Preparation Of Complexes Of Drugs With Tumor Targeting Protein And Study Of Their Anti-tumor Efficacies

Human serum albumin(HSA)is a natural carrier of endogeneous compounds and exogeneous drugs in the human body and play key roles in the transport,distribution and metabolism of drugs.We develop two new technologies to package drug molecules(doxorubicin(DOX)and photosensitizer)into HSA.Furthermore,we demonstrate that such new formaulation show and improved anti-tumor efficacy and enhanced tumor targeting effect.DOX is an effective chemotherapy drug to treat different types of cancers.However,DOX has severe side effects,especially life-threatening cardiotoxicity.We reported a new approach to reduce the toxicity of DOX by embedding DOX inside human serum albumin(HSA).HSA was further fused by molecular biology technique with a tumor-targeting agent,amino-terminal fragment of urokinase(ATF).ATF binds with a high affinity to urokinase receptor which is a cell surface receptor overexpressed in many types of tumors.Even though the as-prepared macromolecule complex(ATF-HSA:DOX)was not as effective as free DOX in killing tumor cells in vitro,in tumor-bearing mice was demonstrated to have stronger tumor-targeting and anti-tumor efficacy compared to free DOX.More importantly,histopathological examinations of the hearts from the mice treated with ATF-HSA:DOX showed a significantly reduced cardiotoxicity compared to that treated with free DOX.These results demonstrate the feasibility of this approach in reducing the cardiotoxicity of DOX while strengthening the anti-tumor efficacy of DOX.Such tumor-targeted albumin packaging strategy can also be applied to other anti-tumor drugs.We obtained the protein crystals of HSA in complex with DOX.Through X-ray data collection and crystal structure analysis,we identify the binding site of DOX in HSA molecule,confirming that HSA is an efficient drug carrier for DOX.Photodynamic therapy(PDT)is a emerging method for treating tumors.A new photosensitizer "Photocyanine" was developed locally at Fuzhou University,and shows promising therapeutic effects for a number of cancer,e.g.,esophageal cancer,and is currently in the second phase of clinical trial.For further improving the tumor targeting of Photocyanine,we develop a new method to form ATF-HSA:Photocyanine nanoparticle.We showed that ATF-HSA:Photocyanine nanoparticle has the capability to target uPAR on the tumor cells.In vivo,ATF-HSA:Photocyanine nanoparticle demonstrates specificity to xenografted tumor in mice.We also report the synthesis of a new type of cationic photosensitizer:a tetra-substituted zinc phthalocyanine with twelve peripheral tertiary amine groups.We formed nanoparticles of this photosensitizer with HSA.We showed that the such nanoparticle had a pH controlled release of the photosensitizer.In consideration of acidic environment of tumor tissue,such nanoparticles can deliver the cargo(photosensitizer)specically to tumor.