pH Triggered Injectable Amphiphilic Hydrogel Containing Doxorubicin and Paclitaxel (original) (raw)
Related papers
A stimuli-responsive hydrogel for doxorubicin delivery
Biomaterials, 2010
The goal of this study was to develop a polymeric carrier for delivery of anti-tumor drugs and sustained release of these agents in order to optimize anti-tumor activity while minimizing systemic effects. We used oligo(poly(ethylene glycol) fumarate) (OPF) hydrogels modified with small negatively charged molecules, sodium methacrylate (SMA), for delivery of doxorubicin (DOX). SMA at different concentrations was incorporated into the OPF hydrogel with a photo-crosslinking method. The resulting hydrogels exhibited sensitivity to the pH and ionic strength of the surrounding environment. Our results revealed that DOX was bound to the negatively charged hydrogel through electrostatic interaction and was released in a timely fashion with an ion exchange mechanism. Release kinetics of DOX was directly correlated to the concentration of SMA in the hydrogel formulations. Anti-tumor activity of the released DOX was assessed using a human osteosarcoma cell line. Our data revealed that DOX released from the modified, charged hydrogels remained biologically active and had the capability to kill cancer cells. In contrast, control groups of unmodified OPF hydrogels with or without DOX did not exhibit any cytotoxicity. This study demonstrates the feasibility of using SMA-modified OPF hydrogels as a potential carrier for chemotherapeutic drugs for cancer treatments.
Nanoscale, 2014
The majority of the localized drug delivery systems are based on polymeric or polypeptide scaffolds, as weak intermolecular interactions of low molecular weight hydrogelators (LMHGs, Mw <500 Da) are significantly perturbed in the presence of anticancer drugs. Here, we present l-alanine derived low molecular weight hydrogelators (LMHGs) that remain injectable even after entrapping the anticancer drug doxorubicin (DOX). These DOX containing nanoassemblies (DOX-Gel) showed promising anticancer activity in mice models. Subcutaneous injection of DOX-Gel near the tumor achieved a greater decrease in tumour load than by intravenous injection of DOX (DOX-IV), and local injection of DOX alone (DOX-Local) at the tumor site. We noticed that DOX-Gel nanocarriers are especially effective when injected during the early stage of tumor progression, and achieve a substantial decrease in tumor load in the long term.
Controlled release of doxorubicin from pH-responsive microgels
Acta Biomaterialia, 2013
Stimuli-responsive hydrogels have enormous potential in drug delivery applications. They can be used for site-specific drug delivery due to environmental variables in the body such as pH and temperature. In this study, we have developed pH-responsive microgels for the delivery of doxorubicin (DOX) in order to optimize its anti-tumor activity while minimizing its systemic toxicity. We used a copolymer of oligo(polyethylene glycol) fumarate (OPF) and sodium methacrylate (SMA) to fabricate the pH-responsive microgels. We demonstrated that the microgels were negatively charged, and the amounts of charge on the microgels were correlated with the SMA concentration in their formulation. The resulting microgels exhibited sensitivity to the pH and ionic strength of the surrounding environment. We demonstrated that DOX was efficiently loaded into the microgels and released in a controlled fashion via an ionexchange mechanism. Our data revealed that the DOX release was influenced by the pH and ionic strength of the solution. Moreover, we designed a phenomenological mathematical model, based on a stretched exponential function, to quantitatively analyze the cumulative release of DOX. We found a linear correlation between the maximum release of DOX calculated from the model and the SMA concentration in the microgel formulation. The anti-tumor activity of the released DOX was assessed using a human chordoma cell line. Our data revealed that OPF-SMA microgels prolonged the cell killing effect of DOX.
A thermosensitive chitosan-based hydrogel for the local delivery of paclitaxel
European Journal of Pharmaceutics and Biopharmaceutics, 2004
A novel injectable thermosensitive in situ gelling hydrogel has been developed. The system, which falls under the BST-Gele platform technology developed at Biosyntech Inc. (Laval, QC, Canada), consists of a chitosan solution (C) neutralized with b-glycerophosphate (GP) that is liquid at room temperature but gels when heated to body temperature. We propose to use this thermosensitive hydrogel for the sustained release of paclitaxel at tumor resection sites in order to prevent local tumor recurrence. The in vitro release profiles demonstrated controlled delivery over 1 month. The initial drug loading substantially affected the release. Local delivery of paclitaxel from the formulation injected intratumorally was investigated using EMT-6 tumors implanted subcutaneously on Balb/c mice. These experiments showed that one intratumoral injection of the thermosensitive hydrogel containing paclitaxel was as efficacious as four intravenous injections of Taxol w in inhibiting the growth of EMT-6 cancer cells in mice, but in a less toxic manner. Further histological analysis revealed that while the proportion of necrotic areas was similar for the C/GP/paclitaxel and the Taxol w-treated tumors, a disparity between tumor-associated inflammatory cell populations may suggest differing anti-tumor mechanisms.
Novel PVA-Based Hydrogel Microparticles for Doxorubicin Delivery
Biomacromolecules, 2008
Micro-and nanoparticles are considered suitable drug delivery systems for their unique features, such as a large surface to volume ratio, and for the possibility to tune their size and hydrophobicity. A polymer/polymer/water emulsion method was used for producing a chemically cross-linked hydrogel made of poly(vinyl alcohol) and of poly(methacrylate) moieties. Mesoscopic investigation of the microparticles was accomplished by laser scanning confocal microscopy. Dynamics of confined water within the gel meshes was studied by quasi-elastic incoherent neutron scattering. Succinoylation of these particles allowed an efficient loading with a maximum doxorubicin payload of about 50% (w/w) of dry microparticles. To evaluate the potentials of such a microdevice for drug delivery, LoVo colon cancer cells have been exposed to doxorubicin loaded microparticles to study the in vitro efficiency of the payload release and the consequent cytotoxic effect.
Journal of Biomaterials Science, Polymer Edition, 2014
The objective of the present study was to develop 2-hydroxypropyl methacrylate-co-polyethylene methacrylate [p(HPMA-co-PEG-MEMA)] hydrogels that are able to efficiently entrap doxorubicin for the application of loco-regional control of the cancer disease. Systemic chemotherapy provides low clinical benefit while localized chemotherapy might provide a therapeutic advantage. In this study, effects of hydrogel properties such as PEG chains length, cross-linking density, biocompatibility, drug loading efficiency, and drug release kinetics were evaluated in vitro for targeted and controlled drug delivery. In addition, the characterization of the hydrogel formulations was conducted with swelling experiments, permeability tests, Fourier transform infrared, SEM, and contact angle studies. In these drughydrogel systems, doxorubicin contains amine group that can be expected a strong Lewis acid-base interaction between drug and polar groups of PEG chains, thus the drug was released in a timely fashion with an electrostatic interaction mechanism. It was observed that doxorubicin release from the hydrogel formulations decreased when the density of cross-linking, and drug/polymer ratio were increased while an increase in the PEG chains length of the macro-monomer (i.e. PEG-MEMA) in the hydrogel system was associated with an increase in water content and doxorubicin release. The biocompatibility of the hydrogel formulations has been investigated using two measures: cytotoxicity test (using lactate dehydrogenase assay) and major serum proteins adsorption studies. Antitumor activity of the released doxorubicin was assessed using a human SNU398 human hepatocellular carcinoma cell line. It was observed that doxorubicin released from all of our hydrogel formulations which remained biologically active and had the capability to kill the tested cancer cells.
Hydrogels for combination delivery of antineoplastic agents
Biomaterials, 2001
The systemic delivery of anticancer agents has been widely investigated during the past decade but localized delivery may o!er a safer and more e!ective delivery approach. We have designed and synthesized a novel hydrogel to locally deliver antineoplastic agents, and demonstrate the di!erent types of release that can be achieved from these hydrogels using three model drugs: methotrexate, doxorubicin, and mitoxantrone. Alginate was chemically modi"ed into low molecular weight oligomers and crosslinked with a biodegradable spacer (adipic dihydrazide) to form biodegradable hydrogels. The model antineoplastic agents were loaded into the hydrogel via three di!erent mechanisms. Methotrexate was incorporated within the pores of the hydrogel and was released by di!usion into the surrounding medium. Doxorubicin was covalently attached to the polymer backbone via a hydrolytically labile linker and was released following the chemical hydrolysis of the linker. Mitoxantrone was ionically complexed to the polymer and was released after the dissociation of this complex. These three release mechanisms could potentially be used to deliver a wide selection of antineoplastic agents, based on their chemical structure. This novel delivery system allows for the release of single or combinations of antineoplastic agents, and may "nd utility in localized antineoplastic agent delivery.
International journal of pharmaceutics, 2007
Paclitaxel (PTX) was loaded into synthetic pH/T-sensitive block copolymer (OSM-PCLA-PEG-PCLA-OSM) solution with various concentrations. The phase diagram of PTX-loaded block copolymer solution shifted to lower temperature region compared to net block copolymer because of the salting-out effect of PTX. Release profiles of PTX showed sustained manner regardless of loading amount of PTX. To evaluate anti-tumor effect of PTX-loaded block copolymer, solutions were injected subcutaneously to tumor-bearing mice and TUNEL assay examined. PTX-loaded block copolymer hydrogel for in vivo use showed good anti-tumor effect for 2 weeks and induced strong apoptosis in tumor tissue. Therefore, we conclude OSM-PCLA-PEG-PCLA-OSM block copolymer as an effective injectable carrier of PTX.
Polymers, 2021
A hydrogel scaffold is a localized drug delivery system that can maintain the therapeutic level of drug concentration at the tumor site. In this study, the biopolymer hydrogel scaffold encapsulating doxorubicin was fabricated from gelatin, sodium carboxymethyl cellulose, and gelatin/sodium carboxymethyl cellulose mixture using a lyophilization technique. The effects of a crosslinker on scaffold morphology and pore size were determined using scanning electron microscopy. The encapsulation efficiency and the release profile of doxorubicin from the hydrogel scaffolds were determined using UV-Vis spectrophotometry. The anti-proliferative effect of the scaffolds against the lung cancer cell line was investigated using an MTT assay. The results showed that scaffolds made from different types of natural polymer had different pore configurations and pore sizes. All scaffolds had high encapsulation efficiency and drug-controlled release profiles. The viability and proliferation of A549 cells...
2014
We report on a novel type of shaped hydrogel microparticles which undergo large, rapid, and reversible volume changes in response to solution pH. The cubic hydrogels are produced as interconnected poly(methacrylic acid) (PMAA) network replicas of mesoporous manganese oxide templates by sequential infiltration of (PMAA) and poly(N-vinylpyrrolidone) (PVPON), followed by cross-linking of PMAA and template dissolution. The integrated advantages of the porous cubic sacrificial templates and responsive PMAA matrix enable synthesis of monodisperse and pH-sensitive hydrogel cubes in a rapid, facile, and reproducible manner. These hydrogel cubes display a reversible 2-fold change in size while maintaining their shape in response to pH variations. The swelling behavior of cubic and spherical hydrogel particles is controlled by the network structure which is regulated by the PMAA molecular weight. These networks maintain their three-dimensional shapes in the dry state. No cytotoxicity is found...