Preparation And Characterization Of Multifunctional Drug Delivery System For Tumor Therapy And Dual-contrast T₁/T₂ Imaging Nanomicelles

In recent years, malignant tumor has become a serious threat to human life and health.Effective diagnosis and treatment of cancer could reduce the mortality rate,which has become a major research topic in today’s scientific community.With the deepening of the research in various fields, rapid development of nanotechnology offers a new way for the diagnosis and treatment of tumor.In this article, we overcame the disadvantage of poor specificity and developed with different purposes of multi-functional polymer transmission system,which is used to load anticancer drugs and MRI contrast agents, to achieve target detection and treatment of tumor.Efficient delivery of anticancer drugs into tumor cells to increase the intracellular drug concentration is a major challenge for cancer therapy due to drug resistance and inefficient cellular uptake. pH-sensitive intracellular tumor targeting is increasingly investigated as a pathway to trigger the release of drugs once the drug carrier reached the unique acidic environment of the solid tumors, resulting in the localization of the polymer in the acidic endosomes and lysosomes. Herein, we report a novel pH-responsive amphiphilic polymer poly(itaconic acid)-poly(ethylene glycol)-poly(L-histidine)(PIA-PEG-PHIS) for use as an anticancer drug carrier. The product was found to form homogeneous and spherical micelles in aqueous media due to its amphiphilic nature measured by dynamic light scattering(DLS) and Transmission electron microscopy(TEM) imaging. In vitro drug release study demonstrated that doxorubicin(DOX) was released in a sustained manner in response to endosome pH conditions(pH 4–6) while inhibited at normal physiological pH. MTT assays demonstrated that PIA-PEG-PHIS were nontoxic and biocompatible. These favorable properties suggested PIA-PEG-PHIS micelles have great potential for targeted cancer chemotherapy.pH responsive intracellular tumor targeting is increasingly investigated as a pathway to trigger the release of anti-tumor drugs once the drug carrier reached the unique acidic environment of the solid tumors or after the drug carrier has been taken up by cells, resulting in the localization of the micelles in the acidic endosomes and lysosomes. Poly(itaconic acid)–poly(ethylene glycol)–folate–poly(L-histidine)(PIA–PEG–FA–PHIS) was synthesized as a carrier for tumor-targeted drug delivery. The micelles were internalized by receptor-mediated endocytosis, and the combination of active targeting and triggered release resulted in apparent cytotoxicity and antitumor activity. The MTT assay showed DOX-loaded micelles had higher and obvious cytotoxicity against Hela cells at pH 5.0 than that at pH 7.4.Cellular uptake experiments revealed that these pH-responsive PIA–PEG–FA–PHIS micelles were taken up in great amounts by receptor-mediated endocytosis and delivered to lysosomes, triggering release of DOX into the cytoplasm. These indicated that the PIA–PEG–FA–PHIS micelles could be a promising drug delivery system with preeminent stability for targeting the hydrophobic drugs to cancer cells and releasing DOX in to the cells by sensing the acidic environment of the endosomes for cancer therapy.We develop a new dual-mode MR contrast agent that becomes activated in an acidic environment, resulting in an increase in the T1-weighted signal(brighter contrast). The designed MR agent is composed of Gd-DTPA surface conjugated the PIA-PEG-FA-DDA-LEV-NH2 coating of SPIO via acid-labile hydrazone bond. We observed that the T1 relaxation rate(1/T1) of the Gd-DTPA complex was quenched when the Gd-DTPA complex was attached to the surface of the SPIO. Upon release of the quenched Gd-DTPA, an increase in the T1 relaxation rate was observed with increase in the T2 relaxation rate(1/T2). These features make our magnetic nanoprobe a potential MR-activatable contrast agent for cancer.In a summary, the cancer diagnostic and therapeutic agents with different characteristics and functions were successfully prepared. These agents have broad application prospects in the fields of diagnosis and treatment of cancer.