Chemotherapy For Gastric Cancer By Finely Tailoring Anti-Her2Anchored Dual Targeting Immunomicelles

Cancer is the second major diseases and has high mortality, seriously threating tohuman health. The traditional treatments of gastric cancer, such as chemotherapy,radiotherapy and surgery have showed some bright future to the cancer patients. However,the traditional methods for cancer treating are accompanied with serious side effects andbad prognosis because they just kill tumor cell or inhibit tumor cell growth. While it isknown that tumor cells behavior is very mysterious, it is difficult to cure but suppress thetumor by the traditional therapy with high metastasis and relapse. On the other hand, thechemotherapy and radiotherapy have stronger effects on tumor cells killing. But they aremethods with high non-specific distribution and high dosage dependence. Increasing thedrug dosage can improve therapeutic index, but the side cytotoxicity to other normaltissues which normally results in low therapeutic efficiency and limits its clinicalapplication. Moreover, the therapy efficiency was always lowered by the multi-drugresistant (MDR). Therefore, it is highly desired to seek for methods with high efficiency,low side-cytotoxicity and MDR for the clinical antitumor therapy.With the development of nanotechnology and nanometarials, novel antitumor drugbased on the nanotechnology offers new hope and ideals for overcoming above mentionedproblems. These obstacles appeared in chemotherapy are expected to be overcome by thenanomedicine. Up to now, a variety of novel nanoparticles based drug and gene deliverysystems were investigated such as liposomes, viral vector. Some in vivo and in vitrodrawbacks such as in vivo instability, the fast clearance in the circulation, insufficienttumor accumulation were improved than the traditional chemotherapy. The effects arefurther expected to improve for the following reasons: weak interactions with the cancercell, endocytosis lessness, the uncontrolled drug release of intracellular specific parts.Therefore, the development of nanomedicine with specific target and intelligent propertiesis urgent issue in chemotherapy.Fortunately, all these obstacles can be successfully overcome by the newly developedpolymeric micelles. Polymeric micelles, which was defined as the polymeric nano carrierswith well-defined hydrophobic core and hydrophilic shell, was selfassembled from theamphipathic block copolymer in aqueous solution. Micelles are characterized by thefollowing properties: in vivo stability, no immunogenicity, repeated injection; nogenotoxicity and cytotoxicity; controlled release of drug and gene; prolonging the actiontime, increased and held the drug concentration in blood; increasing the transfection efficiency and biological utilization degree; avoiding the drug degradation anddegeneration, improving the stability of the drug in vivo. At the same time, among all thenanoparticle delivery systems, as nanoparticle drug delivery systems, micelle have theunique advantages, such as stability in thermodynamics and kinetics, a wide range ofcarried drugs, long retention time in vivo, the realization of active targeting by decoratingwith specific recognition function target molecules in the surface. These unique advantagesmake micelle great potential in cancer treatment.In this thesis, focusing on above key issues in clinical antitumor chemotherapy, wefinely synthesized and tailored well-defined anti-Her2antibody Fab fragment conjugatedthermosensitive immunomicelles (poly (N-isopropylacrylamide-co-N,N-dimethylacrylamide)118-poly(lactide)71, PID118-b-PLA71)(FCIM), which showedinteresting dual targeting function. The thermosensitive poly (N-isopropylacrylamide-co-N,N-dimethylacrylamide)118(PID118) shell with volume phase transition temperature(VPTT:39oC) and the anchored anti-Her2Fab moiety contributed to the passive and activetargeting, respectively. The doxorubicin (DOX) loading capacity of such FCIMs wassuccessfully increased about2times by physically enhanced hydrophobicity of innerreservoir without structural deformation. The cellular uptake and intracellularaccumulation of DOX by temperature regulated passive and antibody navigated activetargeting was4times of Doxil. The cytotoxicity assay against Her2overexpression gastriccancer cells (N87s) showed that the IC50of the FCIMs was about9times lower than thatof Doxil under cooperatively targeting by Fab at T> VPTT. FCIMs showed high serumstability by increasing the corona PID118chain density (Scorona/Nagg). In vivo tissuedistribution was evaluated in Balb/c nude mice bearing gastric cancer. As observed by theIVIS imaging system, the intratumor accumulation of such finely tailored FCIMs systemwas obviously promoted24h post i.v. administration. Due to the high stability andsuper-targeting, the in vivo xenografted gastric tumor growth was significantly inhibitedwith relative tumor volume <2which was much smaller than about5of the control.Through the systemic investigation in this thesis, it was interesting to find that: suchfinely tailored FCIMs with anti-Her2active and temperature regulated passive dualtumor-targeting function show high potent in chemotherapy. This kind of intelligenttargeting nanomicelles are efficient in clinical chemotherapy by lowering side cytotoxicity,enhancing antitumor therapeutic index and improving patient’s pains. We hope our workwas referable and could be instructional for clinical chemotherapy and construction of novel nanomedicine.