Hyaluronic Acid Nanoparticles Based on a Conjugated Oligomer Photosensitizer: Target-Specific Two-Photon Imaging, Redox-Sensitive Drug Delivery, and Synergistic Chemo-Photodynamic Therapy

Abstract

Self-assembled hyaluronic acid (HA) nanoparticles have been extensively investigated as anticancer therapeutic agents due to the biocompatibility, biodegradability, and active targeting characteristics of HA. However, many HA nanoparticles are restricted to the applications in drug delivery for chemotherapy or lack effective imaging agents. Hence, we developed the camptothecin (CPT)-loaded HA-SS-BFVPBT nanoparticles (HSBNPs) as a multifunctional platform for two-photon imaging and synergistic chemo-photodynamic therapy at the same time. A novel conjugated oligomer photosensitizer, BFVPBT, which was conjugated onto HA through the redox-responsive disulfide linkage (SS), could not only provide a hydrophobic domain for the formation of nanoparticles and drug entrapment but also act as a two-photon photosensitizer that can be directly excited and simultaneously used in two-photon imaging and photodynamic therapy (PDT). HeLa cells overexpressing the HA receptor (CD44) were used for in vitro studies, which proved the specific cellular uptake of CPT-loaded HSBNPs and excellent two-photon PDT/chemotherapy synergistic effect. The nanoparticles have also been shown to realize tumor-targeting in vivo imaging in HeLa-tumor-bearing mice. Moreover, the fluorescence of CPT-loaded HSBNPs could be activated due to the degradation by the reductive glutathione (GSH) and overexpressed hyaluronidases (Hyal-1) in cancer cells, and the intracellular drug release rate was quickened, thus improving the probability of precise cancer diagnosis and therapy. Accordingly, this HSBNPs system is also anticipated to be a precise nanocarrier for other imaging and therapeutic agents besides CPT, offering a promising new avenue for imaging-guided efficient cancer therapy.

Mesoporous Silica Nanoparticles: Properties and Strategies for Enhancing Clinical Effect

“…The choice of small molecules for active targeting must match with an appropriate tumor receptor. As previously discussed, HA binds to the overexpressed CD44 receptors on tumor cells, making it an ideal choice for a small molecule targeting agent with MSNs [ 88 , 221 ]. It should be noted that short HA chain lengths should be used when using HA for targeting, as they increase the engulfment efficiency [ 264 ].…”

Applications of Hyaluronic Acid Nanomaterials in Fluorescence/Photoacoustic Imaging and Phototherapy

“…Swierczewska 等 [55] [55] Figure 12 (A) PET imaging, (B) NIR fluorescence imaging, (C) ultrasound (top) and photoacoustic imaging (bottom) of SCC7 tumor-bearing mice; (D) quantitative analysis of the intensity of all imaging modes at the tumor site over time [55] , Copyright 2012, American Chemical Society [24,56] . 人们将 HA 与共轭小分子 [57][58][59] 、共轭聚合 物 [39][40]60] 等结合制备了一系列的纳米材料. 如图 13, Huang 等 [40] [40] Figure 13 (a) Schematic illustration of the overall strategy for HAase detection, fluorescence cell imaging and controlled DOX release; (b) chemical structures of HA-Dox and PFEP [40] , Copyright 2015, American Chemical Society 图 14 HA-SS-BFVPBT 的化学结构 [58] Figure 14 Chemical structure of HA-SS-BFVPBT [58] , Copyright 2019, American Chemical Society 为敏感, 非常适合生物样品的分析 [61] , 常用的有花菁染 料 Cy5.5 [62][63] 、七甲川吲哚花菁染料 IR825 [64] 和吲哚菁 绿 ICG 等 [64][65][66][67][68][69][70][71] .…”

“…人们将 HA 与共轭小分子 [57][58][59] 、共轭聚合 物 [39][40]60] 等结合制备了一系列的纳米材料. 如图 13, Huang 等 [40] [40] Figure 13 (a) Schematic illustration of the overall strategy for HAase detection, fluorescence cell imaging and controlled DOX release; (b) chemical structures of HA-Dox and PFEP [40] , Copyright 2015, American Chemical Society 图 14 HA-SS-BFVPBT 的化学结构 [58] Figure 14 Chemical structure of HA-SS-BFVPBT [58] , Copyright 2019, American Chemical Society 为敏感, 非常适合生物样品的分析 [61] , 常用的有花菁染 料 Cy5.5 [62][63] 、七甲川吲哚花菁染料 IR825 [64] 和吲哚菁 绿 ICG 等 [64][65][66][67][68][69][70][71] .…”

“…Liang 等 [63] [58] Figure 15 CPT-loaded HSBNPs were used for (a) two-photon excitation images of HeLa cells; (b) in vivo FL imaging of HeLa-tumorbearing mice [58] , Copyright 2019, American Chemical Society 图 16 (A) PFOB@IR825-HA-Cy5.5 纳米粒子的制备; (B)复合纳米材 料用于 NIRFL/PA/CT 三模态成像引导的光热肿瘤消融示意图 [63] Figure 16 (A) Preparation of PFOB@IR825-HA-Cy5.5 nanoparticles; (B) schematic diagram of the nanocomposite used for photothermal tumor ablation guided by NIRFL/PA/CT trimodal imaging [63] , Copyright 2017, Elsevier Ltd.…”

A Ratiometric Fluorescent Conjugated Oligomer for Amyloid β Recognition, Aggregation Inhibition, and Detoxification

“…Benefit from the high brightness, low cytotoxicity, outstanding photostability, and exact molecular structure, fluorescent conjugated oligomers have been widely used in biosensing, [ 38 ] imaging, [ 39 ] antibacterial, [ 40,41 ] disease diagnosis and therapy. [ 42,43 ] It is generally believed that amyloid fibril formation follows a nucleation‐dependent polymerization mechanism.…”