Doxorubicin-loaded Hydrogels Research Articles

Development of injectable in situ hydrogels based on hyaluronic acid via Diels-Alder reaction for their antitumor activities studies

The objective of this study was to develop an injectable hydrogel based on furfuryl amine-conjugated hyaluronic acid (FA-conj-HA) and evaluate the in vivo anti-4 T1 tumor activity of doxorubicin-loaded hydrogel (DOX@FA-conj-HAgel). The cargo-free hydrogel (FA-conj-HAgel) was fabricated through a Diels-Alder reaction at 37 °C with FA-conj-HA as a gel material and four armed poly(ethylene glycol)2000-maleimide (4-arm-PEG2000-Mal) as a cross-linker. The bio-safety of FA-conj-HAgel were assessed, and the in vivo antitumor activity of DOX@FA-conj-HAgel was also investigated. Many 3D network structures were observed from scanning electron microscope (SEM) photograph, confirming the successful preparation of FA-conj-HAgel. The absence of cytotoxicity from FA-conj-HAgel was proved by the high viability of 4 T1 cells. In vivo bio-safety studies suggested that the obtained FA-conj-HAgel did not induce acute toxicity or other lesions in treated mice, confirming its high bio-safety. The reduced tumor volumes, hematoxylin-eosin staining (H&E), and TdT-mediated dUTP-biotin nick end labeling (TUNEL) analysis indicated the potent in vivo anti-4 T1 tumor effects of DOX@FA-conj-HAgel. In conclusion, the favorable bio-safety and potent antitumor activity of DOX@FA-conj-HAgel highlighted its potential application in oncological therapy.

New Methacrylated Biopolymer-Based Hydrogels as Localized Drug Delivery Systems in Skin Cancer Therapy.

The aim of the present work was to obtain drug-loaded hydrogels based on combinations of dextran, chitosan/gelatin/xanthan, and poly (acrylamide) as a sustained and controlled release vehicle of Doxorubicin, a drug used in skin cancer therapy that is associated with severe side effects. Hydrogels for use as 3D hydrophilic networks with good manipulation characteristics were produced using methacrylated biopolymer derivatives and the methacrylate group's polymerization with synthetic monomers in the presence of a photo-initiator, under UV light stimulation (365 nm). Transformed infrared spectroscopy analysis (FT-IR) confirmed the hydrogels' network structure (natural-synthetic composition and photocrosslinking), while scanning electron microscopy (SEM) analysis confirmed the microporous morphology. The hydrogels are swellable in simulated biological fluids and the material's morphology regulates the swelling properties: the maximum swelling degree was obtained for dextran-chitosan-based hydrogels because of their higher porosity and pore distribution. The hydrogels are bioadhesive on a biological simulating membrane, and values for the force of detachment and work of adhesion are recommended for applications on skin tissue. The Doxorubicin was loaded into the hydrogels and the drug was released by diffusion for all the resulting hydrogels, with small contributions from the hydrogel networks' relaxation. Doxorubicin-loaded hydrogels are efficient on keratinocytes tumor cells, the sustained released drug interrupting the cells' division and inducing cell apoptosis; we recommend the obtained materials for the topical treatment of cutaneous squamous cell carcinoma.

Multifunctional alginate-based hydrogel with reversible crosslinking for controlled therapeutics delivery

Glycan-based alginate hydrogels have great potential in creating new vehicles with responsive behavior and tunable properties for biomedicine. However, precise control and tunability in properties present major barrier for clinical translation of these materials. Here, we report the synthesis of pH responsive anthracene modified glycan-based hydrogels for selective release of therapeutic molecules. Hydrogels were crosslinked through simultaneous photopolymerization of vinyl groups and photodimerization of anthracene. Incorporation of anthracene into these gels leads to reversible control on crosslinking and transition between gel/sol states through dimerization/dedimerization of anthracene groups. Chemotherapeutic drug doxorubicin-loaded hydrogels were then tested in a cancer mimetic microenvironment where 85% of the drug was released from anthracene-conjugated hydrogels at pH 2 for 6 days. Control on gelation with anthracene incorporation was observed through alterations in modulus, where storage modulus was increased two-fold with anthracene conjugation during photopolymerization and photodimerization. Furthermore, cell survival analysis revealed that anthracene conjugation could selectively compromise cancer cell viability without inducing significant toxicity on healthy fibroblasts. This study combines light-induced control of crosslink density due to anthracene and pH-triggered therapeutics delivery with alginate. The approach would be applicable for systems where multiple control is required with high precision.

Thermo-responsive self-healable hydrogels with extremely mild base degradability and bio-compatibility

To face the increasing demands of self-healing hydrogels with biocompatibility and mild condition degradability, one brand new type of P(NIPAM-FPA-DMA) copolymers were prepared in this study. The copolymers were cross-linked by dihydrazide compound to form acylhydrazone containing self-healable hydrogels without additional catalysis. Herein, the chemical structure, as well as microscopic morphologies, mechanical and self-healing performances of the hydrogels were investigated. The hydrogels showed reversible thermo-responsiveness based on PNIPAM backbone and the phase transition temperature was regulated to body temperature by copolymerization of DMA. Moreover, the hydrogels could be degraded by extremely mild base of NaHCO3 based on phenolic ester bond and showed reversible gel-sol-gel transition under a variety of triggers. The in vitro toxicity experiment showed the self-healable hydrogels have good bio-compatibility. The doxorubicin-loaded hydrogels were prepared and showed controlled release profile. Altogether, these results identified the potential applications of the thermo-responsive self-healable hydrogels in bioscience and biotechnology with bio-safety.

Thermosensitive porphyrin-incorporated hydrogel with four-arm PEG-PCL copolymer (II): doxorubicin loaded hydrogel as a dual fluorescent drug delivery system for simultaneous imaging tracking in vivo

Visualization of a drug delivery system could reveal the pharmacokinetic properties, which is essential for the design of a novel drug delivery system. In vivo optical imaging offers an advanced tool to monitor the drug release process and the therapeutic effect by the combination of fluorescence imaging and bioluminescence imaging. Multispectral fluorescence imaging can separate the drug and the carrier without interference. Herein, a dual fluorescent anti-tumor drug delivery system was monitored with the doxorubicin-loaded hydrogel to further explore the application of the porphyrin-incorporated hydrogel with four-arm PEG-PCL copolymer as a drug carrier, based on the beneficial fluorescence and good biocompatibility of the porphyrin incorporated hydrogel. Using nude mice bearing luciferase expressed hepatic tumor as models, the whole process from the drug delivery to the tumor therapeutic effects were real time visualized simultaneously after administration at interval from 0 to 18 d. The imaging results suggest that the fluorescence signals of the drug and the carrier can be separated and unmixed from the drug-loaded hydrogel successfully, avoiding the interference of the fluorescence signals. The tumor growth or inhibition can be real time tracked and analyzed quantitatively by bioluminescence imaging. Noninvasive continuous tracking the in vivo drug delivery process simultaneously is a potential trend for the precise drug delivery and treatment.

Injectable doxorubicin-loaded hydrogels based on dendron-like β-cyclodextrin–poly(ethylene glycol) conjugates

Dendron-like CD–PEG conjugates with multiple acrylates were synthesized facilely, which can incorporate adamantane-modified doxorubicin and further be crosslinked by POEGMS, to give injectable doxorubicin-loaded hydrogels.

Intracellular Degradable Hydrogel Cubes and Spheres for Anti-Cancer Drug Delivery.

Shape and responsiveness of nanoengineered delivery carriers are crucial characteristics for rapid and efficient delivery of therapeutics. We report on a novel type of micrometer-sized hydrogel particles of controlled shape with dual pH- and redox-sensitivity for intracellular delivery of anticancer drugs. The cubical and spherical poly(methacrylic acid) (PMAA) networks with disulfide links are obtained by cross-linking PMAA with cystamine within hydrogen-bonded multilayers of PMAA/poly(vinylpyrrolidone) (PMAA/PVPON) on sacrificial mesoporous templates. The pH-triggered hydrogel swelling/shrinkage not only affords effective doxorubicin entrapment but also efficient endosomal/lysosomal escape, and redox-triggered degradation provides drug release into the cytosolic space. The hydrogels degrade rapidly to low molecular weight chains in the presence of the typical intracellular concentration of glutathione, which should ensure a rapid renal clearance in vivo. Particle shape is found to affect internalization at the initial step of cell-particle interactions. Drug-loaded spherical particles are found to be 12% more cytotoxic than the corresponding cubes within the first 10 h of cell incubation suggesting more rapid internalization of spheres. Both doxorubicin-loaded hydrogel cubes and spheres demonstrate 50% and 90% cytotoxicity when incubated with HeLa cancer cells for 24 and 48 h, respectively. The presented approach integrates the advantages of pH-sensitivity, enzymatic degradation, and shape-regulated internalization for novel types of "intelligent" three-dimensional networks with programmable behavior for use in controlled delivery of therapeutics.

An injectable drug-loaded hydrogel based on a supramolecular polymeric prodrug.

We reported a novel injectable doxorubicin-loaded hydrogel based on host-guest interaction and Schiff's base reaction. A supramolecular polymeric prodrug was prepared through the inclusion of adamantane-modified doxorubicin into the β-cyclodextrin cavity on the polyaldehyde dextran chain, which was in situ crosslinked by carboxymethyl chitosan.

An injectable and biodegradable hydrogel based on poly(α,β‐aspartic acid) derivatives for localized drug delivery

An injectable hydrogel via hydrazone cross-linking was prepared under mild conditions without addition of cross-linker or catalyst. Hydrazine and aldehyde modified poly(aspartic acid)s were used as two gel precursors. Both of them are water-soluble and biodegradable polymers with a protein-like structure, and obtained by aminolysis reaction of polysuccinimide. The latter can be prepared by thermal polycondensation of aspartic acid. Hydrogels were prepared in PBS solution and characterized by different methods including gel content and swelling, Fourier transformed-infrared spectroscopy, and in vitro degradation experiment. A scanning electron microscope viewed the interior morphology of the obtained hydrogels, which showed porous three-dimensional structures. Different porous sizes were present, which could be well controlled by the degree of aldehyde substitution in precursor poly(aspartic acid) derivatives. The doxorubicin-loaded hydrogels were prepared and showed a pH-sensitive release profile. The release rate can be accelerated by decreasing the environmental pH from a physiological to a weak acidic condition. Moreover, the cell adhesion and growth behaviors on the hydrogel were studied and the polymeric hydrogel showed good biocompatibility.