Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Biomater Sci ; 11(19): 6545-6560, 2023 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-37593851

RESUMO

The therapeutic efficacy of nanomedicines is highly dependent on their access to target sites in the body, and this in turn is markedly affected by their size, shape and transport properties in tissue. Although there have been many studies in this area, the ability to design nanomaterials with optimal physicochemical properties for in vivo efficacy remains a significant challenge. In particular, it is often difficult to quantify the detailed effects of cancer drug delivery systems in vivo as tumour volume reduction, a commonly reported marker of efficacy, does not always correlate with cytotoxicity in tumour tissue. Here, we studied the behaviour in vivo of two specific poly(2-hydroxypropyl methacrylamide) (pHPMA) pro-drugs, with hyperbranched and chain-extended branched architectures, redox-responsive backbone components, and pH-sensitive linkers to the anti-cancer drug doxorubicin. Evaluation of the biodistribution of these polymers following systemic injection indicated differences in the circulation time and organ distribution of the two polymers, despite their very similar hydrodynamic radii (∼10 and 15 nm) and architectures. In addition, both polymers showed improved tumour accumulation in orthotopic triple-negative breast cancers in mice, and decreased accumulation in healthy tissue, as compared to free doxorubicin, even though neither polymer-doxorubicin pro-drug decreased overall tumour volume as much as the free drug under the dosing regimens selected. However, the results of histopathological examinations by haematoxylin and eosin, and TUNEL staining indicated a higher population of apoptotic cells in the tumours for both polymer pro-drug treatments, and in turn a lower population of apoptotic cells in the heart, liver and spleen, as compared to free doxorubicin treatment. These data suggest that the penetration of these polymer pro-drugs was enhanced in tumour tissue relative to free doxorubicin, and that the combination of size, architecture, bioresponsive backbone and drug linker degradation yielded greater efficacy for the polymers as measured by biomarkers than that of tumour volume. We suggest therefore that the effects of nanomedicines may be different at various length scales relative to small molecule free drugs, and that penetration into tumour tissue for some nanomedicines may not be as problematic as prior reports have suggested. Furthermore, the data indicate that dual-responsive crosslinked polymer-prodrugs in this study may be effective nanomedicines for breast cancer chemotherapy, and that endpoints beyond tumour volume reduction can be valuable in selecting candidates for pre-clinical trials.


Assuntos
Pró-Fármacos , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Polímeros/química , Distribuição Tecidual , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Doxorrubicina/química , Linhagem Celular Tumoral , Portadores de Fármacos/química
2.
Mater Horiz ; 10(7): 2706, 2023 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-37098689

RESUMO

Correction for 'Elucidating the role of multivalency, shape, size and functional group density on antibacterial activity of diversified supramolecular nanostructures enabled by templated assembly' by Amrita Sikder et al., Mater. Horiz., 2023, 10, 171-178, https://doi.org/10.1039/D2MH01117D.

3.
Mater Horiz ; 10(1): 171-178, 2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36321619

RESUMO

With the increased prevalence of antibiotic-resistant infections, there is an urgent need to develop novel antibacterial materials. In addition, gaining a complete understanding of the structural features that impart activity toward target microorganisms is essential to enable materials optimisation. Here we have reported a rational design to fabricate antibacterial supramolecular nanoparticles with variable shape, size and cationic group density, by exploiting noncovalent interactions between a shape determining template amphiphile and a cationic amphiphile to introduce charge on the nanoparticle surface. We have shown that the monomeric cationic amphiphile alone showed poor antibacterial activity, whereas nanostructures formed by co-assembling the complementary units showed significantly enhanced antibacterial efficiency. Further, the systematic variation of several structural parameters such as shape, spacing between the cationic groups and size of these nanostructures allowed us to elicit the role of each parameter on the overall antibacterial properties. Finally, we investigated the origin of the differing antibacterial activity of these nanoparticles having different shape and size but with the same molecular composition, by comparing the thermodynamic parameters of their binding interactions with a bacterial membrane mimic.


Assuntos
Nanopartículas , Nanoestruturas , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/uso terapêutico , Nanoestruturas/química , Nanopartículas/química , Bactérias , Termodinâmica
4.
Chemistry ; 28(58): e202201877, 2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-35857384

RESUMO

Herein, a library of trifluoroethyl substituted aminomaleimide derivatives are reported with small size and enhanced emissions in both solution and solid-state. A diCH2 CF3 substituted aminochloromaleimide exhibits the most efficient dual-state emission (Φf >50 % in solution and solid-state), with reduced quenching from protic solvents. This is attributed to the reduction of electron density on the maleimide ring and suppressed π-π stacking in the solid-state. This mechanism was explored in-depth by crystallographic analysis, and modelling of the electronic distribution of HOMO-LUMO isosurfaces and NCI plots. Hence, these dual-state dyes overcome the limitations of single-state luminescence and will serve as an important step forward for this rapidly developing nascent field.

5.
ACS Macro Lett ; 11(4): 498-503, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35575334

RESUMO

Polymers that exhibit a lower critical solution temperature (LCST) have been of great interest for various biological applications such as drug or gene delivery, controlled release systems, and biosensing. Tuning the LCST behavior through control over polymer composition (e.g., upon copolymerization of monomers with different hydrophobicity) is a widely used method, as the phase transition is greatly affected by the hydrophilic/hydrophobic balance of the copolymers. However, the lack of a general method that relates copolymer hydrophobicity to their temperature response leads to exhaustive experiments when seeking to obtain polymers with desired properties. This is particularly challenging when the target copolymers are comprised of monomers that individually form nonresponsive homopolymers, that is, only when copolymerized do they display thermoresponsive behavior. In this study, we sought to develop a predictive relationship between polymer hydrophobicity and cloud point temperature (TCP). A series of statistical copolymers were synthesized based on hydrophilic N,N-dimethyl acrylamide (DMA) and hydrophobic alkyl acrylate monomers, and their hydrophobicity was compared using surface area-normalized octanol/water partition coefficients (Log Poct/SA). Interestingly, a correlation between the Log Poct/SA of the copolymers and their TCPs was observed for the P(DMA-co-RA) copolymers, which allowed TCP prediction of a demonstrative copolymer P(DMA-co-MMA). These results highlight the strong potential of this computational tool to improve the rational design of copolymers with desired temperature responses prior to synthesis.


Assuntos
Acrilamida , Polímeros , Interações Hidrofóbicas e Hidrofílicas , Transição de Fase , Polimerização , Polímeros/química
6.
Biomater Sci ; 10(9): 2328-2344, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35380131

RESUMO

Hyperbranched polymers have many promising features for drug delivery, owing to their ease of synthesis, multiple functional group content, and potential for high drug loading with retention of solubility. Here we prepared hyperbranched N-(2-hydroxypropyl)methacrylamide (HPMA) polymers with a range of molar masses and particle sizes, and with attached dyes, radiolabel or the anticancer drug gemcitabine. Reversible addition-fragmentation chain transfer (RAFT) polymerisation enabled the synthesis of pHPMA polymers and a gemcitabine-comonomer functionalised pHPMA polymer pro-drug, with diameters of the polymer particles ranging from 7-40 nm. The non-drug loaded polymers were well-tolerated in cancer cell lines and macrophages, and were rapidly internalised in 2D cell culture and transported efficiently to the centre of dense pancreatic cancer 3D spheroids. The gemcitabine-loaded polymer pro-drug was found to be toxic both to 2D cultures of MIA PaCa-2 cells and also in reducing the volume of MIA PaCa-2 spheroids. The non-drug loaded polymers caused no short-term adverse effects in healthy mice following systemic injection, and derivatives of these polymers labelled with 89Zr-were tracked for their distribution in the organs of healthy and MIA PaCa-2 xenograft bearing Balb/c nude mice. Tumour accumulation, although variable across the samples, was highest in individual animals for the pHPMA polymer of ∼20 nm size, and accordingly a gemcitabine pHPMA polymer pro-drug of ∼18 nm diameter was evaluated for efficacy in the tumour-bearing animals. The efficacy of the pHPMA polymer pro-drug was very similar to that of free gemcitabine in terms of tumour growth retardation, and although there was a survival benefit after 70 days for the polymer pro-drug, there was no difference at day 80. These data suggest that while polymer pro-drugs of this type can be effective, better tumour targeting and enhanced in situ release remain as key obstacles to clinical translation even for relatively simple polymers such as pHPMA.


Assuntos
Neoplasias , Pró-Fármacos , Acrilamidas , Animais , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Polímeros
7.
Biomacromolecules ; 22(11): 4459-4469, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34495643

RESUMO

The past decades have seen significant research effort in the field of polymers for a range of biomedical applications, driven by the promising prospect of these materials for realizing next generation therapeutics in the clinic. In this regard, it is widely accepted that polymer properties such as chemistry, charge, and block composition, as well as properties of their self-assemblies including size, shape, surface chemistry, and biodegradation, all influence and direct their interactions with cells and biological membranes. In particular, polymer hydrophobicity is a property of interest, with growing evidence demonstrating the significant impact that hydrophobic interactions with lipid membranes and proteins can have on biomaterial application efficacy within the body. However, to date, this phenomenon has been relatively underexplored, and therefore there exists no clear universal understanding to direct polymer design. In this Perspective, we highlight important contributions to this field, focusing on seminal studies which investigate experimentally and theoretically how incorporation of hydrophobic moieties within polymer systems can influence their ultimate properties when used in biomedical applications. In this way, we aim to signify future directions in the design of highly performing polymers for biomedicine, making a case for the importance of standardized computational modeling to achieve widely applicable conclusions and facilitate future translational efforts.


Assuntos
Materiais Biocompatíveis , Polímeros , Interações Hidrofóbicas e Hidrofílicas , Proteínas
8.
Polymers (Basel) ; 13(13)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34279346

RESUMO

Hydrogels based on biopolymers, such as alginate, are commonly used as scaffolds in tissue engineering applications as they mimic the features of the native extracellular matrix (ECM). However, in their native state, they suffer from drawbacks including poor mechanical performance and a lack of biological functionalities. Herein, we have exploited a crystallization-driven self-assembly (CDSA) methodology to prepare well-defined one-dimensional micellar structures with controlled lengths to act as a mimic of fibrillar collagen in native ECM and improve the mechanical strength of alginate-based hydrogels. Poly(ε-caprolactone)-b-poly(methyl methacrylate)-b-poly(N, N-dimethyl acrylamide) triblock copolymers were self-assembled into 1D cylindrical micelles with precise lengths using CDSA epitaxial growth and subsequently combined with calcium alginate hydrogel networks to obtain nanocomposites. Rheological characterization determined that the inclusion of the cylindrical structures within the hydrogel network increased the strength of the hydrogel under shear. Furthermore, the strain at flow point of the alginate-based hydrogel was found to increase with nanoparticle content, reaching an improvement of 37% when loaded with 500 nm cylindrical micelles. Overall, this study has demonstrated that one-dimensional cylindrical nanoparticles with controlled lengths formed through CDSA are promising fibrillar collagen mimics to build ECM scaffold models, allowing exploration of the relationship between collagen fiber size and matrix mechanical properties.

9.
ACS Cent Sci ; 7(1): 30-38, 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33532567

RESUMO

Polymersomes are a class of synthetic vesicles composed of a polymer membrane surrounding an aqueous inner cavity. In addition to their overall size, the thickness and composition of polymersome membranes determine the range of potential applications in which they can be employed. While synthetic polymer chemists have made great strides in controlling polymersome membrane parameters, measurement of their permeability to various analytes including gases, ions, organic molecules, and macromolecules remains a significant challenge. In this Outlook, we compare the general methods that have been developed to quantify polymersome membrane permeability, focusing in particular on their capability to accurately measure analyte flux. In addition, we briefly highlight strategies to control membrane permeability. Based on these learnings, we propose a set of criteria for designing future methods of quantifying membrane permeability such that the passage of a variety of molecules into and out of their lumens can be better understood.

10.
Nat Rev Chem ; 5(1): 21-45, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37118104

RESUMO

Shape and size play powerful roles in determining the properties of a material; controlling these aspects with precision is therefore an important, fundamental goal of the chemical sciences. In particular, the introduction of shape anisotropy at the nanoscale has emerged as a potent way to access new properties and functionality, enabling the exploration of complex nanomaterials across a range of applications. Recent advances in DNA and protein nanotechnology, inorganic crystallization techniques, and precision polymer self-assembly are now enabling unprecedented control over the synthesis of anisotropic nanoparticles with a variety of shapes, encompassing one-dimensional rods, dumbbells and wires, two-dimensional and three-dimensional platelets, rings, polyhedra, stars, and more. This has, in turn, enabled much progress to be made in our understanding of how anisotropy and particle dimensions can be tuned to produce materials with unique and optimized properties. In this Review, we bring these recent developments together to critically appraise the different methods for the bottom-up synthesis of anisotropic nanoparticles enabling exquisite control over morphology and dimensions. We highlight the unique properties of these materials in arenas as diverse as electron transport and biological processing, illustrating how they can be leveraged to produce devices and materials with otherwise inaccessible functionality. By making size and shape our focus, we aim to identify potential synergies between different disciplines and produce a road map for future research in this crucial area.

11.
ACS Macro Lett ; 9(11): 1700-1707, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33299653

RESUMO

The seemingly simple notion of the hydrophobic effect can be viewed from multiple angles involving theory, simulation, and experiments. This viewpoint examines five attributes of predictive models to enhance synthetic efforts as well as experimental methods to quantify hydrophobicity. In addition, we compare existing predictive models against experimental data for polymer surface tension, lower critical solution temperature, solution self-assembly morphology, and degradation behavior. Key conclusions suggest that both the Hildebrand solubility parameters (HSPs) and surface area-normalized Log P (Log P SA-1) values provide unique and complementary insights into polymer phenomena. In particular, HSPs appear to better describe bulk polymer phenomena for thermoplastics such as surface tension, while Log P SA-1 values are well-suited for describing and predicting the behavior of polymers in solution.

12.
Adv Healthc Mater ; 9(22): e2000892, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33073536

RESUMO

The size, shape, and underlying chemistries of drug delivery particles are key parameters which govern their ultimate performance in vivo. Responsive particles are desirable for triggered drug delivery, achievable through architecture change and biodegradation to control in vivo fate. Here, polymeric materials are synthesized with linear, hyperbranched, star, and micellar-like architectures based on 2-hydroxypropyl methacrylamide (HPMA), and the effects of 3D architecture and redox-responsive biodegradation on biological transport are investigated. Variations in "stealth" behavior between the materials are quantified in vitro and in vivo, whereby reduction-responsive hyperbranched polymers most successfully avoid accumulation within the liver, and none of the materials target the spleen or lungs. Functionalization of selected architectures with doxorubicin (DOX) demonstrates enhanced efficacy over the free drug in 2D and 3D in vitro models, and enhanced efficacy in vivo in a highly aggressive orthotopic breast cancer model when dosed over schedules accounting for the biodistribution of the carriers. These data show it is possible to direct materials of the same chemistries into different cellular and physiological regions via modulation of their 3D architectures, and thus the work overall provides valuable new insight into how nanoparticle architecture and programmed degradation can be tailored to elicit specific biological responses for drug delivery.


Assuntos
Polímeros , Neoplasias de Mama Triplo Negativas , Transporte Biológico , Doxorrubicina/farmacologia , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Humanos , Distribuição Tecidual , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
13.
Macromol Rapid Commun ; 41(18): e2000190, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32400917

RESUMO

Polymer-drug conjugates have received considerable attention over the last decades due to their potential for improving the clinical outcomes for a range of diseases. It is of importance to develop methods for their preparation that have simple synthesis and purification requirements but maintain high therapeutic efficacy and utilize macromolecules that can be cleared via natural excretory pathways upon breakdown. Herein, the combination of ring-opening polymerization (ROP) and reversible addition-fragmentation chain-transfer (RAFT) polymerization is described for the straightforward synthesis of amphiphilic, stimuli-responsive, biodegradable, and highly functionalizable hyperbranched polymers. These unimolecular nanoparticles demonstrate a versatile platform for the synthesis of polymer-drug conjugates owing to the inclusion of a Boc-protected polycarbonate moiety in either a block or random copolymer formation. A proof-of-concept study on the complexation of the poorly water-soluble antimicrobial drug usnic acid results in polymer-drug complexes with powerful antimicrobial properties against gram-positive bacteria. Therefore, this work highlights the potential of amphiphilic and biodegradable hyperbranched polymers for antimicrobial applications.


Assuntos
Anti-Infecciosos , Benzofuranos , Anti-Infecciosos/farmacologia , Polimerização , Polímeros
14.
J Control Release ; 323: 549-564, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32371266

RESUMO

Triple negative or basal-like breast cancer (TNBC) is characterised by aggressive progression, lack of standard therapies and poorer overall survival rates for patients. The bad prognosis, high rate of relapse and resistance against anticancer drugs have been associated with a highly abnormal loss of redox control in TNBC cells. Here, we developed docetaxel (DTX)-loaded micellar-like nanoparticles (MLNPs), designed to address the aberrant TNBC biology through the placement of redox responsive cross-links designed into a terpolymer. The MLNPs were derived from poly(ethyleneglycol)-b-poly(lactide)-co-poly(N3-α-ε-caprolactone) with a disulfide linker pendant from the caprolactone regions in order to cross-link adjacent chains. The terpolymer contained both polylactide and polycaprolactone to provide a balance of accessibility to reductive agents necessary to ensure stability in transit, but rapid micellar breakdown and concomitant drug release, when in breast cancer cells with increased levels of reducing agents. The empty MLNPs did not show any cytotoxicity in vitro in 2D monolayers of MDA-MB-231 (triple negative breast cancer), MCF7 (breast cancer) and MCF10A (normal breast epithelial cell line), whereas DTX-loaded reducible crosslinked MLNPs exhibited higher cytotoxicity against TNBC and breast cancer cells which present high intracellular levels of glutathione. Crosslinked and non-crosslinked MLNPs showed high and concentration-dependent cellular uptake in monolayers and tumour spheroids, including when assessed in co-cultures of TNBC cells and cancer-associated fibroblasts. DTX loaded crosslinked MLNPs showed the highest efficacy against 3D spheroids of TNBC, in addition the MLNPs also induced higher levels of apoptosis, as assessed by annexin V/PI assays and increased caspase 3/7 activity in MDA-MB-231 cells in comparison to cells treated with DTX-loaded un-crosslinked MLNP (used as a control) and free DTX. Taken together these data demonstrate that the terpolymer micellar-like nanoparticles with reducible crosslinks have high efficacy in both 2D and 3D in vitro cancer models by targeting the aberrant biology, i.e. loss of redox control of this type of tumour, thus may be promising and effective carrier systems for future clinical applications in TNBC.


Assuntos
Antineoplásicos , Nanopartículas , Neoplasias de Mama Triplo Negativas , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Docetaxel/uso terapêutico , Humanos , Micelas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
15.
ACS Med Chem Lett ; 11(5): 657-663, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32435367

RESUMO

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor. Residual cells at the tumor margin are responsible for up to 85% of GBM recurrences after standard treatment. Despite this evidence, the identification of compounds active on this cell population is still an underexplored field. Herein, starting from the knowledge that kinases are implicated in GBM, we evaluated three in-house pyrazolo[3,4-d]pyrimidines active as Src, Fyn, and SGK1 kinase inhibitors against patient derived cell lines from either the invasive region or contrast-enhanced core of GBM. We identified our Src inhibitor, SI306, as a promising lead compound for eradicating invasive GBM cells. Furthermore, aiming at the development of a feasible oral treatment for GBM, we performed a formulation study using 2D inkjet printing to generate soluble polymer-drug dispersions. Overall, this study led to the identification of a set of polymer-formulated pyrazolo[3,4-d]pyrimidine kinase inhibitors as promising candidates for GBM preclinical efficacy studies.

16.
Biomater Sci ; 8(5): 1329-1344, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-31912808

RESUMO

Combinations of conventional chemotherapeutics with unconventional anticancer agents such as reactive oxygen and nitrogen species may offer treatment benefits for cancer therapies. Here we report a novel polymeric platform combining the delivery of Doxorubicin (DOXO) with the light-regulated release of nitric oxide (NO). An amphiphilic block-copolymer (P1) was designed and synthesized as the drug carrier, with pendant amine groups to attach DOXO via a urea linkage and a NO photodonor (NOPD) activable by visible light. The two grafted-copolymers (P1-DOXO and P1-NOPD) self-assembled via solvent displacement methods into nanoparticles (NPs), containing both therapeutic components (NP1) and, for comparison, the individual NOPD (NP2) and DOXO (NP3). All the NPs were fully characterized in terms of physicochemical, photochemical and photophysical properties. These experiments demonstrated that integration of the NOPD within the polymeric scaffold enhanced the NO photoreleasing efficiency when compared with the free NOPD, and that the proximity to DOXO on the polymer chains did not significantly affect the enhanced photochemical performance. Internalization of the NPs into lung, intestine, and skin cancer cell lines was investigated after co-formulation with Cy5 fluorescent tagged polymers, and cytotoxicity of the NPs against the same panel of cell lines was assessed under dark and light conditions. The overall results demonstrate effective cell internalization of the NPs and a notable enhancement in killing activity of the dual-action therapeutic NP1 when compared with NP2, NP3 and the free DOXO, respectively. This suggests that the combination of DOXO with photoregulated NO release, achieved through the mixed formulation strategy of tailored polymer conjugate NPs, may open new treatment modalities based on the use of NO to improve cancer therapies.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Nanopartículas/química , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico/metabolismo , Polímeros/química , Antibióticos Antineoplásicos/síntese química , Antibióticos Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/síntese química , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/química , Processos Fotoquímicos , Relação Estrutura-Atividade
17.
J Pharm Sci ; 109(3): 1347-1355, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31816297

RESUMO

Amorphous solid dispersions are a promising strategy to overcome poor solubility and stability limitations, reducing the crystallinity of the drug through incorporation within a polymer matrix. However, to achieve an effective amorphous solid dispersion, the polymer and drug must be compatible, otherwise the drug can undergo recrystallization. In this work, we investigated the potential of the enzymatically synthesized poly(glycerol-adipate), as a pharmaceutical tool for producing a nanoamorphous formulation. A polymeric prodrug of poly(glycerol-adipate) was synthesized by coupling mefenamic acid as drug. The amorphicity of the polymeric prodrug was assessed combining differential scanning calorimetry and polarized optical microscopy. The prodrug was then formulated into nanoparticles and studied for stability and drug release in the presence of lipase. To realize the goal of combination drug therapies for overcoming drug resistance and improving treatment outcomes, the prodrug was screened as a solubility enhancer for a series of fenamic drugs and compared with commercially available polymers commonly used in solid dispersions. Screening was carried out by developing a high-throughput miniaturized screening assay using a 2D printer to dispense the polymer and drug combinations. Finally, the collected data showed that drug conjugation could improve drug-polymer compatibility, in addition to facilitating the release of drugs by 2 different mechanisms.


Assuntos
Glicerol , Pró-Fármacos , Adipatos , Química Farmacêutica , Portadores de Fármacos , Estabilidade de Medicamentos , Polímeros , Solubilidade
18.
Bioconjug Chem ; 30(9): 2300-2311, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31441642

RESUMO

Nanomedicine is a promising strategy for improving clinical outcomes for cancer therapies, by improving drug efficacy through enhanced delivery to disease sites. It is of importance for ultimate clinical success to consider the contributing factors to achieving this goal, such as size, chemistry, and functionality of nanoparticle delivery systems, and how these parameters influence tumor localization and uptake. This Topical Review will first discuss the evolution and progress of nanoparticles for cancer drug delivery and the current challenges that remain to be addressed. Strategies for overcoming the limitations of passive targeting through active targeting approaches, and the current state of such nanomedicines in the clinic will be highlighted. Finally, novel approaches toward the design of active targeted nanoparticles building on our growing understanding of nanobio interactions are considered, in order to shed light on future design considerations for accelerating clinical translation of nanomedicines.


Assuntos
Portadores de Fármacos/química , Desenho de Fármacos , Nanomedicina/métodos , Nanopartículas/química , Animais , Humanos
19.
Eur J Pharm Biopharm ; 142: 377-386, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31319123

RESUMO

Poly(glycerol adipate) (PGA) is a biodegradable, biocompatible, polymer with a great deal of potential in the field of drug delivery. Active drug molecules can be conjugated to the polymer backbone or encapsulated in self-assembled nanoparticles for targeted and systemic delivery. Here, a range of techniques have been used to characterise the enzymatic degradation of PGA extensively for the first time and to provide an indication of the way the polymer will behave and release drug payloads in vivo. Dynamic Light Scattering was used to monitor change in nanoparticle size, indicative of degradation. The release of a fluorescent dye, coupled to PGA, upon incubation with enzymes was measured over a 96 h period as a model of drug release from polymer drug conjugates. The changes to the chemical structure and molecular weight of PGA following enzyme exposure were characterised using FTIR, NMR and GPC. These techniques provided evidence of the biodegradability of PGA, its susceptibility to degradation by a range of enzymes commonly found in the human body and the polymer's potential as a drug delivery platform.


Assuntos
Adipatos/química , Plásticos Biodegradáveis/química , Glicerol/química , Polímeros/química , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Humanos , Nanopartículas/química
20.
Biomater Sci ; 7(9): 3832-3845, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31286122

RESUMO

In order for synthetic polymers to find widespread practical application as biomaterials, their syntheses must be easy to perform, utilising freely available building blocks, and should generate products which have no adverse effects on cells or tissue. In addition, it is highly desirable that the synthesis platform for the biomaterials can be adapted to generate polymers with a range of physical properties and macromolecular architectures, and with multiple functional handles to allow derivatisation with 'actives' for sensing or therapy. Here we describe the syntheses of amphiphilic tri- and tetra-block copolymers, using diazabicyclo[5.4.0]undec-5-ene (DBU) as a metal-free catalyst for ring-opening polymerisations of the widely-utilised monomer lactide combined with a functionalised protected cyclic carbonate. These syntheses employed PEGylated macroinitiators with varying chain lengths and architectures, as well as a labile-ester methacrylate initiator, and produced block copolymers with good control over monomer incorporation, molar masses, side-chain and terminal functionality and physico-chemical properties. Regardless of the nature of the initiators, the fidelity of the hydroxyl end group was maintained as confirmed by a second ROP chain extension step, and polymers with acryloyl/methacryloyl termini were able to undergo a second tandem reaction step, in particular thiol-ene click and RAFT polymerisations for the production of hyperbranched materials. Furthermore, the polymer side-chain functionalities could be easily deprotected to yield an active amine which could be subsequently coupled to a drug molecule in good yields. The resultant amphiphilic copolymers formed a range of unimolecular or kinetically-trapped micellar-like nanoparticles in aqueous environments, and the non-cationic polymers were all well-tolerated by MCF-7 breast cancer cells. The rapid and facile route to such highly adaptable polymers, as demonstrated here, offers promise for a range of bio materials applications.


Assuntos
Materiais Biocompatíveis/química , Nanopartículas/química , Polímeros/química , Tensoativos/química , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Feminino , Humanos , Células MCF-7 , Estrutura Molecular , Tamanho da Partícula
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...