Preparation of Organic/Polymer Nanomaterials for Drug Delivery, Bioimaging and Cancer Therapy

有機/聚合物納米材料的製備及其應用於藥物傳遞、生物成像和癌症治療的研究

Student thesis: Doctoral Thesis

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Award date5 Jun 2017

Abstract

Cancer is a global disease and a leading cause of death worldwide. Tremendous progress over the past few decades has been made in the development of engineering nanomaterials for diagnosis and treatment of cancers. A wide variety of therapeutics based on nanostructures have been introduced for cancer treatment due to the enhanced permeability and retention (EPR) effects and multifunctional properties. This thesis is mainly focused on organic and polymeric nanomaterials for biomedical applications including drug delivery, bioimaging and cancer therapy.

Firstly, a self-monitored and self-delivered photosensitizer-doped nanoparticle (NP) drug delivery system is designed for theranostic applications. A donor/acceptor pair of perylene and 5, 10, 15, 20-tetro (4-pyridyl) porphyrin (H2TPyP) is co-doped into a chemotherapeutic anticancer drug curcumin (Cur) matrix. In the system, Cur works as a chemotherapeutic agent. The green fluorescence of Cur molecules is quenched (OFF) in the form of NPs and can be subsequently recovered (ON) upon release in tumor cells, which enables additional imaging and real-time self-monitoring capabilities. H2TPyP is used for photodynamic therapy (PDT) which also emits efficient NIR fluorescence for diagnosis via Förster Resonance Energy Transfer (FRET). By exploiting the emission characteristics of these two emitters, the combinatorial drugs provide a real-time dual-fluorescent imaging/tracking system in vitro and in vivo which simultaneously show a high drug loading capacity (77.6 wt.% of Cur). More importantly, the as-prepared NPs show high cancer therapeutic efficiency both in vitro and in vivo.

Secondly, we successfully developed a novel, versatile and controllable strategy for preparing pure nanodrugs (PNDs) via an anodized aluminium oxide (AAO) template-assisted method. With this approach, we prepared PNDs of an anti-cancer drug (VM-26) with precisely controlled sizes reaching the sub-20 nm range. This template-assisted approach has much higher feasibility for mass production comparing to the conventional reprecipitation method. The present method is further demonstrated to be easily applicable for a wide range of hydrophobic biomolecules without the need of custom molecular modifications and can be extended for preparing all-in-one nanostructures with different functional agents.

Thirdly, we prepared several fluorescent organic NPs based on small molecules for bioimaging and PDT. First, we fabricated a highly stable NIR fluorescent organic nanoprobes based on an anthraquinone derivate for noninvasive long-term cellular imaging, which displays low cytotoxicity, significant aggregation-induced emission (AIE) properties and a large Stokes shift (> 175 nm). Then we prepared fluorescent organic nanoprobes based on three carbazole derivatives with intense blue, green and orange-red emissions for both one- and two-photon fluorescent imaging. The three compounds consist of two or four electron-donating carbazole groups linked to a central dicyanobenzene electron acceptor. Steric hindrance from the carbazole groups leads to non-coplanar 3D molecular structures favorable to fluorescence in solid state, while the donor-acceptor structures endow the molecules with good two-photon excited emission properties. Subsequently, for the first time, we applied organic nanostructures based on thermally activated delayed fluorescent (TADF) emitters for singlet oxygen generation. With extremely small energy gap between the excited singlet state (S1) and long-lived triplet state states (T1), the intersystem conversion between S1 and T1 of these heavy-metal-free organic nanostructures can occur easily, which is beneficial to PDT. We further showed that this strategy also works well for exciplex-type TADF emitters prepared by mixing suitable donors and acceptors which have no TADF characteristics themselves. These novel metal-free water-dispersible TADF nanostructures will open new perspectives for photosensitizer applications in biomedical areas.

Lastly, a biocompatible electron donor-acceptor conjugated semiconducting polymer nanoparticles (PPor-PEG NPs) with light-harvesting unit was prepared and developed for highly effective photoacoustic imaging (PAI) guided photothermal therapy (PTT). Combined with the additional merits including donor-acceptor pair to favor electron transfer and fluorescence quenching effect after NP formation, the photothermal conversion efficiency of the PPor-PEG NPs was determined to be 62.3%, which is the highest value among reported polymer NPs. Moreover, the as-prepared PPor-PEG NP not only exhibited a remarkable cell-killing ability but also achieved 100 % tumor elimination, demonstrating its excellent photothermal therapeutic efficacy. Finally, the as-prepared water-dispersible PPor-PEG NPs showed good biocompatibility and biosafety, making them a promising candidate for future clinical applications in cancer theranostics.