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1.
ACS Appl Mater Interfaces ; 13(36): 43290-43300, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34464079

RESUMO

We report the first successful combination of three distinct high-throughput techniques to deliver the accelerated design, synthesis, and property screening of a library of novel, bio-instructive, polymeric, comb-graft surfactants. These three-dimensional, surface-active materials were successfully used to control the surface properties of particles by forming a unimolecular deep layer on the surface of the particles via microfluidic processing. This strategy deliberately utilizes the surfactant to both create the stable particles and deliver a desired cell-instructive behavior. Therefore, these specifically designed, highly functional surfactants are critical to promoting a desired cell response. This library contained surfactants constructed from 20 molecularly distinct (meth)acrylic monomers, which had been pre-identified by HT screening to exhibit specific, varied, and desirable bacterial biofilm inhibitory responses. The surfactant's self-assembly properties in water were assessed by developing a novel, fully automated, HT method to determine the critical aggregation concentration. These values were used as the input data to a computational-based evaluation of the key molecular descriptors that dictated aggregation behavior. Thus, this combination of HT techniques facilitated the rapid design, generation, and evaluation of further novel, highly functional, cell-instructive surfaces by application of designed surfactants possessing complex molecular architectures.

2.
ACS Appl Mater Interfaces ; 13(33): 38969-38978, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34399054

RESUMO

Controlling the microstructure of materials by means of phase separation is a versatile tool for optimizing material properties. Phase separation has been exploited to fabricate intricate microstructures in many fields including cell biology, tissue engineering, optics, and electronics. The aim of this study was to use phase separation to tailor the spatial location of drugs and thereby generate release profiles of drug payload over periods ranging from 1 week to months by exploiting different mechanisms: polymer degradation, polymer diluent dissolution, and control of microstructure. To achieve this, we used drop-on-demand inkjet three-dimensional (3D) printing. We predicted the microstructure resulting from phase separation using high-throughput screening combined with a model based on the Flory-Huggins interaction parameter and were able to show that drug release from 3D-printed objects can be predicted from observations based on single drops of mixtures. We demonstrated for the first time that inkjet 3D printing yields controllable phase separation using picoliter droplets of blended photoreactive oligomers/monomers. This new understanding gives us hierarchical compositional control, from droplet to device, allowing release to be "dialled up" without manipulation of device geometry. We exemplify this approach by fabricating a biodegradable, long-term, multiactive drug delivery subdermal implant ("polyimplant") for combination therapy and personalized treatment of coronary heart disease. This is an important advance for implants that need to be delivered by cannula, where the shape is highly constrained and thus the usual geometrical freedoms associated with 3D printing cannot be easily exploited, which brings a hitherto unseen level of understanding to emergent material properties of 3D printing.


Assuntos
Anti-Hipertensivos/química , Doença das Coronárias/tratamento farmacológico , Portadores de Fármacos/química , Excipientes/química , Indóis/química , Polímeros/química , Anti-Hipertensivos/farmacologia , Dioxanos/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Humanos , Indóis/farmacologia , Metacrilatos/química , Transição de Fase , Poliésteres/química , Impressão Tridimensional , Pirrolidinonas/química , Relação Estrutura-Atividade
3.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200185

RESUMO

Segmented polyurethane ionomers find prominent applications in the biomedical field since they can combine the good mechanical and biostability properties of polyurethanes (PUs) with the strong hydrophilicity features of ionomers. In this work, PU ionomers were prepared from a carboxylated diol, poly(tetrahydrofuran) (soft phase) and a small library of diisocyanates (hard phase), either aliphatic or aromatic. The synthesized PUs were characterized to investigate the effect of ionic groups and the nature of diisocyanate upon the structure-property relationship. Results showed how the polymer hard/soft phase segregation was affected by both the concentration of ionic groups and the type of diisocyanate. Specifically, PUs obtained with aliphatic diisocyanates possessed a hard/soft phase segregation stronger than PUs with aromatic diisocyanates, as well as greater bulk and surface hydrophilicity. In contrast, a higher content of ionic groups per polymer repeat unit promoted phase mixing. The neutralization of polymer ionic groups with silver or zinc further increased the hard/soft phase segregation and provided polymers with antimicrobial properties. In particular, the Zinc/PU hybrid systems possessed activity only against the Gram-positive Staphylococcus epidermidis while Silver/PU systems were active also against the Gram-negative Pseudomonas aeruginosa. The herein-obtained polyurethanes could find promising applications as antimicrobial coatings for different kinds of surfaces including medical devices, fabric for wound dressings and other textiles.


Assuntos
Materiais Biocompatíveis/farmacologia , Transição de Fase , Poliuretanos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Prata/química , Staphylococcus epidermidis/efeitos dos fármacos , Zinco/química , Teste de Materiais , Resistência à Tração
4.
Pharmaceutics ; 13(2)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546301

RESUMO

Glioblastoma (GBM) is the most common, malignant and aggressive brain tumour in adults. Despite the use of multimodal treatments, involving surgery, followed by concomitant radiotherapy and chemotherapy, the median survival for patients remains less than 15 months from diagnosis. Low penetration of drugs across the blood-brain barrier (BBB) is a dose-limiting factor for systemic GBM therapies, and as a result, post-surgical intracranial drug delivery strategies are being developed to ensure local delivery of drugs within the brain. Here we describe the effects of PEGylated poly(lactide)-poly(carbonate)-doxorubicin (DOX) nanoparticles (NPs) on the metabolic activity of primary cancer cell lines derived from adult patients following neurosurgical resection, and the commercially available GBM cell line, U87. The results showed that non-drug-loaded NPs were well tolerated at concentrations of up to 100 µg/mL while tumour cell-killing effects were observed for the DOX-NPs at the same concentrations. Further experiments evaluated the release of DOX from polymer-DOX conjugate NPs when incorporated in a thermosensitive in situ gelling poly(DL-lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA/PEG) matrix paste, in order to simulate the clinical setting of a locally injected formulation for GBM following surgical tumour resection. These assays demonstrated drug release from the polymer pro-drugs, when in PLGA/PEG matrices of two formulations, over clinically relevant time scales. These findings encourage future in vivo assessment of the potential capability of polymer-drug conjugate NPs to penetrate brain parenchyma efficaciously, when released from existing interstitial delivery systems.

5.
Biomater Sci ; 9(1): 38-50, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33179646

RESUMO

Stimuli-responsive amphiphilic block copolymers have emerged as promising nanocarriers for enhancing site-specific and on-demand drug release in response to a range of stimuli such as pH, the presence of redox agents, and temperature. The formulation of amphiphilic block copolymers into polymeric drug-loaded nanoparticles is typically achieved by various methods (e.g. oil-in-water emulsion solvent evaporation, solid dispersion, microphase separation, dialysis or microfluidic separation). Despite much progress that has been made, there remain many challenges to overcome to produce reliable polymeric systems. The main drawbacks of the above methods are that they produce very low solid contents (<1 wt%) and involve multiple-step procedures, thus limiting their scope. Recently, a new self-assembly methodology, polymerisation-induced self-assembly (PISA), has shown great promise in the production of polymer-derived particles using a straightforward one-pot approach, whilst facilitating high yield, scalability, and cost-effectiveness for pharmaceutical industry protocols. We therefore focus this review primarily on the most recent studies involved in the design and preparation of PISA-generated nano-objects which are responsive to specific stimuli, thus providing insight into how PISA may become an effective formulation strategy for the preparation of precisely tailored drug delivery systems and biomaterials, while some of the current challenges and limitations are also critically discussed.


Assuntos
Nanopartículas , Polímeros , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Polimerização
6.
Carbohydr Polym ; 253: 117277, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33278948

RESUMO

Thermoplastic, polysaccharide-based plastics are environmentally friendly. However, typical shortcomings include lack of water resistance and poor mechanical properties. Nanocomposite manufacturing using pure, highly linear, polysaccharides can overcome such limitations. Cast nanocomposites were fabricated with plant engineered pure amylose (AM), produced in bulk quantity in transgenic barley grain, and cellulose nanofibers (CNF), extracted from agrowaste sugar beet pulp. Morphology, crystallinity, chemical heterogeneity, mechanics, dynamic mechanical, gas and water permeability, and contact angle of the films were investigated. Blending CNF into the AM matrix significantly enhanced the crystallinity, mechanical properties and permeability, whereas glycerol increased elongation at break, mainly by plasticizing the AM. There was significant phase separation between AM and CNF. Dynamic plasticizing and anti-plasticizing effects of both CNF and glycerol were demonstrated by NMR demonstrating high molecular order, but also non-crystalline, and evenly distributed 20 nm-sized glycerol domains. This study demonstrates a new lead in functional polysaccharide-based bioplastic systems.


Assuntos
Amilose/química , Plásticos Biodegradáveis/química , Celulose/química , Nanocompostos/química , Nanofibras/química , Extratos Vegetais/química , Amilose/isolamento & purificação , Beta vulgaris/química , Celulose/isolamento & purificação , Cristalização , Farinha , Glicerol/química , Hordeum/química , Permeabilidade , Plastificantes/química , Maleabilidade , Amido/química , Resistência à Tração , Temperatura de Transição
7.
Molecules ; 25(22)2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33207806

RESUMO

Pyrazolo[3,4-d]pyrimidines represent an important class of heterocyclic compounds well-known for their anticancer activity exerted by the inhibition of eukaryotic protein kinases. Recently, pyrazolo[3,4-d]pyrimidines have become increasingly attractive for their potential antimicrobial properties. Here, we explored the activity of a library of in-house pyrazolo[3,4-d]pyrimidines, targeting human protein kinases, against Staphylococcus aureus and Escherichia coli and their interaction with ampicillin and kanamycin, representing important classes of clinically used antibiotics. Our results represent a first step towards the potential application of dual active pyrazolo[3,4-d]pyrimidine kinase inhibitors in the prevention and treatment of bacterial infections in cancer patients.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Pirazóis/síntese química , Pirazóis/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Filogenia , Domínios Proteicos , Inibidores de Proteínas Quinases/química , Proteínas Quinases/química , Pirazóis/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento
8.
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
9.
Eur J Pharm Biopharm ; 157: 108-120, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33068736

RESUMO

Glioblastoma is a malignant brain tumour with a median survival of 14.6 months from diagnosis. Despite maximal surgical resection and concurrent chemoradiotherapy, reoccurrence is inevitable. To try combating the disease at a stage of low residual tumour burden immediately post-surgery, we propose a localised drug delivery system comprising of a spray device, bioadhesive hydrogel (pectin) and drug nanocrystals coated with polylactic acid-polyethylene glycol (NCPPs), to be administered directly into brain parenchyma adjacent to the surgical cavity. We have repurposed pectin for use within the brain, showing in vitro and in vivo biocompatibility, bio-adhesion to mammalian brain and gelling at physiological brain calcium concentrations. Etoposide and olaparib NCPPs with high drug loading have shown in vitro stability and drug release over 120 h. Pluronic F127 stabilised NCPPs to ensure successful spraying, as determined by dynamic light scattering and transmission electron microscopy. Successful delivery of Cy5-labelled NCPPs was demonstrated in a large ex vivo mammalian brain, with NCPP present in the tissue surrounding the resection cavity. Our data collectively demonstrates the pre-clinical development of a novel localised delivery device based on a sprayable hydrogel containing therapeutic NCPPs, amenable for translation to intracranial surgical resection models for the treatment of malignant brain tumours.

10.
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.

11.
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
12.
Mol Pharm ; 17(6): 2083-2098, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32348676

RESUMO

Key challenges hindering the clinical translation of the use of nanoparticles (NP) for delivery of drugs to tumors are inadequate drug loading and premature drug release. This study focused on understanding the conditions required to produce nanoparticles that can reach their target site with sufficient drug loading and drug retention for effective pharmacological action. Etoposide, etoposide phosphate, and teniposide were screened against modified poly(glycerol) adipate (PGA) based polymers by monitoring drug release from 40% drug in polymer films and using Fourier transform infrared spectroscopy (FTIR) and contact angle measurements to help understand the release results. Polymers were matched with the specific drugs based on the interactions observed. NP were then prepared by an interfacial deposition method. NPs were characterized and resulted in drug loadings ranging from 3.5% and 5%, respectively, for etoposide phosphate and etoposide with PGA modified with stearate (PGA85%C18) up to 13.4% for teniposide with PGA modified with tryptophan (PGA50%Try) and drug release of just 22-35% over 24 h. Assessment of cytotoxicity showed that etoposide nanoparticles with PGA85%C18 were more potent than an equivalent amount of free drug. This screening method to match polymers to drugs to monitor based drug and polymer interactions thus resulted in the formulation of nanoparticles with higher drug loading and slower release and potential for further development for clinical applications.


Assuntos
Portadores de Fármacos/química , Polímeros/química , Liberação Controlada de Fármacos , Nanopartículas/química , Poliésteres/química
13.
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
14.
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
15.
Enzyme Microb Technol ; 132: 109439, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31731963

RESUMO

Lipase-immobilized nanomaterials with high activity and stable reusability would have a great impact in different fields. However, developing such materials has proven to be challenging. Herein, polymer (pAcDED)-coated magnetic nanoparticles (MNPs) displaying long alkyl chains, either octyl (C8) or hexadecyl (C16), have been prepared and used for immobilization of Candida rugosa lipase. The aim of the study was to develop magnetic supports able to bind enzyme via interfacial activation thus to stabilized the lipase open conformation. Among the developed nanosupports, the one endowed with the longest alkyl chains (MNPs-pAcDED-C16) provided the best efficiencies of the immobilized enzyme (70% vs. tributyrin and 130% vs. ethyl butyrate). Such results suggest both enzyme adsorption in open conformation and a change of enzyme specificity during immobilization. The MNPs-pAcDED-C16 system also showed better resistance to temperature inactivation in the 25-70 °C temperature range compared to free lipase and good reusability (4 consecutive cycles). The overall performances together with the convenience in the recovery offered by magnetic separation indicate our surface-modified MNPs as efficient and environmentally compatible materials for lipase immobilization.


Assuntos
Candida/enzimologia , Enzimas Imobilizadas/metabolismo , Lipase/metabolismo , Nanocompostos/química , Adsorção , Estabilidade Enzimática , Proteínas Fúngicas/metabolismo , Concentração de Íons de Hidrogênio , Cinética , Nanopartículas de Magnetita , Temperatura
16.
Polymers (Basel) ; 11(10)2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31557875

RESUMO

The enzymatically synthesized poly (glycerol adipate) (PGA) has demonstrated all the desirable key properties required from a performing biomaterial to be considered a versatile "polymeric-tool" in the broad field of drug delivery. The step-growth polymerization pathway catalyzed by lipase generates a highly functionalizable platform while avoiding tedious steps of protection and deprotection. Synthesis requires only minor purification steps and uses cheap and readily available reagents. The final polymeric material is biodegradable, biocompatible and intrinsically amphiphilic, with a good propensity to self-assemble into nanoparticles (NPs). The free hydroxyl group lends itself to a variety of chemical derivatizations via simple reaction pathways which alter its physico-chemical properties with a possibility to generate an endless number of possible active macromolecules. The present work aims to summarize the available literature about PGA synthesis, architecture alterations, chemical modifications and its application in drug and gene delivery as a versatile carrier. Following on from this, the evolution of the concept of enzymatically-degradable PGA-drug conjugation has been explored, reporting recent examples in the literature.

17.
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
18.
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
19.
Bioconjug Chem ; 30(5): 1371-1384, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30946570

RESUMO

Animal models are effective for assessing tumor localization of nanosystems but difficult to use for studying penetration beyond the vasculature. Here, we have used well-characterized HCT116 colorectal cancer spheroids to study the effect of nanoparticle (NP) physicochemical properties on penetration and uptake. Incubation of spheroids with Hoechst 33342 resulted in a dye gradient, which facilitated discrimination between the populations of cells in the core and at the periphery of spheroids by flow cytometry. This approach was used to compare doxorubicin and liposomal doxorubicin (Caelyx) and a range of model poly(styrene) nanoparticles of different sizes (30 nm, 50 nm, 100 nm) and with different surface chemistries (50 nm uniform plain, carboxylated, aminated and a range of NPs and polyethylene glycol modified NPs prepared from a promising new functionalized biodegradable polymer (poly(glycerol-adipate), PGA). Unmodified poly(styrene) nanoparticles (30 nm/50 nm) were able to penetrate to the core of HCT116 spheroids more efficiently than larger poly(styrene) nanoparticles (100 nm). Surprisingly, penetration of 30 and 50 nm particles was as good as clinically relevant doxorubicin concentrations. However, penetration was reduced with higher surface charge. PGA NPs of 100 nm showed similar penetration into spheroids as 50 nm poly(styrene) nanoparticles, which may be related to polymer flexibility. PEG surface modification of polymeric particles significantly improved penetration into the spheroid core. The new model combining the use of spheroids Hoechst staining and flow cytometry was a useful model for assessing NP penetration and gives useful insights into the effects of NPs' physical properties when designing nanomedicines.


Assuntos
Neoplasias Colorretais/metabolismo , Nanopartículas , Esferoides Celulares/metabolismo , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Benzimidazóis/metabolismo , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , Corantes Fluorescentes/metabolismo , Células HCT116 , Humanos , Tamanho da Partícula , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Propriedades de Superfície
20.
Mol Pharm ; 15(10): 4654-4667, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30142269

RESUMO

The problem of predicting small molecule-polymer compatibility is relevant to many areas of chemistry and pharmaceutical science but particularly drug delivery. Computational methods based on Hildebrand and Hansen solubility parameters, and the estimation of the Flory-Huggins parameter, χ, have proliferated across the literature. Focusing on the need to develop amorphous solid dispersions to improve the bioavailability of poorly soluble drug candidates, an innovative, high-throughput 2D printing method has been employed to rapidly assess the compatibility of 54 drug-polymer pairings (nine drug compounds in six polymers). In this study, the first systematic assessment of the in silico methods for this application, neither the solubility parameter approach nor the calculated χ, correctly predicted drug-polymer compatibility. The theoretical limitations of the solubility parameter approach are discussed and used to explain why this approach is fundamentally unsuitable for predicting polymer-drug interactions. Examination of the original sources describing the method for calculating χ shows that only the enthalpic contributions to the term have been included, and the corrective entropic term is absent. The development and application of new in silico techniques, that consider all parts of the free energy of mixing, are needed in order to usefully predict small molecule-polymer compatibility and to realize the ambition of a drug-polymer screening method.


Assuntos
Polímeros/química , Estabilidade de Medicamentos , Simulação de Dinâmica Molecular , Preparações Farmacêuticas/química , Solubilidade , Termodinâmica
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