permeable to retain function. Herein, we demonstrate the one-pot synthesis of therapeutic enzyme-loaded vesicles with size-selective permeability using polymerization-induced self-assembly (PISA) enabling the encapsulated enzyme to function from within a confined domain. This strategy increased the proteolytic stability and reduced antibody recognition compared to the free protein or a PEGylated conjugate, thereby reducing potential dose frequency and the risk of immune response. Finally, the efficacy of encapsulated l-asparaginase (clinically used for leukemia treatment) against a cancer line was demonstrated, and its biodistribution and circulation behavior in vivo was compared to the free enzyme, highlighting this methodology as an attractive alternative to the covalent PEGylation of enzymes.

18.
ACS Sens ; 3(5): 967-975, 2018 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-29634243

RESUMO

Continuous monitoring using nanoparticle-based sensors has been successfully employed in complex biological systems, yet the sensors still suffer from poor long-term stability partially because of the scaffold materials chosen to date. Organosilica core-shell nanoparticles containing a mixture of covalently incorporated pH-sensitive (shell) and pH-insensitive (core) fluorophores is presented as a continuous pH sensor for application in biological media. In contrast to previous studies focusing on similar materials, we sought to investigate the sensor characteristics (dynamic range, sensitivity, response time, stability) as a function of material properties. The ratio of the fluorescence intensities at specific wavelengths was found to be highly sensitive to pH over a physiologically relevant range (4.5-8) with a response time of <100 ms, significantly faster than that of previously reported response times using silica-based particles. Particles produced stable, pH-specific signals when stored at room temperature for more than 80 days. Finally, we demonstrated that the nanosensors successfully monitored the pH of a bacterial culture over 15 h and that pH changes in the skin of mouse cadavers could also be observed via in vivo fluorescence imaging following subcutaneous injection. The understanding gained from linking sensor characteristics and material properties will inform the next generation of optical nanosensors for continuous-monitoring applications.


Assuntos
Técnicas Biossensoriais/instrumentação , Concentração de Íons de Hidrogênio , Nanopartículas/química , Compostos Orgânicos/química , Dióxido de Silício/química , Animais , Bactérias/química , Meios de Cultura , Camundongos , Microscopia Eletrônica de Varredura , Imagem Óptica , Espectroscopia Fotoeletrônica , Pele/química
19.
J Control Release ; 277: 1-13, 2018 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-29501721

RESUMO

The development of therapeutic resistance to targeted anticancer therapies remains a significant clinical problem, with intratumoral heterogeneity playing a key role. In this context, improving the therapeutic outcome through simultaneous targeting of multiple tumor cell subtypes within a heterogeneous tumor is a promising approach. Liposomes have emerged as useful drug carriers that can reduce systemic toxicity and increase drug delivery to the tumor site. While clinically used liposomal drug formulations show marked therapeutic advantages over free drug formulations, ligand-functionalized liposomes that can target multiple tumor cell subtypes may further improve the therapeutic efficacy by facilitating drug delivery to a broader population of tumor cells making up the heterogeneous tumor tissue. Ligand-directed liposomes enable the so-called active targeting of cell receptors via surface-attached ligands that direct drug uptake into tumor cells or tumor-associated stromal cells, and so can increase the selectivity of drug delivery. Despite promising preclinical results demonstrating improved targeting and anti-tumor effects of ligand-directed liposomes, there has been limited translation of this approach to the clinic. Key challenges for translation include the lack of established methods to scale up production and comprehensively characterize ligand-functionalized liposome formulations, as well as the inadequate recapitulation of in vivo tumors in the preclinical models currently used to evaluate their performance. Herein, we discuss the utility of recent ligand-directed liposome approaches, with a focus on dual-ligand liposomes, for the treatment of solid tumors and examine the drawbacks limiting their progression to clinical adoption.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/tendências , Neoplasias/tratamento farmacológico , Pesquisa Médica Translacional/tendências , Animais , Antineoplásicos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Humanos , Ligantes , Lipossomos , Neoplasias/metabolismo , Neoplasias/patologia , Pesquisa Médica Translacional/métodos
20.
Nanoscale ; 10(9): 4258-4266, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29436549

RESUMO

The conjugation of ligands to nanoparticle platforms for the target delivery of therapeutic agents to the tumor tissue is one of the promising anti-cancer strategies. However, conventional nanoparticle platforms are not so effective in terms of the selectivity and transfection efficiency. In this study, we designed and developed a dual-target drug/gene delivery system based on lipid-coated calcium phosphate (LCP) nanoparticles (NPs) for significantly enhanced siRNA cellular uptake and transfection efficiency. LCP NPs loaded with therapeutic siRNA were conjugated with a controlled number of folic acid and/or EGFR-specific single chain fragment antibody (ABX-EGF scFv). The uptake of ABX-EGF scFv-modified (LCP-scFv) and folic acid-modified LCP NPs (LCP-FA) by human breast tumor cells (MDA-MB-468) was significantly higher with an optimal ligand density on each NP surface (LCP-125scFv and LCP-100FA). Co-conjugation with sub-optimal dual ligands (50 FA and 75 ABX-EGF scFv) per LCP NP (LCP-50FA-75scFv) further enhanced the cellular uptake. More significantly, much more NPs were delivered to the MDA-MB-468 tumor tissue in the nude mouse model when LCP-50FA-75scFv NPs were used. Therefore, the new dual-ligand LCP NPs may be a valuable targeting system for human breast cancer diagnosis and therapy.


Assuntos
Fosfatos de Cálcio/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , RNA Interferente Pequeno/administração & dosagem , Neoplasias de Mama Triplo Negativas , Animais , Linhagem Celular Tumoral , Humanos , Ligantes , Lipídeos , Camundongos , Camundongos Nus , Anticorpos de Cadeia Única
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