近期奈米醫藥增加了藥物在癌症腫瘤治療方面的進展，然而腫瘤仍存在異質性結構，使得有效提升藥物累積和穿透遞送成為了兩大新難題。雖然透過被動增強的滲透性和保留之效應（EPR effect）可以改善奈米醫藥在腫瘤的累積，但是通過該機制之藥物僅有一小部分給藥劑量提升，並不足以達到顯著效果。另外，腫瘤的組織屏障阻礙了奈米醫藥在腫瘤深度的滲透，導致奈米醫藥釋放藥物於腫瘤的血管周圍細胞中，而降低治療的功效。為了解決這個問題，我們首先發展氧化石墨烯上，修飾海綿狀碳材料，並加入脂質雙層為石墨烯奈米海綿，兼作光熱藥物和高載藥之石墨烯奈米複合材，用近紅外光照射時，光熱可釋放出載負的藥物多西紫杉醇和氣化的全氟己烷。此外，我們也用腫瘤靶向蛋白修飾於石墨烯奈米海綿，並通過胞吞作用來提升穿透腫瘤。相對於270 nm的石墨烯奈米海綿，40 nm的石墨烯奈米海綿於腫瘤累積增加了200倍。此外，除了遞送到腫瘤中的藥物釋放到腫瘤之外，經過單一次10分鐘近紅外光照射後，所產生的化學和光熱治療協同，16天內可成功地破壞並抑制異種移植腫瘤，且沒有其他毒性傷害。此外，在治療後60天內也未觀察到腫瘤復發狀況。
而在第二部分中，我們進一步用石墨烯量子點，其具有超小尺寸（2-5 nm），穿膜能力，和獨特的物理化學性質，來做為腫瘤滲透治療載體。我們將石墨烯量子點包裹在pH敏感高分子微包中，此石墨烯量子點奈米複合材料，可以透過酸應答來增強腫瘤累積，並接著通過外部近紅外光照射，刺激藥物釋放並滲透到腫瘤深處，同時克服低腫瘤累積和腫瘤滲透的限制。通過pH敏感性，將可讓此複合材粒徑從150 nm聚集到450 nm，來增加粒子在腫瘤滯留的機會，進一步再照射近紅外光後，會使奈米複合材料分解成5 nm的抗癌藥物多柔比星載負石墨烯量子點，促進穿透到深部腫瘤組織。這種奈米複合材料也成功地抑制了異種移植腫瘤。
最後，我們針對原位腦瘤治療，設計一種分層靶向石墨烯複合材，運輸含有兩種抗癌藥物的雙腫瘤穿透粒子（硼摻雜石墨烯量子點載負多柔比星，和pH應答樹枝狀高分子載負帕博西尼）。另外由於針對腦部腫瘤治療，血腦屏障是一個相當大的阻礙，因此我們進一步修飾狂犬病病毒糖蛋白（RVG）包膜之奈米複合體。通過RVG可繞過血腦屏障之特性，並一樣透過酸性應答之分層靶向，來增加腫瘤中藥物的累積。由高週波磁場效應驅動，能夠使石墨烯量子點上產生感應電流，並排斥而將複合體分解成2-5 nm大小的雙重腫瘤穿透材，硼摻雜石墨烯量子點和pH應答樹枝狀高分子，並且同時攜帶雙抗癌藥物向深部腫瘤的穿透遞送達到協同治療效果。通過繞過血腦屏障，酸性提升累積，以及雙穿透材遞送藥物至原位腦腫瘤，我們最終實現以非接觸式磁場誘發藥物滲透和化學療法的協同作用，成功延長了帶有原位腦瘤之老鼠的存活時間。

Despite recent advances in enhanced nanotherapeutics, the challenges of effective accumulation and penetrated delivery from tumor heterogeneity still exist. Although the accumulation of nanoparticles could be improved at the tumor through the enhanced permeability and retention effect, only a small fraction of the administered dose was accumulated through this mechanism. Moreover, the physiological barrier of the tumor obstructs the penetration of nanoparticles into the tumor, causing nanoparticles to release the cargos in the perivascular cells of tumors and decreasing the therapeutic efficacy. To address this issue, a sponge-like carbon material on graphene nanosheet (graphene nanosponge)-supported lipid bilayers (lipo-GNS) that doubles as a photothermal agent and a high cargo payload platform and releases a burst of drug/energy (docetaxel (DTX) and gasified perfluorohexane (PFH)) and intense heat upon near-infrared irradiation was developed. Ultrasmall lipo-GNS (40 nm) modified with a tumor-targeting protein that penetrates tumor spheroids through transcytosis exhibited a 200-fold increase in accumulation relative to a 270 nm variant of the lipo-GNS. Furthermore, a combination of therapeutic agents (DTX and PFH) delivered by lipo-GNS into tumors was gasified and released into tumor spheroids and successfully ruptured and suppressed xenograft tumors in 16 days without distal harm when subjected to a single 10 min near-infrared laser treatment. Moreover, no tumor recurrence was observed over 60 days post-treatment.
In the second part, graphene quantum dots with ultrasmall size (2-5 nm), transmembrane capability, and unique physicochemical properties were utilized for penetrated therapy. Graphene quantum dots nanocomposites encapsulated in pH-sensitive micelles can enhance the accumulation responsively, and penetrate the cargos via external stimuli, which overcome the limitation of low accumulation and poor penetration. A size conversion of the nanocomposites at the tumor is demonstrated, which enhances the accumulation by enlarging the particle size from 150 nm to 450 nm via pH-sensitivity, and further disassembling 450 nm of nanocomposites into 5 nm of anticancer drugs loaded-graphene quantum dots, facilitating the penetrated delivery into the deep tumor tissue. This nanocomposite integrated with combinational therapy successfully suppresses xenograft tumors without distal harm. Finally, a hierarchical targeted hybrid that acts as a stealthy and magnetolytic carrier that transports dual tumor-penetrating agents incorporating two drugs (boron-doped graphene quantum dots (B-GQD)/doxorubicin and pH-responsive dendrimers (pH-Den)/palbociclib) was developed. The developed rabies virus glycoprotein (RVG)-enveloped hybrids (RVG-hybrids) amplify the accumulation of drugs in tumors by bypassing the blood brain barriers (BBB) and achieving hierarchical targeting. The penetrated delivery of dual pH-Den and B-GQD drugs to deep tumors is actuated by magnetoelectric effects, which are able to generate electrostatic repulsion and disassemble the hybrids into components of a few nanometers in size. The synergy of magnetoelectric drug penetration and chemotherapy was achieved by delivery of the theranostic B-GQDs and pH-Den to orthotopic brain tumors, which significantly prolonged the host survival time.

Chapter 1 Introduction ...... 1
Chapter 2 Literature Review and Theory ...... 6
2.1 Introduction of photothermal therapy based on graphene-materials ...... 6
2.2 Structural features of graphene-based materials ...... 11
2.3 Photothermal therapy (PTT) with combination treatments ...... 15
2.3.1 PTT with chemotherapy ...... 15
2.3.2 PTT with photodynamic therapy (PDT) ...... 16
2.3.3 PTT with ultrasonic treatment ...... 19
2.3.4 PTT with gene delivery ...... 20
2.4 Bio-functionalized photothermal therapy ...... 21
2.4.1 Biocompatibility-enhanced PTT ...... 21
2.4.2 Ligand-Targeted PTT ...... 24
2.4.3 Smart function-modified PTT ...... 25
2.5 Multimodalities-enhanced photothermal therapy ...... 26
2.5.1 Fluorescent agent-decorated GO for PTT enhancement ...... 26
2.5.2 Imaging-guided PTT by inorganic nanoparticle decoration ...... 28
2.6 Low-power efficient photothermal therapy ...... 31
2.6.1 GO conjugated with nanoparticle for low-power photothermal conversion ...... 31
2.6.2 High penetration integrated with low-power PTT ...... 32
2.7 Nanocomposite structure-modified photothermal therapy ...... 35
2.7.1 GO-based nanocapsules for enhanced PTT ...... 35
2.7.2 GO-based 3-D hybrid for photothermal chemotherapy ...... 37
2.8 Introduction of functional nanoparticles for tumor penetration ...... 38
2.9 Tumor penetrating by size changeability ...... 41
2.9.1 Stimuli-trigger (Outer factors) ...... 42
2.9.1.1 Light ...... 42
2.9.1.2 Ultrasound ...... 43
2.9.1.3 Magnetic field ...... 44
2.9.2 Tumor microenvironment (Inner factors) ...... 45
2.9.2.1 Overexpressed MMP ...... 45
2.9.2.2 Low pH ...... 47
2.9.2.3 Low oxygen concentration ...... 49
2.10 Tumor penetrating by ligand functionalization ...... 49
2.10.1 Albumin ...... 50
2.10.2 IF7 ...... 50
2.10.3 RGD ...... 51
2.10.4 Transferrin ...... 53
2.10.5 Cell ...... 55
2.11 Tumor penetrating by modulation of tumor microenvironments ...... 55
2.11.1 Tumor extracellular matrix disruption ...... 55
2.11.2 Vascular disruption ...... 58
2.12 Tumor penetrating by combinational strategies ...... 61
2.12.1 Size + Ligand functionalization ...... 61
2.12.2 Ligand functionalization + Modulation ...... 65
2.12.3 Size + Modulation ...... 66
Chapter 3 Experimental Procedures ...... 70
3.1 Synthesis of graphene-based materials ...... 70
3.2 Synthesis of pH-sensitive polymers and dendrimers ...... 73
3.3 Preparation and characteristics of graphene-based nanocomposites ...... 74
3.4 Drugs loading on graphene-based nanocomposites ...... 76
3.5 Drug release ...... 78
3.6 Cell lines and animals ...... 78
3.7 Cellular uptake, distribution, and cytotoxicity ...... 79
3.8 Multicellular spheroids chip fabrication ...... 80
3.9 Multicellular spheroids chip evaluation of graphene-based materials ...... 80
3.10 Penetrated depth evaluation of collagens and tumor spheroids ...... 81
3.11 Heterotopic and orthotopic intracranial tumor study by IHC staining ...... 82
3.12 Biodistribution and survival rate with synergistic chemotherapy in vivo ...... 83
Chapter 4 The Penetrated Delivery by Lipo-Graphene Nanosponges ...... 86
4.1 Introduction ...... 86
4.2 Results and Discussion ...... 90
4.2.1 Synthesis and characterization of Lf-lipo-GNS ...... 90
4.2.2 Size effects on cell uptake ...... 100
4.2.3 In vitro photothermo-chemo-therapy and photolytic therapy ...... 106
4.2.4 In vivo study ...... 108
4.3 Conclusion ...... 118
Chapter 5 Hierarchically Targeted and Penetrated Delivery by pH-sensitive GQD Nanoaircrafts ...... 120
5.1 Introduction ...... 120
5.2 Results and Discussion ...... 124
5.2.1 Synthesis and characterizations of size-changeable nanoaircrafts ...... 124
5.2.2 Evaluations of enhanced accumulation and penetrated delivery ...... 131
5.2.3 Multicellular tumor penetration and intercellular delivery ...... 134
5.2.4 In vivo study ...... 140
5.3 Conclusions ...... 145
Chapter 6 Magnetoelectric Penetrated Delivery of Theranostic Graphene/Drugs by Virus-Inspired GQDs Nanohybrids ...... 146
6.1 Introduction ...... 146
6.2 Results and Disscussion ...... 150
6.2.1 Synthesis and Characterization of Hybrids ...... 150
6.2.2 HFMF-Treated Hybrids ...... 160
6.2.3 Cytotoxicity and Cell Uptake of Hybrids ...... 163
6.2.4 Penetration of Hybrids in Tumor Spheroids ...... 167
6.2.5 In vivo Study ...... 173
6.3 Conclusions ...... 189
Chapter 7 Conclusions ...... 190
7.1 The Penetrated Delivery of Drug and Energy to Tumors by Lipo-Graphene Nanosponges for Photolytic Therapy ...... 190
7.2 Hierarchically Targeted and Penetrated Delivery of Drugs to Tumors by Size-Changeable Graphene Quantum Dot Nanoaircrafts for Photolytic Therapy ...... 190
7.3 Magnetoelectric Penetrated Delivery of Theranostic Graphene/Drugs to Deep Glioblastoma by Dual Virus-Inspired/Hierarchical Targeted Hybrids ...... 191
Reference ...... 192
Curriculum Vitae (CV) ...... 209

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