To find out an effective, specific, and low toxic cancer treatment is an important and urgent need. There are two strategies to achieve the goal. One is to prepare self-assembled micelles forming by a conjugation or complexation of an anticancer drug with a hydrophilic polymer for boosting solubility and promoting tumor targeting of drugs with the enhanced permeability and retention (EPR) effect. The other is to select a targetable hydrophilic polymer to form carrier system for anticancer drugs or to introduce the monoclonal antibody into carrier systems (micelles or nanoparticles), both of which are able to specifically target to cancer cells. A combination of two strategies into a carrier system would be able to enhance the effectiveness of cancer treatment. In this study, antibody targetable and self-assemble micelles composed of either hyaluronic acid (HA) conjugation with SN-38 or HA complexation with doxorubicin (Dox) will be designed and developed. HA is a biodegradable and biocompatible polymer, and has a strong affinity to CD44 receptor, which is overexpressed in many tumors. Therefore, HA-anticancer drug conjugates or complexes may allow efficient and specific receptor-mediated drug uptake by tumor. SN38 is considered as a potent antineoplatic agent, it is not available in clinical use due to poor physiochemical properties and unstable formulation. Dox is effective to various tumors, but the cardiac toxicity is hard to be tolerated. Cetuximab (Erbitux®) and trastuzumab (Herceptin®) are effective monoclonal antibody to colon and breast tumor cell, respectively; they are not curative, but the former combined with SN38 and the later with Dox could increase clinical efficacy. Furthermore, both can play a role as a tumor targetable antibody to specifically direct carrier system to tumor. In the first year, the preparation of self-assemble micelles composed of either HA conjugation with SN-38 (HA-SN38 conjugate) or complexation with Dox (HA-Dox complex) in DMSO with the aid of adding mPEG (methoxy(polyethylene glycol)) will be formulated and optimized. The influence of adding DSPE-PEG (distearoylphosphatidylethanolamine -N- [methoxy(poly(ethylene glycol))]) in water on the self-assemble ability and the stability of resulting HA-SN38/mPEG and HA-Dox/mPEG micelles will be further evaluated. In the second year, HA-SN38/mPEG and HA-Dox/mPEG self-assemble micelles will be evaluated for physicochemical properties, stability, in vitro cytotoxicity and specificity, in vivo antitumor activity, pharmacokinetic parameters, and safety. In the meantime, antibody targetable HA-SN38/mPEG and HA-Dox/mPEG self-assemble micelles will be prepared. The conjugation of thiolated cetuximab and transtuzumab with DSPE-PEG (DSPE-PEGcetuximab and -transtuzumab) will be firstly prepared and optimized. Then both will be introduced during the formation of self-assembled HA-SN38/mPEG and HA-Dox/mPEG micelles by “post-insertion” technique to enhance antibody targetable ability to colon and breast cancer (HA-SN38/mPEG/DSPE-PEG-cetuximab and HA-Dox/mPEG/DSPE-PEG-transtuzumab). In the third year, HA-SN38/mPEG/DSPE-PEG-cetuximab and HA-Dox/mPEG/DSPE-PEG-transtuzumab will be evaluated for physicochemical properties, stability, in vitro cytotoxicity and specificity, in vivo antitumor activity, pharmacokinetic parameters, and safety. The establishment of antibody targetable and self-assemble micelles as therapeutic pharmaceutical platform with applicable manufacture process could provide an effective, specific, and low toxic anticancer therapy for patients to make cancer no longer a frightening disease at all.
|Effective start/end date||8/1/13 → 7/31/14|
- Nanoparticle drug carrier
- hyaluronic acid
- γ-glutamic acid