Evaluation of Doxorubicin-loaded Echogenic Macroemulsion for Targeted Drug Delivery.

BACKGROUND: The latest technology trend in targeted drug delivery highlights stimuliresponsive particles that can release an anticancer drug in a solid tumor by responding to external stimuli. OBJECTIVE: This study aims to design, fabricate, and evaluate an ultrasound-responsive drug delivery vehicle for an ultrasound-mediated drug delivery system. METHODS: The drug-containing echogenic macroemulsion (eME) was fabricated by an emulsification method using the three phases (aqueous lipid solution as a shell, doxorubicin (DOX) contained oil, and perfluorohexane (PFH) as an ultrasound-responsive agent). The morphological structure of eMEs was investigated using fluorescence microscopy, and the size distribution was analyzed by using DLS. The echogenicity of eME was measured using a contrast-enhanced ultrasound device. The cytotoxicity was evaluated using a breast cancer cell (MDA-MB-231) via an in vitro cell experiment. RESULTS: The obtained eME showed an ideal morphological structure that contained both DOX and PFH in a single particle and indicated a suitable size for enhancing ultrasound response and avoiding complications in the blood vessel. The echogenicity of eME was demonstrated via an in vitro experiment, with results showcasing the potential for targeted drug delivery. Compared to free DOX, enhanced cytotoxicity and improved drug delivery efficiency in a cancer cell were proven by using DOX-loaded eMEs and ultrasound. CONCLUSION: This study established a platform technology to fabricate the ultrasound-responsive vehicle. The designed drug-loaded eME could be a promising platform with ultrasound technology for targeted drug delivery.

Fabrication and Evaluation of Ultrasound-Responsive Emulsion Loading Paclitaxel for Targeted Chemotherapy.

Chemotherapy is the most widely used cancer treatment, but it has several drawbacks such as adverse side effects and low bioavailability. To address these limitations, various drug delivery systems have been investigated, including liposomes, micelles, and emulsions. These drug delivery technologies have been improving the efficacy and safety of conventional chemotherapy. This study presents an emerging drug delivery technology for targeted chemotherapy using drug-loaded ultrasound-responsive emulsion (URE) as a drug carrier and ultrasound technology for external activation. URE was designed to be responsive to ultrasound energy and fabricated by using an emulsification technique. To investigate this technology, paclitaxel, as a model drug, was used and encapsulated into URE. The size distribution, morphology, and drug release behavior of paclitaxel-loaded URE (PTX-URE) were characterized, and the echogenicity of PTX-URE was assessed by using ultrasound imaging equipment. The cellular uptake and cytotoxicity of PTX-URE with ultrasound were evaluated in breast cancer cells (MDA-MB-231). Our in vitro results indicate that the combination of PTX-URE and ultrasound significantly enhanced cellular uptake by 10.6-fold and improved cytotoxicity by 24.1% compared to PTX alone. These findings suggest that the URE platform combined with ultrasound is a promising technology to improve the drug delivery efficiency for chemotherapy.

Thermoresponsive Polymer-Antibiotic Conjugates Based on Gradient Copolymers of 2-Oxazoline and 2-Oxazine.

A polymer-antibiotic conjugate with thermoresponsive properties near body temperature is presented. The backbone polymer is a copolymer of 2-n-propyl-2-oxazine (PropOzi) and methoxycarbonylethyl-2-oxazoline (C2MestOx) which is conjugated with the broad-spectrum antibiotic, cefazolin, via modification of the methyl ester group of C2MestOx. The resulting polymer-antibiotic conjugate has a cloud point temperature near body temperature, meaning that it can form a homogenous solution if cooled, but when injected into a skin-mimic at 37 °C, it forms a drug depot precipitate. Cleavage of the ester linker leads to quantitative release of the pristine cefazolin (with some antibiotic degradation observed) and redissolution of the polymer. When Escherichia coli were treated with polymer-antibiotic conjugate total clearance is observed within 12 h. The power of this approach is the potential for localized antibiotic delivery, for example, at a specific tissue site or into infected phagocytic cells.

Poly(2-allylamidopropyl-2-oxazoline)-Based Hydrogels: From Accelerated Gelation Kinetics to In Vivo Compatibility in a Murine Subdermal Implant Model.

A rapid photo-curing system based on poly(2-ethyl-2-oxazoline-co-2-allylamidopropyl-2-oxazoline) and its in vivo compatibility are presented. The base polymer was synthesized from the copolymerization of 2-ethyl-2-oxazoline (EtOx) and the methyl ester containing 2-methoxycarboxypropyl-2-oxazoline (C3MestOx) followed by amidation with allylamine to yield a highly water-soluble macromer. We showed that spherical hydrogels can be obtained by a simple water-in-oil gelation method using thiol-ene coupling and investigated the in vivo biocompatibility of these hydrogel spheres in a 28-day murine subdermal model. For comparison, hydrogel spheres prepared from poly(ethylene glycol) were also implanted. Both materials displayed mild, yet typical foreign body responses with little signs of fibrosis. This is the first report on the foreign body response of a poly(2-oxazoline) hydrogel, which paves the way for future investigations into how this highly tailorable class of materials can be used for implantable hydrogel devices.

Injectable biocompatible poly(2-oxazoline) hydrogels by strain promoted alkyne-azide cycloaddition.

Poly(2-alkyl-2-oxazoline) (PAOx) hydrogels are tailorable synthetic materials with demonstrated biomedical applications, thanks to their excellent biocompatibility and tunable properties. However, their use as injectable hydrogels is challenging as it requires invasive surgical procedures to insert the formed hydrogel into the body due to their nonsoluble 3D network structures. Herein, we introduce cyclooctyne and azide functional side chains to poly(2-oxazoline) copolymers to induce in situ gelation using strain promoted alkyne-azide cycloaddition. The gelation occurs rapidly, within 5 min, under physiological conditions when two polymer solutions are simply mixed. The influence of several parameters, such as temperature and different aqueous solutions, and stoichiometric ratios between the two polymers on the structural properties of the resultant hydrogels have been investigated. The gel formation within tissue samples was verified by subcutaneous injection of the polymer solution into an ex vivo model. The degradation study of the hydrogels in vitro showed that the degradation rate was highly dependent on the type of media, ranging from days to a month. This result opens up the potential uses of PAOx hydrogels in attempts to achieve optimal, injectable drug delivery systems and tissue engineering.

Poly(2-oxazoline) Hydrogels: State-of-the-Art and Emerging Applications.

The synthesis of poly(2-oxazoline)s has been known since the 1960s. In the last two decades, they have risen in popularity thanks to improvements in their synthesis and the realization of their potential in the biomedical field due to their "stealth" properties, stimuli responsiveness, and tailorable properties. Even though the bulk of the research to date has been on linear forms of the polymer, they are also of interest for creating network structures due to the relatively easy introduction of reactive functional groups during synthesis that can be cross-linked under a variety of conditions. This opinion article briefly reviews the history of poly(2-oxazoline)s and examines the in vivo data on soluble poly(2-oxazoline)s to date in an effort to predict how hydrogels may perform as implantable materials. This is followed by an overview of the most recent hydrogel synthesis methods and emerging applications, and is concluded with a section on the future directions predicted for these fascinating yet underutilized polymers.

Clinical efficacy of initial intratympanic steroid treatment on sudden sensorineural hearing loss with diabetes.

OBJECTIVE: The purpose of this study is to compare the efficacy of intratympanic steroid injection (ITSI) with that of systemic steroids as an initial treatment of sudden sensorineural hearing loss (SNHL) with diabetes. STUDY DESIGN: Prospective, nonrandomized multicenter clinical trial. SETTING: Multicenter study in Busan and Masan, South Korea. SUBJECTS AND METHODS: A total of 114 sudden SNHL patients who were diagnosed with diabetes were divided into peroral (PO) group (n = 48), intravenous (IV) group (n = 32), and intratympanic (IT) group (n = 34). In the PO group, prednisolone was used orally for 10 days, per schedule. In the IV group, prednisolone was administered intravenously for seven days, followed by oral administration of tapered doses for another several days. In the IT group, dexamethasone was injected into the tympanic cavity four times within a two-week period. Hearing outcome was assessed before and after the treatment. RESULTS: All groups showed significant improvement with criteria of 15 dB (P < 0.05). However, there was no significant difference in hearing gain and recovery rate among groups (P > 0.05). Systemic steroid treatment was stopped for two patients in the IV group and for one in the PO group due to uncontrolled hyperglycemia. However, in the IT group, there were no patients who failed to control their blood sugar level. CONCLUSION: ITSI is as effective as systemic steroid treatment for sudden SNHL patients with diabetes and it can avoid undesirable side effects. Therefore, we consider ITSI to be a more reasonable alternative as an initial treatment for sudden SNHL patients with diabetes.