Study Of Long-circulation Thermosensetive Liposomes Contain Docetaxel

Cancer is one of the most diseases that threatened human's life. It is now well recognized that when systemic chemotherapy is used in the treatment of solid tumors, it is almost impossible to achieve therapeutic levels of drug at the tumor site without damaging normal organs and tissues. One solution to this problem is to encapsulate the drug in a biocompatible material that can be injected into the blood stream with the intention of delivering drug to a required pathological sites, (e.g. solid tumor tissue). Four key requirements of drug carrier design are essential to the overall function and performance of the carrier system. These requirements are "Retain, Evade, Target, and Release". Over the last 30 years, lipid-based drug carrier systems have been developed that can retain drug, evade the body's defense, system and and target (passively and specifically) the interstitial tissue of tumors. Conventional liposomes have been clinically evaluated and approved in the treatment of various diseases, and the"Stealth" formulation has been approved for clinical use in Kaposi's sarcoma. Undoubtedly, drug does leak out of liposomes that have accumulated in tumor tissue, and there are situations where such slow release has providedtherapeutic benefit and may be efficacious. However, the ability to control and produce a burst release would be extremely advantageous and may prove to be an essential step in providing efficacious levels of drug in the tumor. The single biggest challenge, therefore, now facing drug delivery (for liposomes and other carriers) is to initiate and produce release of the encapsulated drug only at the diseased site and at controllable rates. For this to happen, the carrier/drug relationship must be triggered to change from the stable or kinetic trap requirement of the delivery phase to one of gross instability at the site. In 1978, Yatvin et al. suggested using a temperature-sensitive liposome to achieve this type of effect, and their ground-breaking efforts paved the way for many additional studies, as reviewed by Kong and Dewhirst. Our efforts have focused on developing a new thermal-sensitive drug delivery system containing Docetaxel that has been optimized for both mild hyperthermic temperatures (42℃to 44℃) that are readily achievable in the clinic and rapid release times of drug. We report here the design, development, stability, in vitro characterization, thermosensitive released in vivo, pharmacokinetics and pharmacodynamics test of a new thermal-sensitive lipid formulation that can be triggered to release drug rapidly and at clinically attainable hyperthermic temperatures. Our in vivo studies show the advantages that the new lipid composition has compared with existing liposome formulations. The studies also provide insight into the mechanism of action, which involves only a few mol% of MSPC contained in the gel-phase DPPC bilayer of the LTSLs to increase the overall phase transition-induced permeability of the bilayer to the encapsulated drug.