In situ forming biodegradable poly(ε-caprolactone) microsphere systems: a challenge for transarterial embolization therapy. In vitro and preliminary ex vivo studies.

BACKGROUND: In situ forming biodegradable poly(ε-caprolactone) (PCL) microspheres (PCL-ISM) system was developed as a novel embolic agent for transarterial embolization (TAE) therapy of hepatocellular carcinoma (HCC). Ibuprofen sodium (Ibu-Na) was loaded on this platform to evaluate its potential for the treatment of post embolization syndrome. METHODS: The influence of formulation parameters on the size/shape, encapsulation efficiency and drug release was investigated using mixture experimental design. Regression models were derived and used to optimize the formulation for particle size, encapsulation efficiency and drug release profile for TAE therapy. An ex vivo model using isolated rat livers was established to assess the in situ formation of microspheres. RESULTS: All PCL-ISM components affected the studied properties and fitting indices of the regression models were high (Radj2 = 0.810 for size, 0.964 encapsulation efficiency, and 0.993 or 0.971 for drug release at 30 min or 48 h). The optimized composition was: PCL = 4%, NMP = 43.1%, oil = 48.9%, surfactant = 2% and drug = 2%. Ex vivo studies revealed that PCL-ISM was able to form microspheres in the hepatic arterial bed. CONCLUSIONS: PCL-ISM system provides a novel tool for the treatment of HCC and post-embolization syndrome. It is capable of forming microspheres with desirable size and Ibu-Na release profile after injection into blood vessels.

Indocyanine green delivery systems for tumour detection and treatments.

Indocyanine green (ICG) is a cyanine compound that displays fluorescent properties in the near infrared region. This dye is employed for numerous indications but nowadays its major application field regards tumour diagnosis and treatments. Optical imaging by near infrared fluorescence provides news opportunities for oncologic surgery. The imaging of ICG can be useful for intraoperative identification of several solid tumours and metastases, and sentinel lymph node detection. In addition, ICG can be used as an agent for the destruction of malignant tissue, by virtue of the production of reactive oxygen species and/or induction of a hyperthermia effect under irradiation. Nevertheless, ICG shows several drawbacks, which limit its clinical application. Several formulative strategies have been studied to overcome these problems. The rationale of the development of ICG containing drug delivery systems is to enhance the in vivo stability and biodistribution profile of this dye, allowing tumour accumulation and resulting in better efficacy. In this review, ICG containing nano-sized carriers are classified based on their chemical composition and structure. In addition to nanosystems, different formulations including hydrogel, microsystems and others loaded with ICG will be illustrated. In particular, this report describes the preparation, in vitro characterization and in vivo application of ICG platforms for cancer imaging and treatment. The promising results of all systems confirm their clinical utility but further studies are required prior to evaluating the formulations in human trials.

Development of thermosensitive chitosan/glicerophospate injectable in situ gelling solutions for potential application in intraoperative fluorescence imaging and local therapy of hepatocellular carcinoma: a preliminary study.

OBJECTIVES: Thermosensitive chitosan/glycerophosphate (C/GP) solutions exhibiting sol-gel transition around body temperature were prepared to develop a class of injectable hydrogel platforms for the imaging and loco-regional treatment of hepatocellular carcinoma (HCC). Indocyanine green (ICG) was loaded in the thermosensitive solutions in order to assess their potential for the detection of tumor nodules by fluorescence. METHODS: The gel formation of these formulations as well as their gelling time, injectability, compactness and resistance of gel structure, gelling temperature, storage conditions, biodegradability, and in vitro dye release behavior were investigated. Ex vivo studies were carried out for preliminary evaluation using an isolated bovine liver. RESULTS: Gel strengths and gelation rates increased with the cross-link density between C and GP. These behaviors are more evident for C/GP solutions, which displayed a gel-like precipitation at 4°C. Furthermore, formulations with the lowest cross-link density between C and GP exhibited the best injectability due to a lower resistance to flow. The loading of the dye did not influence the gelation rate. ICG was not released from the hydrogels because of a strong electrostatic interaction between C and ICG. Ex vivo preliminary studies revealed that these injectable formulations remain in correspondence of the injected site. CONCLUSIONS: The developed ICG-loaded hydrogels have the potential for intraoperative fluorescence imaging and local therapy of HCC as embolic agents. They form in situ compact gels and have a good potential for filling vessels and/or body cavities.