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1.
Macromol Rapid Commun ; : e2000208, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32529734

RESUMO

Although a range of polymer-protein polyion complex (PIC) micelle systems have been developed in the literature, relatively little attention has been paid to the influence of polymer structure on the assembly, or to the mechanism of disassembly. In this work, Förster resonance energy transfer is used in combination with light sheet fluorescence microscopy and isothermal calorimetry to monitor the formation and stability of PIC micelles with various carboxylic-acid-based binding blocks in MCF-7 cancer spheroid models. All micelles are stable in the presence of free protein, but are unstable in solutions with an ionic strength >200 mm and prone to disassembly at reduced pH. Introducing carbon spacers between the backbone and the binding carboxylic acid results in improved PIC micelle stability at physiological pH, but also increases the pKa of the binding moiety, resulting in improved protein release upon cell uptake. These results give important insights into how to tune PIC micelle stability for controlled protein release in biological environments.

2.
J Am Chem Soc ; 142(25): 10989-10995, 2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32476414

RESUMO

Polymer hexosomes are block copolymer solution morphologies that adopt an internal structure composed of an inverse hexagonal (HII) phase. To date, most polymer hexosomes are reportedly rotationally symmetric solid structures that possess a common feature where hexagonally ordered inverted cylinders rotate along a central axis of symmetry to form circular hoops. Here, we report on the formation of polymer hexosomes whose inverted cylinders orient in an unusual manner, forming hoops that are noncircular. For topological reasons, this led to the generation of four defects in the resulting hexosome structure. We find that these defect-bearing hexosomes are hollow, thereby resembling polymer vesicles or polymersomes with an inverse hexagonal cylindrical morphology in the shell. The topological defects of these so-called "vesicular hexosomes" are enticing as they could serve as a platform to spatially anchor targeting ligands or biomolecules on the surface, while the hollow cylindrical shell and the vesicular lumen could spatially accommodate cargoes within the different domains. We propose that these vesicular hexosomes do not form via a conventional nucleation-growth self-assembly pathway, but rather via a two-step process involving first liquid-liquid phase separation followed by polymer microphase separation.

3.
ACS Appl Mater Interfaces ; 12(27): 30221-30233, 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32515935

RESUMO

The effect of the hydrophobic block length on the morphologies of polymerization-induced self-assembled (PISA) nanoparticles is well understood. However, the influence of drug loading on the phase morphology of the nanoparticles during the PISA process, and the resulting biological function of PISA nanoparticles, has barely been investigated. In this work, we show that the addition of a drug, curcumin, during the PISA process shifts the phase diagram toward different morphologies. The PISA system was based on hydrophilic poly(2-(methacryloyloxy)ethylphosphorylcholine) (PMPC), which was chain extended with hydrophobic methyl methacrylate (MMA) in various concentrations of curcumin. According to transmission electron microscopy, the presence of curcumin led to the transition of, for example, worms to polymersome and micelles to worms analysis. To understand the interaction between polymer particles and drug, small-angle X-ray scattering (SAXS), small-angle neutron scattering (SANS), and fluorescence lifetime measurements were carried out. These measurements show that curcumin is predominantly located in the core in the case of micelles and worms while it is found in the shell of polymersomes. The change in morphology influences the cellular uptake by MCF-7 cells and the movement of the particles in multicellular cancer spheroids (3D model). With the increasing amount of drug, the cellular uptake of micelles and worms was enhanced with the increasing grafting density of MPC chains, which contrasts the decreasing cellular uptake in the higher drug-loaded polymersomes due to the lower shell hydration.

4.
Adv Healthc Mater ; 9(13): e2000261, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32424998

RESUMO

There is a need for improved nanomaterials to simultaneously target cancer cells and avoid non-specific clearance by phagocytes. An ellipsoidal polymersome system is developed with a unique tunable size and shape property. These particles are functionalized with in-house phage-display cell-targeting peptide to target a medulloblastoma cell line in vitro. Particle association with medulloblastoma cells is modulated by tuning the peptide ligand density on the particles. These polymersomes has low levels of association with primary human blood phagocytes. The stealth properties of the polymersomes are further improved by including the peptide targeting moiety, an effect that is likely driven by the peptide protecting the particles from binding blood plasma proteins. Overall, this ellipsoidal polymersome system provides a promising platform to explore tumor cell targeting in vivo.

5.
Macromol Rapid Commun ; : e2000166, 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32383502

RESUMO

Three monoamino-substituted anthraquinone derivatives (AAQs), that is, 1-aminoanthraquinone (AAQ), 1-(methylamino)anthraquinone (MAAQ), and 1-(benzamido)anthraquinone (BAAQ), incorporated with various additives [e.g., triethanolamine (TEAOH) and phenacyl bromide (PhC(═O)CH2 Br)] are investigated for their roles as photoinitiating systems of free radical photopolymerization of (meth)acrylate monomers upon the exposure to UV to green LEDs. The AAQs-based photoinitiating systems, AAQ/TEAOH/PhC(═O)CH2 Br and BAAQ/TEAOH/PhC(═O)CH2 Br photoinitiators exhibit the highest efficiency for the free radical photopolymerization of DPGDA under the irradiation of blue LED and UV LED, respectively, which is consistent with the extent of overlap between their absorption spectra and the emission spectra of the LEDs. AAQ/TEAOH/PhC(═O)CH2 Br photoinitiator can also initiate the free radical photopolymerization of different (meth)acrylate monomers, with an efficiency dependent on the chemical structures of these monomers.

6.
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.

7.
Biomacromolecules ; 21(3): 1222-1233, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32022540

RESUMO

Tumor targeting has revolutionized cancer research, especially active cellular targeting of nanoparticles, where they are specifically homed to the pathological site to deliver the therapeutics. This strategy, which involves the utilization of affinity ligands on the surface of the nanocarriers, minimizes the nonspecific uptake of nanocarriers and the subsequent harmful side effects in healthy cells. Estrone, one of the mammalian estrogens, has affinity for estrogen receptors (ERα), which are overexpressed in hormone-responsive breast cancers. Despite holding promise, the potential of estrone in active targeting of nanoparticles has barely been explored. Herein, we developed an estrone-appended polyion complex (PIC) micelle to deliver melittin, a cytotoxic peptide, to breast cancer cells. Amino functionalization of estrone was performed to conjugate estrone to the diblock polymer synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization. Estrone-conjugated poly(ethylene glycol) methyl ether methacrylate-b-poly tert-butyl methacrylate (POEGMEMA-PtBuMA) could complex with melittin to form PIC micelles of size around 60 nm ensuing from the electrostatic interaction of the deprotected polymer and melittin in aqueous media. Poly(ethylene glycol) methyl ether acrylate-b-poly acrylic acid (POEGMEA-PAA) was also later incorporated to afford PIC micelles that could exhibit similar cytotoxicity to free melittin in the cytotoxicity studies. The estrone-attached PIC micelles exhibited improved cytotoxicity in two-dimensional (2D) and three-dimensional (3D) cellular models of MCF-7 cells. Cross-linking of the PIC micelles was also performed to improve the stability of the micelles and prevent melittin degradation from enzymatic attack. Flow cytometry demonstrated an enhanced cellular uptake greater than sixfold with the estrone-conjugated PIC micelles, thereby establishing a profound difference in the targeting efficacy of the PIC micelles between MCF-7 and MDA-MB-231 cells. Furthermore, the distribution of the PIC micelles in the spheroids was revealed by light sheet microscopy. The results demonstrate the potential of estrone-anchored PIC micelles for targeted delivery of therapeutics to hormone-responsive breast cancer cells.

8.
Macromol Rapid Commun ; 41(1): e1900499, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31736180

RESUMO

Nanocellulose is an excellent carrier to deliver drugs, as the material is biocompatible and has a desirable non-spherical shape. However, nanocellulose displays low solubility in aqueous solution and needs to be modified with water-soluble polymers in order to achieve high colloidal stability. In this study, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl or (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO)-oxidized cellulose nanofibers bearing carboxylic acid moieties (TOCNs) are modified by nitrile imine-mediated tetrazole/carboxylic acid ligation. The advantage of this reaction is that TOCNs do not need to be modified further and the polymer with tetrazole end-functionalities can be directly clicked onto the TOCNs forming fluorescent functional groups. Poly(2-hydroxyethyl acrylate) with a tetrazole end-functionality is prepared using RAFT polymerization. The polymer is mixed with TOCNs and after irradiation at λ = 326 nm for 10 h, fluorescent pHEA-g-TOCNs are obtained. The polymer-grafted nanocellulose is found to disperse well in water and has only limited albumin binding. The uptake of these nanoparticles by MCF-7 breast cancer cell lines can now be monitored by fluorescent microscopy without further modification. Excess negatively charged carboxylic groups of TOCNs allow doxorubicin loading by electrostatic interactions at various drug-loading capacities. Higher drug loading is more efficient in inhibiting the cell proliferation, highlighting the effect of drug loading on toxicity.

9.
Macromol Biosci ; 20(1): e1900221, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31800165

RESUMO

It is known that the size of gold nanoparticles (GNPs) is not the only determining factor in the uptake by cells such as cancer cells. The surface functionalization plays a crucial role, in particular the nature of the ligand as well as the molecular weight and the grafting density. Here, poly(2-hydroxy ethyl) acrylate (pHEA) with molecular weights ranging from 10, 20 to 39 g mol-1 via reversible addition-fragmentation chain transfer polymerization is synthesized. These polymers are used directly to coat GNPs with sizes of 20, 40, and 70 nm as the trithiocarbonate functionality can strongly bind to the gold surface. The library of nine GNP is found to be nontoxic against lung carcinoma cells A549 and has negligible albumin protein absorption as determined by quartz crystal microbalance. Laser scanning confocal microscopy and flow cytometry reveal that GNP coated with medium length pHEA displays the highest cellular uptake while the effect of the size is not statistically significant. In contrast, multicellular tumor spheroids, which is a 3D model that simulates the tissue, enable the penetration of GNP coated with the longest pHEA chain while it also appears that smaller GNPs have now a clear advantage.

10.
Nanoscale ; 11(48): 23259-23267, 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31782458

RESUMO

Recently the role of protein absorption in nanoparticle drug delivery has gathered significant attention as the protein corona can significantly decide on the fate of nanoparticles in the body. Although it is known that the surface chemistry will significantly influence the amount and type of bound protein, there is little known about the effect of surface roughness and surface topography on the interaction. In this work, we show how patchy nanoparticles can noticeably reduce the adsorption of proteins compared to spherical nanoparticles with a smooth surface as demonstrated using six ABC triblock terpolymers based on glucose, mannose and galactose. To obtain patchy nanoparticles, poly(2-d-sugar ethyl acrylate)-b-poly (n-butyl acrylate)-b-poly(4-vinyl pyridine) (PSugEA-b-PBuA-b-P4VP) was prepared by reversible addition-fragmentation chain-transfer (RAFT) polymerization and assembled into nanoparticles with a patch-like appearance and a hydrodynamic diameter of around 130-160 nm. As control, smooth nanoparticles were prepared from poly(2-d-sugar ethyl acrylate)-b-poly (n-butyl acrylate)-b-polystyrene (PSugEA-b-PBuA-b-PS). The patchy nanoparticles displayed significantly reduced protein absorption when exposed to serum-supplemented cell culture media, as observed using dynamic light scattering. The smooth particles, however, supported the formation of a large protein corona. Additionally, an enrichment of haemoglobin was observed in the corona compared to the serum protein in solution. The amount of albumin on the surface was observed to be dependent on the type of sugar with glucose resulting in the highest absorption. The protein corona led to cellular uptake that was unrelated to the underlying sugar, which was supposed to help targeting specific cell lines. This example demonstrated how the protein corona can override any attempts to target receptor expressing cells.


Assuntos
Nanopartículas/química , Nanopartículas/metabolismo , Coroa de Proteína/química , Coroa de Proteína/metabolismo , Adsorção , Animais , Proteínas Sanguíneas/metabolismo , Linhagem Celular , Sistemas de Liberação de Medicamentos , Glicosilação , Humanos , Polímeros/química , Polímeros/metabolismo , Propriedades de Superfície
11.
ACS Appl Mater Interfaces ; 11(35): 32328-32338, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31393104

RESUMO

The influence of interfacial shear strength (IFSS) between processed short S-glass fibers (250 and 350 µm in length, 5 µm in diameter) and the dental resin (a mixture of urethane dimethacrylate and triethylene glycol dimethacrylate monomers) on the mechanical properties has been studied experimentally. The surface profile of short S-glass fibers was modified using a selective atomic level metal etching process and simple silanization process to enhance the interfacial properties. The S-glass fibers were etched in acid solutions to increase the surface roughness and selectively remove Al3+ and Mg2+ ions, which promoted the mechanical and chemical interfacial bonding reactions. The single glass fiber tensile and microdroplet pull-out tests were performed to investigate the effects of interfacial properties on the flexural strength of the resultant composites. The surface modified S-glass fibers showed an increase of 11-40% in IFSS compared to untreated glass fibers. Composites reinforced with 350 µm length glass fibers (AR-70), which were treated in piranha solution for 4 h, showed the highest improvement in overall mechanical properties, flexural strength (34.2%), modulus (9.7%), and breaking energy (51.9%), compared to the untreated fiber-reinforced composites. The modified Lewis-Nielsen equation was developed using the effective fiber length factor to accurately predict the modulus of the short fiber-reinforced composites and validated with experimental results.


Assuntos
Resinas Compostas/química , Vidro/química , Teste de Materiais , Metacrilatos/química , Polietilenoglicóis/química , Ácidos Polimetacrílicos/química , Poliuretanos/química , Resistência ao Cisalhamento , Estresse Mecânico , Propriedades de Superfície
12.
ACS Appl Mater Interfaces ; 11(31): 28278-28288, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31290309

RESUMO

Understanding the nature of the drug-polymer interactions in micellar drug delivery systems and what happens with the drug and the polymer once the complex has formed is essential for the rational design of the polymeric matrices suitable for a particular drug. In this work, glycopolymeric vesicles-a block copolymer, poly(1-O-methacryloyl-ß-d-fructopyranose)-b-poly(methyl methacrylate), (PFru36-PMMA160),-designed to target tumor cells loaded with two drugs, ellipticine and curcumin, were characterized. Advanced solid-state NMR spectroscopy and single-crystal/powder X-ray diffraction (XRD) combined with CASTEP calculations shed light on the nature of the drug, the polymer, and their interactions. While the low drug loading (ca. 5%) ensured that the structure, size, and shape of the polymeric vesicles did not change significantly, the solid-state forms of the drugs changed markedly. Upon loading into the vesicles, ellipticine favored a highly ordered form distinctly different from the bulk drug as indicated by 13C solid-state NMR spectroscopy. A detailed analysis of the CASTEP-calculated 13C spectra derived from crystallographic data based on the lowest mean absolute error showed the best match with form I. Moreover, ellipticine before loading was found as a new polymorph and was described by single-crystal XRD as a new orthorhombic Form III. Likewise, curcumin, originally present in monoclinic Form I was found to recrystallize as metastable orthorhombic Form II inside the vesicles. Intermolecular interactions between the polymeric vesicles and the drugs, ellipticine as well as curcumin, were detected using 2D 1H magic angle spinning experiments, indicating that the drugs are localized in the hydrophobic layer of the vesicles.


Assuntos
Antineoplásicos/química , Curcumina/química , Portadores de Fármacos/química , Glicoconjugados/química , Ressonância Magnética Nuclear Biomolecular , Interações Hidrofóbicas e Hidrofílicas
13.
Macromol Rapid Commun ; 40(16): e1900234, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31210405

RESUMO

The design and development of photoinitiating systems applicable to UV or even visible light delivered from light-emitting diodes (LEDs) has been attracting increasing attention due to their great potential applications in various fields. Compared to the strategy of synthesizing novel compounds, the exploration of existing chemicals with interesting photochemical/photophysical properties for their usage as photoinitiators is more appealing and easily commercialized. Nevertheless, a number of compounds such as monoamino-substituted anthraquinone derivatives, which are intensively investigated for their photophysical and photochemical properties, have seldom been studied for their roles as photoinitiators under LED irradiation. Herein, three monoamino-substituted anthraquinone derivatives, that is, 1-aminoanthraquinone, 1-(methylamino)anthraquinone and 1-(benzamido)anthraquinone, are studied for their potential as photoinitiators. The photoinitiation mechanism of these monoamino-substituted anthraquinone derivatives, when combined with iodonium salt, is first clarified using computational quantum chemistry, fluorescence, steady-state photolysis, and electron spin resonance spin-trapping techniques. Then, their photoinitiation ability for the cationic photopolymerization of epoxide and divinyl ether monomers is also investigated.


Assuntos
Antraquinonas/química , Luz , Antraquinonas/síntese química , Cátions/síntese química , Cátions/química , Estrutura Molecular , Processos Fotoquímicos , Polimerização
14.
Chem Soc Rev ; 48(15): 4019-4035, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31187792

RESUMO

Polymersomes are self-assembled hollow membrane sacs that are not only able to encapsulate hydrophobic and/or hydrophilic molecules, but also possess exceptional chemical and physical stability, structural versatility, and surface modifiability. For the above reasons, polymersomes have in recent years emerged as a powerful tool for a wide range of applications in the fields of biomimicry and drug delivery. The full potential of polymersomes, however, has yet to be harnessed due to a lack of appreciation of existing shape control methods. This very much contrasts the field of inorganic nanoparticle synthesis where non-spherical hollow metal nanoparticles are routinely prepared and used. Here, we summarize recent efforts over the past decade to study the morphological transformation of conventionally spherical polymersomes into non-spherical polymersomes.

15.
Chem Sci ; 10(9): 2725-2731, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30996990

RESUMO

The creation of "soft" deformable hollow polymeric nanoparticles with complex non-spherical shapes via block copolymer self-assembly remains a challenge. In this work, we show that a perylene-bearing block copolymer can self-assemble into polymeric membrane sacs (polymersomes) that not only possess uncommonly faceted polyhedral shapes but are also intrinsically fluorescent. Here, we further reveal for the first time an experimental visualization of the entire polymersome faceting process. We uncover how our polymersomes facet through a sphere-to-polyhedron shape transformation pathway that is driven by perylene aggregation confined within a topologically spherical polymersome shell. Finally, we illustrate the importance in understanding this shape transformation process by demonstrating our ability to controllably isolate different intermediate polymersome morphologies. The findings presented herein should provide opportunities for those who utilize non-spherical polymersomes for drug delivery, nanoreactor or templating applications, and those who are interested in the fundamental aspects of polymersome self-assembly.

16.
Angew Chem Int Ed Engl ; 58(22): 7335-7340, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-30866152

RESUMO

Recent years have seen an increased interest in the use of ABC triblock terpolymers to bottom-up assemble multicompartment patchy nanoparticles. Despite these experimental and theoretical efforts, the applications of polymer-based patchy nanoparticles remain rather limited. One of the major challenges that eclipses their potential is the lack of knowledge to selectively encapsulate cargoes within different compartments that are separated in the nanometer length scale. Here, strategies are reported to segregate two chemically distinct molecules in either the patches or core compartment of patchy nanoparticles that bear a (bioactive) sugar corona. The potential use of these bioactive patchy nanoparticles containing compartmentalized cargoes for simultaneous drug delivery with real-time release monitoring capabilities is further demonstrated.

17.
Sci Rep ; 9(1): 3851, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30846858

RESUMO

Interfacial bonding between fibre and matrix is most critical to obtain enhanced mechanical properties of the resulting composites. Here we present a new surface tailoring method of selective wet etching and organosilicon monomers (3-(Trimethoxysilyl) propyl methacrylate, TMSPMA) deposition process on the short S-Glass fibre as a reinforcing material, resulting in increased mechanical retention and strong chemical bonding between glass fibres and polymer resin (a mixture of triethylene glycol dimethacrylate (TEGDMA) and urethane dimethacrylate (UDMA) monomers). The effect of surface modification on fibre matrix interfacial strength was investigated through microdroplet tests. An S-Glass fibre treated with piranha solution (a mixture of H2O2 and H2SO4) for 24 hours followed by TMSPMA surface silanization shows highest increase up to 39.6% in interfacial shear strength (IFSS), and critical fibre length could be reduced from 916.0 µm to 432.5 µm. We find the optimal surface treatment condition in that the flexural strength of dental composites reinforced by the S-Glass fibres enhanced up to 22.3% compared to the composites without fibre surface treatments. The significant elevation in strength is attributed to changes in the surface roughness of glass fibres at atomic scale, specifically by providing the multiplied spots of the chemical bridge and nano-mechanical interlocking. The findings offer a new strategy for advanced tailoring of short S-Glass fibres to maximise the mechanical properties of biomedical and dental composites.

18.
Biomater Sci ; 7(4): 1652-1660, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30724288

RESUMO

INTRODUCTION: Ovarian cancer is often diagnosed at a late stage, when disease has spread to extra-pelvic regions such as the omentum. There are limited treatment options available for women with extensive disease and tumours often relapse after current chemotherapy regimens. Therefore, novel drugs should be investigated for the treatment of ovarian cancer. A 3D organotypic model of ovarian cancer can provide a specific platform for the evaluation of nano-drugs. Using patient derived primary cells, the 3D model mimics the ovarian metastatic microenvironment allowing efficient and reproducible testing of many nanoparticles. Dichlororuthenium(ii) (p-cymene) (1,3,5-triaza-7-phosphaadamantane) (RAPTA-C) conjugated fructose-micelles have been used as the promising nano-drug for the treatment of metastatic cancer. Therefore we aimed to investigate the anti-metastatic properties of RAPTA-C conjugated micelles in ovarian cancer metastasis. METHODS: Ovarian cancer cell adhesion and invasion into a model of omentum were analyzed with and without RAPTA-C conjugated micelles in a range of conditions. RESULTS: We observed that RAPTA-C showed low general toxicity to both primary healthy and cancer cell lines. RAPTA-C loaded micelles significantly enhance the internalization of ruthenium inside the cells compared to free drugs. RAPTA-C did not affect adhesion of OVCAR4 ovarian cancer cells; however, it significantly inhibited invasion of these cells within the omentum model, either in its free form or as cargos inside the micelles. However, when OVCAR4 were treated prior to implantation, invasion was not inhibited. CONCLUSION: A 3D organotypic model provides a clinically relevant and simple method to evaluate the efficiency of nano-drug treatment of ovarian cancer. The ability to inhibit metastasis of RAPTA-C delivered in fructose coated nanoparticles was investigated for the first time via this model. These results provide a good basis to continue the development of this nano-drug in vivo.


Assuntos
Antineoplásicos/farmacologia , Modelos Biológicos , Compostos Organometálicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Cimenos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Frutose/química , Humanos , Micelas , Nanopartículas/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Neoplasias Ovarianas/patologia , Células Tumorais Cultivadas
19.
ACS Macro Lett ; 8(1): 95-101, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30775156

RESUMO

Naturally occurring glycoconjugates possess carbohydrate moieties that fulfill essential roles in many biological functions. Through conjugation of carbohydrates to therapeutics or imaging agents, naturally occurring glycoconjugates are mimicked and efficient targeting or increased cellular uptake of glycoconjugated macromolecules is achieved. In this work, linear and cyclic glucose moieties were functionalized with methacrylates via enzymatic synthesis and used as building blocks for intramolecular cross-linked single-chain glycopolymer nanoparticles (glyco-SCNPs). A set of water-soluble sub-10 nm-sized glyco-SCNPs was prepared by thiol-Michael addition cross-linking in water. Bioactivity of various glucose-conjugated glycopolymers and glyco-SCNPs was evaluated in binding studies with the glucose-specific lectin Concanavalin A and by comparing their cellular uptake efficiency in HeLa cells. Cytotoxicity studies did not reveal discernible cytotoxic effects, making these SCNPs promising candidates for ligand-based targeted imaging and drug delivery.

20.
Biomacromolecules ; 20(4): 1545-1554, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30768256

RESUMO

Drug delivery carriers are now widely established because they can increase the therapeutic efficiency of drugs. In general, the aim in this field is to create effective carriers that have large amounts of drugs loaded to minimize drug carrier material that needs to be disposed of. However, there has been little attention so far in the literature on the effect of the amount of loaded drugs on the biological activity. In this paper, we are trying to answer the question of how the drug-loading content will affect the in vitro activity. We use two methods to load paclitaxel (PTX) into micelles based on the glycopolymer, poly(1- O-methacryloyl-ß-d-fructopyranose)- block-poly(methyl methacylate) (Poly(1- O-MAFru)35- b-PMMA145). In the one-step method, the drug is loaded into the particles during the self-assembly process. However, the size of nanoparticle increased with the PTX content from 26 to 50 nm, triggering enhanced cellular uptake by MCF-7 and MDA-MB-231, which was caused by changes in diameter size and not by changes in drug concentration. To keep the nanoparticle size constant, preformed micelles were loaded with PTX (two-step process). The increasing amount of loaded drug led to decreased cellular uptake and reduced cytotoxicity by the cancer cell lines. Small-angle neutron scattering and small-angle X-ray scattering, supported by transmission electron microscopy and dynamic light scattering, exposed the PTX location in the shell. This caused shrinkage of the shell and lower levels of shell hydration, resulting in lower cellular uptake and lower cytotoxicity. Upon the release of PTX, the shell regained its original level of hydration. We could show that because drug loading causes morphology changes, in either the shell or the size, it is impossible to separate the parameters that will influence the biological activity. Although the same phenomenon may not apply to every drug delivery system, it needs to be considered that except for the well-known parameters that affect cell uptake-size, shape, surface chemistry, type of nanoparticle, and presence of bioactive groups-the amount of loaded drugs might change the physicochemical parameters of the nanoparticle and thus the in vitro and potentially the in vivo outcomes.


Assuntos
Portadores de Fármacos , Glicoconjugados , Micelas , Nanopartículas/química , Paclitaxel , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Glicoconjugados/síntese química , Glicoconjugados/química , Glicoconjugados/farmacocinética , Glicoconjugados/farmacologia , Humanos , Células MCF-7 , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Tamanho da Partícula
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