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1.
ACS Appl Mater Interfaces ; 12(22): 24531-24543, 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32378873

RESUMO

Polymeric micelles are typically characterized as core-shell structures. The hydrophobic core is considered as a depot for hydrophobic molecules, and the corona-forming block acts as a stabilizing and solubilizing interface between the core and aqueous milieu. Tremendous efforts have been made to tune the hydrophobic block to increase the drug loading and stability of micelles, whereas the role of hydrophilic blocks is rarely investigated in this context, with poly(ethylene glycol) (PEG) being the gold standard of hydrophilic polymers. To better understand the role of the hydrophilic corona, a small library of structurally similar A-B-A-type amphiphiles based on poly(2-oxazoline)s and poly(2-oxazine)s is investigated by varying the hydrophilic block A utilizing poly(2-methyl-2-oxazoline) (pMeOx; A) or poly(2-ethyl-2-oxazoline) (pEtOx; A*). In terms of hydrophilicity, both polymers closely resemble PEG. The more hydrophobic block B bears either a poly(2-oxazoline) and poly(2-oxazine) backbone with C3 (propyl) and C4 (butyl) side chains. Surprisingly, major differences in loading capacities from A-B-A > A*-B-A > A*-B-A* is observed for the formulation with two poorly water-soluble compounds, curcumin and paclitaxel, highlighting the importance of the hydrophilic corona of polymer micelles used for drug formulation. The formulations are also characterized by various nuclear magnetic resonance spectroscopy methods, dynamic light scattering, cryogenic transmission electron microscopy, and (micro) differential scanning calorimetry. Our findings suggest that the interaction between the hydrophilic block and the guest molecule should be considered an important, but previously largely ignored, factor for the rational design of polymeric micelles.

2.
Mol Pharm ; 17(6): 1835-1847, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32315193

RESUMO

Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase of the family of statins have been suggested as therapeutic options in various tumors. Atorvastatin is a statin with the potential to cross the blood-brain barrier; however, the concentrations necessary for a cytotoxic effect against cancer cells exceed the concentrations achievable via oral administration, which made the development of a novel atorvastatin formulation necessary. We characterized the drug loading and basic physicochemical characteristics of micellar atorvastatin formulations and tested their cytotoxicity against a panel of different glioblastoma cell lines. In addition, activity against tumor spheroids formed from mouse glioma and mouse cancer stem cells, respectively, was evaluated. Our results show good activity of atorvastatin against all tested cell lines. Interestingly, in the three-dimensional (3D) models, growth inhibition was more pronounced for the micellar formulation compared to free atorvastatin. Finally, atorvastatin penetration across a blood-brain barrier model obtained from human induced-pluripotent stem cells was evaluated. Our results suggest that the presented micelles may enable much higher serum concentrations than possible by oral administration; however, if transport across the blood-brain barrier is sufficient to reach the therapeutic atorvastatin concentration for the treatment of glioblastoma via intravenous administration remains unclear.

3.
Macromol Biosci ; 20(1): e1900178, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31596553

RESUMO

Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14-20 mg L-1 ) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT-loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI-H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro.

4.
Biomacromolecules ; 20(8): 3041-3056, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31318531

RESUMO

Despite decades of research, our understanding of the molecular interactions between drugs and polymers in drug-loaded polymer micelles does not extend much beyond concepts such as "like-dissolves-like" or hydrophilic/hydrophobic. However, polymer-drug compatibility strongly affects formulation properties and therefore the translation of a formulation into the clinics. Specific interactions such as hydrogen-bonding, π-π stacking, or coordination interactions can be utilized to increase drug loading. This is commonly based on trial and error and eventually leads to an optimized drug carrier. Unfortunately, due to the unique characteristics of each drug, the deduction of advanced general concepts remains challenging. Furthermore, the introduction of complex moieties or specifically modified polymers hampers systematic investigations regarding polymer-drug compatibility as well as clinical translation. In this study, we reduced the complexity to isolate the crucial factors determining drug loading. Therefore, the compatibility of 18 different amphiphilic polymers for five different hydrophobic drugs was determined empirically. Subsequently, the obtained specificities were compared to theoretical compatibilities derived from either the Flory-Huggins interaction parameters or the Hansen solubility parameters. In general, the Flory-Huggins interaction parameters were less suited to correctly estimate the experimental drug solubilization compared to the Hansen solubility parameters. The latter were able to correctly predict some trend regarding good and poor solubilizers, yet the overall predictive strength of Hansen solubility parameters is clearly unsatisfactory.

5.
Bioimpacts ; 7(3): 177-192, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29159145

RESUMO

Introduction: The current work was aimed to design and synthesize novel crosslinked pH-sensitive gelatin/pectin (Ge/Pec) hydrogels using different polymeric ratios and to explore the effect of polymers and degree of crosslinking on dynamic, equilibrium swelling and in vitro release behavior of the model drug (Mannitol). Methods: The Ge/Pec based hydrogels were prepared using glutaraldehyde as the crosslinker. Various structural parameters that affect their release behavior were determined, including swelling study, porosity, sol-gel analysis, average molecular weight between crosslinks (Mc), volume fraction of polymer (V2,s), solvent interaction parameter (χ) and diffusion coefficient. The synthesized hydrogels were subjected to various characterization tools like Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and DSC differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Results: The hydrogels show highest water uptake and release at lower pH values. The FTIR spectra showed an interaction between Ge and Pec, and the drug-loaded samples also showed the drug-related peaks, indicating proper loading of the drug. DSC and TGA studies confirmed the thermal stability of hydrogel samples, while SEM showed the porous nature of hydrogels. The drug release followed non-Fickian diffusion or anomalous mechanism. Conclusion: Aforementioned characterizations reveal the successful formation of copolymer hydrogels. The pH-sensitive swelling ability and drug release behavior suggest that the rate of polymer chain relaxation and drug diffusion from these hydrogels are comparable which also predicts their possible use for site-specific drug delivery.

6.
J Am Chem Soc ; 139(32): 10980-10983, 2017 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-28750162

RESUMO

Polymer micelles offer the possibility to create a nanoscopic environment that is distinct from the bulk phase. They find applications in catalysis, drug delivery, cleaning, etc. Often, one simply distinguishes between hydrophilic and hydrophobic, but fine-tuning of the microenvironment is possible by adjusting the structure of the polymer amphiphile. Here, we investigated a small library of structurally similar amphiphiles based on poly(2-oxazoline)s and poly(2-oxazine)s with respect to their solubilization capacity for two extremely water insoluble drugs, curcumin and paclitaxel. We found very significant and orthogonal specificities even if only one methylene group is exchanged between the polymer backbone and side chain. More strikingly, we observed profound synergistic and antagonistic solubilization patterns for the coformulation of the two drugs. Our findings shed new light on host-guest interaction in polymer micelles and such pronounced host-guest specificities in polymer micelles may not only be interesting in drug delivery but also for applications such as micellar catalysis.


Assuntos
Antineoplásicos/administração & dosagem , Curcumina/administração & dosagem , Portadores de Fármacos/química , Oxazinas/química , Oxazóis/química , Paclitaxel/administração & dosagem , Tensoativos/química , Antineoplásicos/química , Curcumina/química , Micelas , Paclitaxel/química , Solubilidade , Água/química
7.
Des Monomers Polym ; 20(1): 419-433, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29491813

RESUMO

Eudragit E 100 and polycaprolactone (PCL) floating microspheres for enhanced gastric retention and drug release were successfully prepared by oil in water solvent evaporation method. Metronidazole benzoate, an anti-protozoal drug, was used as a model drug. Polyvinyl alcohol was used as an emulsifier. The prepared microspheres were observed for % recovery, % degree of hydration, % water uptake, % drug loading, % buoyancy and % drug release. The physico-chemical properties of the microspheres were studied by calculating encapsulation efficiency of microspheres and drug release kinetics. Drug release characteristics of microspheres were studied in simulated gastric fluid and simulated intestinal fluid i.e., at pH 1.2 and 7.4 respectively. Fourier transform infrared spectroscopy was used to reveal the chemical interaction between drug and polymers. Scanning electron microscopy was conducted to study the morphology of the synthesized microspheres.

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