| Malignancy(commonly known as cancer) is one of the main causes of morbidity and mortality in the whole world. Chemotherapy is the most important treatment of cancer. However, small molecular antineoplastic drugs have many disadvantages, such as some side effects to normal cells and tissues and inefficiency against multi-drug resistant tumour cells. In order to solve the problems mentioned above, the antitumor drugs are loaded into nanocarriers through chemical conjugation or physical encapsulation to improve chemotherapy efficacy. In this thesis, we mainly focus on the polyleucine micelle with modified terminal group.(1)Charge-Reversal polyleucine micelle. The amino or carboxyl group-terminated poly(ethylene glycol)-block-poly(L-leucine)(i.e., Ami-PEG-b-PLLeu or Car-PEG-b-PLLeu, respectively) block copolymer was synthesized through the ring-opening polymerization(ROP) of L-leucine N-carboxyanhydride(L-Leu NCA) initiated by the amino-modified allyloxy poly(ethylene glycol)(APEG) and subsequent "thiol-ene" click reaction. The chemical structures of block copolymers were systematically characterized. Ami-PEG-b-PLLeu, Car-PEG-b-PLLeu, and a mixture of the two(1:1, mol:mol) could all self-assemble into micelles, which were referred as AmiPM, CarPM, and Ami/Car PM with positive, negative, and reversible charges, respectively. Doxorubicin, a model anthracycline antineoplastic agent, was loaded into micelles through nanoprecipitation, yielding AmiPM/DOX, CarPM/DOX, and Ami/CarPM/DOX, respectively. The charge of Ami/CarPM/DOX reversed from negative to positive as the decrease of solution’s pH for 7.4 to about 6.8, that is, tumor extracellular pH(i.e., pHe). As a result, the charge-reversal Ami/CarPM/DOX exhibited optimal endocytosis and cytotoxicity in relation to the positive AmiPM/DOX and negative Car PM/DOX. The results demonstrated the DOX-loaded Ami/CarPM with an equivalent amount of amino and carboxyl groups on the surface were potential charge-reversal drug delivery system for the enhanced intracellular drug delivery.( 2) Selected mesomeric polyleucine micelle with cRGD decoration. The configuration of polypeptide can affect the properties of self-assembly and control the drug release behavior. In this work, three kinds of amphiphilic diblock copolymers consisting of APEG, and dextrorotatory(PDLeu), levorotatory(PLLeu), or mesomeric polyleucine(PDLLeu) were synthesized through the ROP of D-Leu NCA, L-Leu NCA, or equivalent D-Leu NCA and L-Leu NCA with amino-terminated APEG as a macroinitiator. The obtained copolymers of APEG-b-PDLeu, APEG-b-PLLeu, APEG-b-PDLLeu, and equimolar APEG-b-PDLeu and APEG-b-PLLeu spontaneously self-assembled into spherical micelles in aqueous condition. The micelle with a mesomeric polypeptide core(PDLM) showed smaller diameter and more uniform distribution compared to those with dextrorotatory(PDM), levorotatory(PLM), and racemic polypeptide cores(PD/LM). Doxorubicin(DOX) was loaded into the four kinds of micelles through nanoprecipitation, and PDLM exhibited the highest drug loading efficiency than the other three ones. In view of the most excellent properties of PDLM, c(RGDfC) was conjugated to the end of APEG in APEG-b-PDLLeu through thiol-ene click reaction, yielding c RGD-PEG-b-PDLLeu as the matrix of targeting micelle. The outside cRGD of cRGD-PEG-b-PDLLeu micelle(R-PDLM) could identify the αvβ3 integrin receptor on the surface of some tumor cells. The DOX-loaded R-PDLM(R-PDLM/DOX) exhibited upregulated endocytosis and cytotoxicity compared with the untargeted one and free DOX because of the targeting effect. Therefore, the cRGD-modified PDLLeu micelle was hopeful to be a potential nanoscale polymeric nanovehicle for targeting drug delivery. |
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