Synthesis Of Near Infrared PH-Responsive Amphiphilic Polymer And Its Application In Drug Delivery

For decades, nanoparticle drug carrier systems based on multiblock amphiphilic polymers have make great advances in the fields of diagnosis and therapy for cancer. Through the design and synthesis for novel particles, the biocompatibility, selectivity and utilization of nanomaterials have been improved, and they can decrease the side effect of drugs. In addition, it improves people’s comprehension against cancer. These nanomaterials have great potential for the diagnosis and therapy of cancer in the future.This thesis bases on the multiblock amphiphilic drug carrier system. Ring-opening polymerization, reversible addition-fragmentation chain transfer (RAFT) Polymerization and Click reaction were used to synthesize kinds of multifunctional polymers, which has potential application on the diagnosis and therapy of cancer.At the beginning in Chapter Two, two different cyanine dyes and a relative quencher were synthesized as the basis for the following studies. The as-prepared middle ring substituted Cy7.5 has large Stokes shift and good stability. It was used as the fluorescence probe conjugated to the polymers in the following three chapters to detect the trace of polymers in the cells. Cy5.5 with linear chain has little Stokes shift, and it has satisfactory characters of stack quenching. Via a process of Fluorescence Resonance Energy Transfer (FRET) with the quencher, the fluorescence intensity of Cy5.5 would decrease to a very low level. It could be utilized to synthesize fluorescence probes with "ON-OFF" performance for the detection of cancer cells.A triblock pH-responsive polymer was synthesized in Chapter Three. An amino modified RAFT agent was used to initiate the ring-opening polymerization of aspartic acid NCA.2-Hydroxyethyl methacrylate was polymerized by a radical polymerization to offer its hydroxyl as the initiator for the polymerization of ε-caprolactone, which was used as the hydrophobic part. Oligo(ethylene glycol) methacrylate (OEGMA) was polymerized subsequently as the hydrophilic part to construct the amphiphilic polymer. After the synthesis of the skeleton, hydrazine hydrate was used to make a hydrazinolysis of the branch chain of poly(aspartic acid). Then the doxorubicin was conjugated by a hydrazone band. Polymers could self-assemble to nanoparticles with a diameter of 47 nm in aqueous phase. After conjugation with Cy7.5, it formed a near-infrared fluorescent pH-responsive polymer.After construction of the amphiphilic polymer, the goal was changed to fulfil the targeting transportation. In Chapter Four, a RAFT agent with higher activity was used to obtain the polymer with a galactose modified methacrylate for the targeting transportation and drug delivery for liver cancer cells. After assembling to micelles, the polymers were charactered for cytotoxicity, cellular internalization and other measurements in vitro. It was found that this triblock polymer possessed satisfactory biocompatibility and selectivity to liver cancer cells. The micelles could release doxorubicin rapidly into the nuclei in the acidic microenvironment of cancer cells and killed the cells to meet the demand of therapy.Next, we changed the target group to folic acid which was suitable for more cancer cells. The interaction between folic acid and folate receptors which were over-expressed on the surface of many cancer cells was used improve the endocytosis of cancer cells for the polymers. In Chapter Five, a similar structure was used to construct a triblock polymer, and the model of drug carrying was changed from chemical bonding to physical encapsulation. The doxorubicin was released in a faster rate and thoroughly in the experiments. Through the study in breast cancer cells (MCF7) and liver cancer cells (HepG2), it was indicated that the effect of targeting could improve the endocytosis of target cells and the polymers had satisfactory effect of therapy.Our next object was to fulfil the diagnose of cancer cells after the targeting transportation and drug delivery. In Chapter Six, a diblock amphiphilic polymer system was constructed. Kinds of tertiary amine with different terminal groups had been used to synthesize precisely controlled pH-responsive polymer system. Cy5.5 and the NIR quencher were conjugated to the same polymer chains respectively and were mixed to prepare micelles. They emitted weak fluorescence and the intensity of fluorescence increased sharpy in acidic condition realizing the "ON-OFF" effectIn this thesis, kinds of targeting, pH-responsive, fluorescence detecting and multifunctional drug carrier were synthesized by constructing the multiblock amphiphilic polymers, and they completed the tarting transportation, drug delivery and fluorescence detecting for cancer cells to fulfil the demands of diagnosis and therapy for cancer.