Date of Award
Doctor of Philosophy
Photodynamic therapy (PDT) is an emerging, externally activatable, treatment modality for various diseases, especially for cancer therapy. Similar to radiotherapy, the mode of action with PDT involves the use of electromagnetic radiation to generate radical species in situ. However, PDT is a much milder approach for cancer treatment. Because of the unique physicochemical properties of fullerenes (such as C60), many potential biomedical applications, including PDT, became possible with them. As a main principle of PDT, the anticancer properties of various fullerene preparations usually result from their ability to generate cytotoxic reactive oxygen species (ROS), after photoexcitation. However, because of the existence of the two Bio-Windows (700−1100 nm), as the other conventional photosensitizers applied in PDT, fullerenes are usually triggered by visible light, which cannot penetrate thick bio-tissues. The utilization of fullerenes is confined to treating tumors on the lining of internal organs or cavities or just under the skin and is less efficacious when treating deep-located and large tumors. In recent years, fortunately, the application of NIR laser to PDT can achieve deeper penetration than that of visible light, because most biomolecules absorb minimally in the NIR range; thus, a vehicle that can transduce NIR laser to visible light is extremely desired for this technology.
Lanthanide-doped crystalline nanoparticles are emerging types of nanomaterials that exhibit many useful features for biomedical applications, because of their excitation absorbance extended in NIR, which significantly improved the tissue penetration and minimized unexpected thermal damage from traditional phototherapy with UV-Vis excited photosensitizers. Its anti-Stokes emission with narrow absorption in NIR, multiple emission bands, and excellent photostability enable multiplexed detection, NIR triggered drug release and NIR phototherapies (e.g. PDT) in deep tissues. By surface functionalization and combination of photosensitizers (such as PDT reagent C60), the biomedical application of lanthanide photo upconversion can be greatly extended, such as photo bioimaging and cancer phototherapy. Furthermore, the combination with other therapeutic methods, such as photothermal therapy (PTT) (e.g., AuNRs), chemotherapy (e.g., Doxorubicin (Dox)), and immunotherapy (e.g., BMS 202), will help improve cancer therapy.
In this study, novel upconverting systems were synthesized with NaYF4:Yb/Er nanocrystals, and core-shell NaYF4:Nd/Yb@NaYF4:Yb/Er UCNPs were rationally synthesized through low-temperature hydrothermal and thermal decomposition methods, exhibiting upconverting photoluminescence emissions at the wavelength of 525, 538, 653, and 839 nm, under 980 and 808 nm laser radiation respectively. The UCNPs were firstly surface modified with silanization of tetraethyl orthosilicate (TEOS) and aminopropyltrimethoxysilane (APTMS) for water solubility improvement and amine terminals decoration. Subsequently, via a carbodiimide coupling reaction, UCNPs were grafted with benzoyloxy pyrrolidine-based C60 derivatives, as photosensitizers. C60 was functionalized with multiple reactive groups with a simple Prato reaction. Besides, gold nanorods (AuNRs) with localized surface plasmon resonance (LSPR) at 980 nm were synthesized, carboxylic polyethylene glycol (PEG) functionalized and covalently conjugated around the UCNPs@C60 nanocomposite to obtain a bifunctional nanoplatform for simultaneous PTT and PDT. Notably, under NIR laser irradiation, singlet oxygen was effectively generated from an upconverting photodynamic combination of UCNPs and C60, while localized hyperthermia was simultaneously induced by the LSPR activity of AuNRs. Its therapeutic evaluation was successfully validated both in vitro (breast cancer cell lines MCF-7 and MDA-MB-231) and in vivo (Mouse 4T1 breast tumor model), exhibiting significant PDT+PDT synergistic effects in cancer therapy (e.g., 70% higher than PDT alone).
To further improve the cancer therapeutic application of UCNP@C60, NIR-controlled drug release was introduced for enhanced cancer chemotherapy. Based on the 808 nm excited core-shell UCNPs with grafted bifunctionalized C60, the DOX was further covalently conjugated, through oxalyl chloride (sensitive to reactive oxygen species), for the purposes of controlled release after the sequence of NIR radiation, Lanthanide upconverting luminescence, and ROS generating process. With significantly high drug loading efficiency (30.7%) through covalent bonds, a controlled DOX release has been successfully achieved through single NIR radiation. The therapeutic efficacy was evaluated in vitro through incubating breast cancer cell line MCF-7 under a significantly mild NIR irradiation and low dosage of the nanoplatforms. The product UCNP@C60@DOX exhibited excellent cancer phototherapy, with an IC50 of 1.5 μg/mL (~77 times decreased comparing with PDT+PTT). Furthermore, according to cell viability comparative analysis, such nanocomposite presents a remarkable synergistic therapeutic effect (~60% IC50 decrease comparing with DOX alone) by combining PDT into controlled DOX release and cancer chemotherapy.
Besides DOX initiated chemotherapy, immunotherapeutic drug BMS 202 (a PD-1/PD-L1 inhibiter) was also introduced into a NIR-ROS system, combining with ROS responsive thioether phosphatidylcholines vesicles to play the role of controlled drug release. Through a method of lipid thin-film hydration assembling, the NIR-ROS reactor of UCNP@C60 along with different drugs was encapsulated with ROS responsive thioether phosphatidylcholines, which can be oxidized by sequentially generated ROS to induce a vesicle collapse, during NIR irradiation. Meanwhile, the continuously generated cytotoxic ROS provides efficient PDT for combined antitumor therapy. The experimental viability results confirmed that our design of ROS sensitive vesicle combined UCNP@C60 exhibits excellent biocompatibility with high drug loading efficiency and NIR controlled drug release. After the drug loading, a significantly 54% higher cancer treatment efficacy was obtained, compared with those from UCNP@C60 (PDT) alone, as well as 39% higher than bare DOX (chemotherapy). Altogether, as alternatives to traditional phosphatidylcholines, ROS-sensitive liposomes combined with UCNP@C60 (UCNP@C60@Slipo) are promising NIR responsive carriers for the controlled delivery of drugs.
In summary, lanthanide photo upconverting nanomaterial has been successfully synthesized, surface modified, and conjugated with C60 derivatives. The NIR triggered upconverting photodynamic (NIR-ROS) nanoplatforms have been characterized with luminescence, ROS evaluation, cytotoxicity, long-term stability and then successfully confirmed its cancer therapeutic applications through combined photothermal therapy, controlled chemotherapy, and multifunctional NIR controlled anticancer drug release. Altogether, this research work that integrated lanthanide upconversion photoluminescence, fullerene involved photodynamic effect, gold nanorod involved photothermal effect, and NIR controlled drug release, has demonstrated a comprehensive strategy for enhanced simultaneous cancer therapy and drug delivery under the same NIR irradiation.
Recieved from ProQuest
Ma, Lei, "Combination Of Nir Triggered Lanthanide Upconverting Nanoplatforms With Fullerene For Controlled Drug Release And Photo Cancer Therapy" (2021). Open Access Theses & Dissertations. 3428.