Design And Behavior Control Of Smart Anti-cancer Polymer-drug Self-assemblies

Chemotherapy, as an important treatment modality, has been widely used in cancer therapy. Traditional administration of anti-tumor drugs brings to severe side effects and limited efficacy. A promising countermeasure of overcoming the drawbacks is to use nanoparticles as drug carriers. Our dissertation presented here focuses on the design and preparation of "smart" drug delivery systems with controllable targeting capacity and release behaviors. This work can be categorized into five main parts as follows:In Chapter1, we introduced the structural characteristics of tumor tissues and cancerous cells distinguished from normal ones. Then, we summarized the latest trends of researches on designing "smart" drug carriers from two aspects: stimulus-responded tumor targeting delivery and controllable drug release behavior.In Chapter2, polyethylene glycol detachable graft copolymer, mPEG-g-p(NAS-co-BMA), was synthesized by grafting the2-(?-methoxy)PEGyl-1,3-dioxan-5-ylamine onto the poly(N-(acryloyloxy) succinimide-co-butyl methacrylate). Pseudo in situ cross-linking of the mPEG-g-p(NAS-co-BMA) was performed in dimethylformamide/PBS buffer (v/v1/1) by an acid-labile diamine cross-linker bearing two symmetrical cyclic orthoesters. The cross-linked (CL) micelles with different contents of mPEG segments represented different morphologies. The CL micelles containing approximate one mPEG segment exhibited'echini'morphology whereas the CL micelle with approximate three mPEG segments formed nanowires. Hydrolysis rate of the CL micelles is highly pH-dependent and much more rapid at mild acid than physiological condition. Hydrolyzates of the CL micelles formed vesicles because new amphiphilic copolymers were formed. Paclitaxel (PTX) was successfully loaded into the CL micelles and a controlled and pH-dependent release behavior was observed. No obvious cytotoxicity was found for the CL micelles at concentration as high as800mg L-1.In Chapter3, we demonstrated a new drug delivery technology--utilizing prodrug nanoassemblies to entrap other free drugs.Biotin-polyethylene glycol-doxorubicin prodrug (BPD) was synthesized as the model amphiphilic polymeric prodrug. The BPD was used to entrap free doxorubicin (Dox) and camptothecin (CPT). It was found that the drug contents of BPD-Dox and BPD-CPT reached to39%and26%, respectively. We examined the cytotoxicity and the cell uptaken capacity of the prodrug/drug complex by MTT assay and CLSM. The prodrug-drug complex showed comparable therapy efficacy of free drugs in cancerous cells and effectively restrained the side effect of drugs in non-cancerous cells. The BPD-CPT complexes have shown some satisfactory performances in vitro experiments. This work provides a new strategy to construct drug delivery systems loaded with therapeutic agents for improving drug loading capacity and therapeutic efficiency.In Chapter4, we prepared a novel tumor specific drug delivery system 'nano-flower' which was consisted of two polymer components: octadecyl-b-polyethylene glycol (biotin)-benzoic imine-b-octadecyl ester (CPCB) and octadecyl-b-polyethylene glycol-hydrazone-b-doxorubicin (CPD). Due to the covalent conjugation of Dox on polymer chains and the shielding of target ligands by folded PEG chains, the 'nano-flower' might effectively prevent the premature leak of Dox and decrease the specific contact with receptors outside the tumor tissues. With the decrease in pH value, the 'nano-flower' exhibited a half-open state to expose the target ligands on the surface under tumor acidic conditions and fully bloomed to release Dox under endosomal acidic conditions. The pH-triggered blooming behavior made the 'nano-flower' accomplish a process of tumor-triggered cell uptake and intercellular drug release, which might be a good candidate for chemotherapy.In Chapter5, we synthesized an ABA-typed polymer, octadecyl-polyethylene glycol (biotin)-(o-nitrobenzyl)-octadecyl ester (CPB-p-C) with an o-nitrobenzyl group inserted between polyethylene glycol (PEG) and octadecyl ester, as an illumination-activated tumor targeting accessory for micelle-based drug carriers. In our approach, the functional accessory could form a flower-like structure with folded PEG segments in aqueous solution to hide targeting biotin ligands in the core of the mixed micelle. Thus the specific binding between biotin and Avidin was suppressed by the steric hindrance of a PEG shell. Upon illumination, the flower-like structure of CPB-p-C was destroyed due to the cleavage of o-nitrobenzyl group and the biotin moieties were exposed on the surface of the micelle through the stretching process of PEG segments, generating ligand-receptor mediated targeting delivery. By confocal laser scanning microscopy (CLSM) and flow cytometry, the illumination activated tumor targeting delivery was studied. We also investigated the influence of the amount of functional accessory in the mixed micelle on the targeting property and identified the optimal amount of CPB-p-C to achieve the minimized side effects and the optimized illumination activated tumor targeting activity. The observed properties of CPB-p-C qualify it as a promising functional accessory to endow traditional drug delivery systems with tumor selectivity.