Dual-Stimuli-Sensitive Smart Hydrogels Containing Magnetic Nanoparticles as Antitumor Local Drug Delivery Systems-Synthesis and Characterization.

The aim of this study was to develop an innovative, dual-stimuli-responsive smart hydrogel local drug delivery system (LDDS), potentially useful as an injectable simultaneous chemotherapy and magnetic hyperthermia (MHT) antitumor treatment device. The hydrogels were based on a biocompatible and biodegradable poly(ε-caprolactone-co-rac-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-rac-lactide) (PCLA-PEG-PCLA, PCLA) triblock copolymer, synthesized via ring-opening polymerization (ROP) in the presence of a zirconium(IV) acetylacetonate (Zr(acac)4) catalyst. The PCLA copolymers were successfully synthesized and characterized using NMR and GPC techniques. Furthermore, the gel-forming and rheological properties of the resulting hydrogels were thoroughly investigated, and the optimal synthesis conditions were determined. The coprecipitation method was applied to create magnetic iron oxide nanoparticles (MIONs) with a low diameter and a narrow size distribution. The magnetic properties of the MIONs were close to superparamagnetic upon TEM, DLS, and VSM analysis. The particle suspension placed in an alternating magnetic field (AMF) of the appropriate parameters showed a rapid increase in temperature to the values desired for hyperthermia. The MIONs/hydrogel matrices were evaluated for paclitaxel (PTX) release in vitro. The release was prolonged and well controlled, displaying close to zero-order kinetics; the drug release mechanism was found to be anomalous. Furthermore, it was found that the simulated hyperthermia conditions had no effect on the release kinetics. As a result, the synthesized smart hydrogels were discovered to be a promising antitumor LDDS, allowing simultaneous chemotherapy and hyperthermia treatment.

Synthesis and Characterization of New Biodegradable Injectable Thermosensitive Smart Hydrogels for 5-Fluorouracil Delivery.

In this paper, injectable, thermosensitive smart hydrogel local drug delivery systems (LDDSs) releasing the model antitumour drug 5-fluorouracil (5-FU) were developed. The systems were based on biodegradable triblock copolymers synthesized via ring opening polymerization (ROP) of ε-caprolactone (CL) in the presence of poly(ethylene glycol) (PEG) and zirconium(IV) acetylacetonate (Zr(acac)4), as co-initiator and catalyst, respectively. The structure, molecular weight (Mn) and molecular weight distribution (D) of the synthesized materials was studied in detail using nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC) techniques; the optimal synthesis conditions were determined. The structure corresponded well to the theoretical assumptions. The produced hydrogels demonstrated a sharp sol-gel transition at temperature close to physiological value, forming a stable gel with good mechanical properties at 37 °C. The kinetics and mechanism of in vitro 5-FU release were characterized by zero order, first order, Higuchi and Korsmeyer-Peppas mathematical models. The obtained results indicate good release control; the kinetics were generally defined as first order according to the predominant diffusion mechanism; and the total drug release time was approximately 12 h. The copolymers were considered to be biodegradable and non-toxic; the resulting hydrogels appear to be promising as short-term LDDSs, potentially useful in antitumor therapy.

Hydrogels Based on Poly(Ether-Ester)s as Highly Controlled 5-Fluorouracil Delivery Systems-Synthesis and Characterization.

A novel and promising hydrogel drug delivery system (DDS) capable of releasing 5­fluorouracil (5-FU) in a prolonged and controlled manner was obtained using ε­caprolactone­poly(ethylene glycol) (CL-PEG) or rac­lactide-poly(ethylene glycol) (rac­LA-PEG) copolymers. Copolymers were synthesized via the ring-opening polymerization (ROP) process of cyclic monomers, ε­caprolactone (CL) or rac-lactide (rac-LA), in the presence of zirconium(IV) octoate (Zr(Oct)4) and poly(ethylene glycol) 200 (PEG 200) as catalyst and initiator, respectively. Obtained triblock copolymers were characterized by nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC) techniques; the structure and tacticity of the macromolecules were determined. The relationship between the copolymer structure and the reaction conditions was evaluated. The optimal conditions were specified as 140 °C and 24 h. In the next step, CL-PEG and rac-LA-PEG copolymers were chemically crosslinked using hexamethylene diisocyanate (HDI). Selected hydrogels were subjected to in vitro antitumor drug release studies, and the release data were analyzed using zero-order, first-order, and Korsmeyer-Peppas mathematical models. Controlled and prolonged (up to 432 h) 5-FU release profiles were observed for all examined hydrogels with first-order or zero-order kinetics. The drug release mechanism was generally denoted as non-Fickian transport.

Smart Hydrogels - Synthetic Stimuli-Responsive Antitumor Drug Release Systems.

Among modern drug formulations, stimuli-responsive hydrogels also called "smart hydrogels" deserve a special attention. The basic feature of this system is the ability to change their mechanical properties, swelling ability, hydrophilicity, bioactive molecules permeability, etc., influenced by various stimuli, such as temperature, pH, electromagnetic radiation, magnetic field and biological factors. Therefore, stimuli-responsive matrices can be potentially used in tissue engineering, cell cultures and technology of innovative drug delivery systems (DDSs), releasing the active substances under the control of internal or external stimuli. Moreover, smart hydrogels can be used as injectable DDSs, due to gel-sol transition connected with in situ cross-linking process. Innovative smart hydrogel DDSs can be utilized as matrices for targeted therapy, which enhances the effectiveness of tumor chemotherapy and subsequently limits systemic toxicity. External stimulus sensitivity allows remote control over the drug release profile and gel formation. On the other hand, internal factors provide drg accumulation in tumor tissue and reduce the concentration of active drug form in healthy tissue. In this report, we summarise the basic knowledge and chemical strategies for the synthetic smart hydrogel DDSs applied in antitumor therapy.