Mesoporous platinum@copper selenide-based NIR-II photothermal agents with photothermal conversion efficiency over 80% for photoacoustic imaging and targeted cancer therapy
介孔鉑@硒化銅基NIR-II光熱劑,光熱轉換效率超過80%,用於光聲成像和標靶癌症治療
Highlight 強調
- •A mesoporous platinum@copper selenide-based NIR-II photothermal agent was prepared.
製備了介孔鉑@硒化銅基近紅外線-II光熱劑。 - •This photothermal agent has the photothermal conversion efficiency over 80%.
此光熱劑的光熱轉換效率達80%以上。 - •This photothermal agent was used for NIR-II photoacoustic imaging and targeted cancer therapy.
此光熱劑用於 NIR-II 光聲成像和標靶癌症治療。 - •This photothermal agent provides new insights into the design of novel multifunctional biomedical nanomaterials.
這種光熱劑為新型多功能生物醫學奈米材料的設計提供了新的見解。
Abstract 抽象的
Elevating photothermal conversion efficiency (PCE) is the key to enhance curative efficacy during photothermal therapy. Nevertheless, current functionalized or synthetic methods for preparing photothermal agents with high PCE are too complicated, greatly hindering the development of photothermal therapy. In this study, we developed a tumor-targeting flower-like nanocomposite termed mesoporous platinum nanoparticles@Cu2-xSe-AS1411 (MPNPs@Cu2-xSe-AS1411, denoted as MPCSA) with remarkable PCE for high-resolution photoacoustic (PA) imaging guided photothermal/chemodynamic therapy for tumor ablation. We discovered that MPNPs served as carriers for delivering PA contrast agents. Cu2-xSe nanosheets emerged as promising near-infrared-II (NIR-II) PA imaging and photothermal/chemodynamic therapy agents owing to their strong localized surface plasmon resonance property in the NIR-II region. The amine-modified AS1411 aptamer, which is connected to the surface of the flower-like MPNPs@Cu2-xSe can target the nucleolar protein on the surface of 4T1 cells, achieving the accumulation of MPCSA at the tumor site in mice. Notably, these MPCSA nano-flowers exhibited an excellent PCE up to 82.33 % under 1064 nm laser irradiation, resulting in highly efficient cancer cell ablation and greatly hindering in vivo tumor growth. This study has paved the way for imaging-guided accurate cancer diagnosis and targeted cancer therapy.
提高光熱轉換效率(PCE)是提高光熱治療療效的關鍵。然而,目前製備高PCE光熱劑的功能化或合成方法過於複雜,大大阻礙了光熱療法的發展。在這項研究中,我們開發了一種靶向腫瘤的花狀奈米複合材料,稱為介孔鉑奈米顆粒@Cu 2- x Se-AS1411(MPNPs@Cu 2- x Se-AS1411,表示為MPCSA ),具有顯著的高解析度光聲PCE( PA)成像引導光熱/化學動力學治療腫瘤消融。我們發現 MPNP 作為傳遞 PA 造影劑的載體。 Cu 2- x Se 奈米片由於其在 NIR-II 區域具有強大的局部表面等離子體共振特性,成為有前途的近紅外線 II (NIR-II) PA 成像和光熱/化學動力學治療劑。胺修飾的AS1411適配體連接到花狀MPNPs@Cu 2- x Se表面,可以靶向4T1細胞表面的核仁蛋白,實現MPCSA在小鼠腫瘤部位的累積。值得注意的是,這些MPCSA奈米花在1064 nm雷射照射下表現出高達82.33%的優異PCE,從而實現高效的癌細胞消融並極大地阻礙體內腫瘤生長。這項研究為影像引導的準確癌症診斷和標靶癌症治療鋪平了道路。
提高光熱轉換效率(PCE)是提高光熱治療療效的關鍵。然而,目前製備高PCE光熱劑的功能化或合成方法過於複雜,大大阻礙了光熱療法的發展。在這項研究中,我們開發了一種靶向腫瘤的花狀奈米複合材料,稱為介孔鉑奈米顆粒@Cu 2- x Se-AS1411(MPNPs@Cu 2- x Se-AS1411,表示為MPCSA ),具有顯著的高解析度光聲PCE( PA)成像引導光熱/化學動力學治療腫瘤消融。我們發現 MPNP 作為傳遞 PA 造影劑的載體。 Cu 2- x Se 奈米片由於其在 NIR-II 區域具有強大的局部表面等離子體共振特性,成為有前途的近紅外線 II (NIR-II) PA 成像和光熱/化學動力學治療劑。胺修飾的AS1411適配體連接到花狀MPNPs@Cu 2- x Se表面,可以靶向4T1細胞表面的核仁蛋白,實現MPCSA在小鼠腫瘤部位的累積。值得注意的是,這些MPCSA奈米花在1064 nm雷射照射下表現出高達82.33%的優異PCE,從而實現高效的癌細胞消融並極大地阻礙體內腫瘤生長。這項研究為影像引導的準確癌症診斷和標靶癌症治療鋪平了道路。
Graphical abstract 圖文摘要
Keywords 關鍵字
Mesoporous platinum
Copper selenide nano-flower
NIR-II photothermal agents
Photoacoustic imaging
Targeted cancer therapy
介孔鉑
硒化銅奈米花
NIR-II光熱劑
光聲成像
癌症標靶治療
1. Introduction 一、簡介
Light irradiation is a common external and remote stimulus, offering substantial advantages in curative efficacy for cancer phototherapy. NIR light-triggered photothermal therapy (PTT) has attracted considerable interest, owing to its non-invasive feature and the capability to penetrate deep tissues and ablate tumors in complex vascularized tumor microenvironment (TME) by the local heating effect [1], [2]. The utilization of NIR light as external stimulus offers simultaneous spatial and temporal control of local heating effect, thereby minimizing the harmful side effects. Localized surface plasmon resonance (LSPR) refers to the collective or coherent oscillation of free charge carrier in plasmonic material that confined at the interface [3]. Building upon the advantages of the intrinsic subwavelength characteristic of spatial profile, LSPR can accumulate the light and energy at nanomaterial scale and greatly enhance light-matter interactions, thus generating a locally increased electromagnetic field. When biological tissues, including skin, muscle, fat, and blood, are treated with NIR light, the plasmonic photothermal agents accumulated at the tumor site would undergo the light-to-heat conversion, simultaneously resulting in a rapid increase in local temperature and even hyperthermia condition, thereby ablating cancer cells and inhibiting the tumor growth. To date, the majority of the photothermal agents have been prepared to explore the first near-infrared biological window (NIR-I, 650–900 nm), exhibiting shallow tissue penetration and poor photothermal conversion efficiency (PCE) [4], [5]. For example, traditional organic photothermal materials, i.e., indocyanine green, phthalocyanine, porphyrin, and polyaniline, show insufficient PCE and severe photobleaching problem, greatly hindering their application [6]. Additionally, carbon-based photothermal nanomaterials, including carbon nanotubes [7], carbon nanodots [8], and reduced graphene oxide [9], exhibit low light absorption coefficient and require complicated synthetic and functionalized process. Compared to that of NIR-I light irradiation, the exposure under the second NIR light irradiation (NIR-II, 1000–1400 nm) can result in a higher maximum permissible exposure of skin at the power density of 1.0 W/cm2. NIR-II plasmonic inorganic nanomaterials, i.e., noble metals, semiconductors, and their hybrid structure, exhibit greater potential for clinical translation compared to other photothermal agents, due to their inherent characteristics, such as excellent photostability, remarkable PCE, facile functionalization process, tunable morphology and atomic structure, adjustable water solubility, as well as superior biocompatibility [2]. Thus, it is necessary to design and construct a novel inorganic agent in combination with PTT and other tumor treatments for enhancing curative efficacy.
光照射是一種常見的外部和遠端刺激,為癌症光療的療效提供了巨大的優勢。近紅外光觸發光熱療法(PTT)因其非侵入性特徵以及能夠穿透深層組織並通過局部加熱效應在復雜的血管化腫瘤微環境(TME)中消融腫瘤的能力而引起了人們的廣泛關注[1] , [2 ] 。利用近紅外光作為外部刺激可以同時控制局部加熱效應的空間和時間,從而最大限度地減少有害的副作用。局域表面等離子體共振(LSPR)是指限制在界面處的等離子體材料中自由載子的集體或相干振盪[3] 。利用空間輪廓固有的亞波長特性的優勢,局部表面等離子體共振可以在奈米材料尺度上累積光和能量,大大增強光與物質的相互作用,從而產生局部增強的電磁場。當皮膚、肌肉、脂肪和血液等生物組織受到近紅外線照射時,腫瘤部位累積的等離子體光熱劑會發生光熱轉換,同時導致局部溫度迅速升高,甚至導致局部溫度升高。下,從而消融癌細胞並抑制腫瘤生長。 迄今為止,大多數光熱劑已製備用於探索第一個近紅外線生物窗口(NIR-I,650-900 nm),表現出淺組織穿透和較差的光熱轉換效率(PCE) [4 ] , [5 ] 。例如,傳統的有機光熱材料吲哚菁綠、酞菁、卟啉、聚苯胺等都存在PCE不足和嚴重的光漂白問題,極大地阻礙了其應用[6] 。此外,碳基光熱奈米材料,包括碳奈米管[7] 、碳奈米點[8]和還原氧化石墨烯[9] ,光吸收係數低,需要複雜的合成和功能化過程。與NIR-I光照射相比,第二次NIR-II光照射(NIR-II,1000-1400 nm)在1.0 W/cm 2的功率密度下可導致更高的皮膚最大允許暴露量。 NIR-II等離子體無機奈米材料,即貴金屬、半導體及其雜化結構,由於其固有的特性,如優異的光穩定性、顯著的PCE、簡單的功能化過程、可調諧等,與其他光熱劑相比,表現出更大的臨床轉化潛力。 因此,有必要設計和建構一種新型無機製劑,與PTT和其他腫瘤治療相結合,以提高療效。
光照射是一種常見的外部和遠端刺激,為癌症光療的療效提供了巨大的優勢。近紅外光觸發光熱療法(PTT)因其非侵入性特徵以及能夠穿透深層組織並通過局部加熱效應在復雜的血管化腫瘤微環境(TME)中消融腫瘤的能力而引起了人們的廣泛關注[1] , [2 ] 。利用近紅外光作為外部刺激可以同時控制局部加熱效應的空間和時間,從而最大限度地減少有害的副作用。局域表面等離子體共振(LSPR)是指限制在界面處的等離子體材料中自由載子的集體或相干振盪[3] 。利用空間輪廓固有的亞波長特性的優勢,局部表面等離子體共振可以在奈米材料尺度上累積光和能量,大大增強光與物質的相互作用,從而產生局部增強的電磁場。當皮膚、肌肉、脂肪和血液等生物組織受到近紅外線照射時,腫瘤部位累積的等離子體光熱劑會發生光熱轉換,同時導致局部溫度迅速升高,甚至導致局部溫度升高。下,從而消融癌細胞並抑制腫瘤生長。 迄今為止,大多數光熱劑已製備用於探索第一個近紅外線生物窗口(NIR-I,650-900 nm),表現出淺組織穿透和較差的光熱轉換效率(PCE) [4 ] , [5 ] 。例如,傳統的有機光熱材料吲哚菁綠、酞菁、卟啉、聚苯胺等都存在PCE不足和嚴重的光漂白問題,極大地阻礙了其應用[6] 。此外,碳基光熱奈米材料,包括碳奈米管[7] 、碳奈米點[8]和還原氧化石墨烯[9] ,光吸收係數低,需要複雜的合成和功能化過程。與NIR-I光照射相比,第二次NIR-II光照射(NIR-II,1000-1400 nm)在1.0 W/cm 2的功率密度下可導致更高的皮膚最大允許暴露量。 NIR-II等離子體無機奈米材料,即貴金屬、半導體及其雜化結構,由於其固有的特性,如優異的光穩定性、顯著的PCE、簡單的功能化過程、可調諧等,與其他光熱劑相比,表現出更大的臨床轉化潛力。 因此,有必要設計和建構一種新型無機製劑,與PTT和其他腫瘤治療相結合,以提高療效。
Photoacoustic (PA) imaging is a promising biomedical imaging technique which combines the advantages of conventional optical imaging and ultrasound imaging modalities [10]. When biological tissue is under the pulsed laser irradiation, endogenous or exogenous contrast agents would convert light into heat. Subsequently, the biological tissue undergoes thermoelastic expansion and thus generates acoustic waves which can be collected through an ultrasound transducer and transformed into PA images by data processing techniques [11], [12]. In general, optimal PA contrast agents possess high tissue penetration, outstanding sensitivity, excellent photostability, superior biocompatibility, and biodegradability [13], [14], [15]. However, traditional PA imaging primarily utilizes PA contrast agents in the range of visible light (400–650 nm) or NIR-I region [16]. Biological tissues can undergo strong optical adsorption and scattering, thus resulting in shallow penetration depth and low contrast [17]. Compared to visible light and NIR-I, PA imaging in NIR-II biological window can reduce severe optical scattering on biological tissue, weaken the background signal interference, offer a strong PA signal with a up to 7-cm penetration depth and a 100-μm spatial resolution [18], exceeding the optical diffusion limit as well as the penetration depth of traditional optical imaging technique [19]. Up to now, some materials, including carbon nanotubes [20], copper sulfides/selenides [21], [22], gold nanomaterials [23], and conjugated polymers [24], have been utilized as bioactive probes for NIR-II PA imaging-guided cancer diagnosis and therapy. Nevertheless, reports on the design and construction of NIR-II PA probes with excellent targeting and therapeutic efficacy are scarce to date. Nowadays, it is crucial to develop a novel PA probe with enhanced targeting efficacy.
光聲(PA)成像是一種有前途的生物醫學成像技術,它結合了傳統光學成像和超音波成像方式的優點[10] 。當生物組織受到脈衝雷射照射時,內源性或外源性造影劑會將光轉化為熱。隨後,生物組織經歷熱彈性膨脹,從而產生聲波,聲波可以透過超音波換能器收集,並透過數據處理技術轉化為 PA 圖像[11] 、 [12] 。一般來說,最佳的PA造影劑具有高組織滲透性、出色的靈敏度、優異的光穩定性、優異的生物相容性和生物降解性[13] 、 [14] 、 [15] 。然而,傳統的PA影像主要使用可見光範圍(400-650 nm)或NIR-I區域的PA造影劑[16] 。生物組織會發生強烈的光學吸收和散射,從而導致穿透深度淺和對比度低[17] 。 與可見光和NIR-I相比,NIR-II生物窗口中的PA成像可以減少生物組織上嚴重的光散射,削弱背景訊號幹擾,提供強PA訊號,穿透深度可達7厘米,穿透深度可達100-100倍。到目前為止,一些材料,包括碳奈米管[20] 、硫化銅/硒化物[21] 、 [22] 、金奈米材料[23]和共軛聚合物[24] ,已被用作NIR-II PA的生物活性探針影像引導的癌症診斷和治療。然而,迄今為止,關於具有優異靶向性和治療效果的NIR-II PA探針的設計和構建的報導還很少。如今,開發具有增強標靶功效的新型 PA 探針至關重要。
光聲(PA)成像是一種有前途的生物醫學成像技術,它結合了傳統光學成像和超音波成像方式的優點[10] 。當生物組織受到脈衝雷射照射時,內源性或外源性造影劑會將光轉化為熱。隨後,生物組織經歷熱彈性膨脹,從而產生聲波,聲波可以透過超音波換能器收集,並透過數據處理技術轉化為 PA 圖像[11] 、 [12] 。一般來說,最佳的PA造影劑具有高組織滲透性、出色的靈敏度、優異的光穩定性、優異的生物相容性和生物降解性[13] 、 [14] 、 [15] 。然而,傳統的PA影像主要使用可見光範圍(400-650 nm)或NIR-I區域的PA造影劑[16] 。生物組織會發生強烈的光學吸收和散射,從而導致穿透深度淺和對比度低[17] 。 與可見光和NIR-I相比,NIR-II生物窗口中的PA成像可以減少生物組織上嚴重的光散射,削弱背景訊號幹擾,提供強PA訊號,穿透深度可達7厘米,穿透深度可達100-100倍。到目前為止,一些材料,包括碳奈米管[20] 、硫化銅/硒化物[21] 、 [22] 、金奈米材料[23]和共軛聚合物[24] ,已被用作NIR-II PA的生物活性探針影像引導的癌症診斷和治療。然而,迄今為止,關於具有優異靶向性和治療效果的NIR-II PA探針的設計和構建的報導還很少。如今,開發具有增強標靶功效的新型 PA 探針至關重要。
Cancer is one of the most severe diseases and a main cause of death in human beings worldwide [25]. In terms of cancer therapy, the conventional single modal treatment approach has several drawbacks, such as negligible treatment effect, poor target ability, high toxicity towards biological tissues, and vulnerability to relapse. The utilization of multimodal combination therapy can effectively solve the above-mentioned obstacles. Associated with the growth, progression, and development of cancer disease, TME plays a pivotal part in the occurrence and evolution of tumors. In comparison with normal tissue microenvironment, TME possesses some unique features in many aspects, including hypoxia [26], elevated glutathione (GSH) level [27], and low pH environment [28]. Therefore, it is pivotal to develop multimodal combined cancer treatment method to overcome the obstacles and enhance curative efficiency.
癌症是全世界人類最嚴重的疾病之一,也是人類死亡的主要原因[25] 。在癌症治療方面,傳統的單一模式治療方法有治療效果不佳、標靶性差、對生物組織毒性大、易復發等缺點。採用多模式合併治療可以有效解決上述障礙。 TME與癌症疾病的生長、進展和發展有關,在腫瘤的發生和進化中發揮關鍵作用。與正常組織微環境相比,TME在許多方面具有一些獨特的特徵,包括缺氧[26] 、穀胱甘肽(GSH)水平升高[27]和低pH環境[28] 。因此,開發多模式聯合癌症治療方法以克服障礙並提高療效至關重要。
癌症是全世界人類最嚴重的疾病之一,也是人類死亡的主要原因[25] 。在癌症治療方面,傳統的單一模式治療方法有治療效果不佳、標靶性差、對生物組織毒性大、易復發等缺點。採用多模式合併治療可以有效解決上述障礙。 TME與癌症疾病的生長、進展和發展有關,在腫瘤的發生和進化中發揮關鍵作用。與正常組織微環境相比,TME在許多方面具有一些獨特的特徵,包括缺氧[26] 、穀胱甘肽(GSH)水平升高[27]和低pH環境[28] 。因此,開發多模式聯合癌症治療方法以克服障礙並提高療效至關重要。
Nowadays, chemodynamic therapy (CDT) has emerged as an effective therapeutic anticancer method based on Fenton/Fenton-like reactions. In comparison with photodynamic therapy which activates by laser irradiation to generate reactive oxygen species (ROS), CDT is a persistent cancer therapy approach which directly utilizes endogenous chemical energy to trigger ROS production under hypoxic condition [16], [29]. Multivalent transition metals, especially for iron, copper, and manganese, involve in Fenton/Fenton-like reactions which can elevate the levels of intracellular ROS in tumor tissues [30]. Specifically, high-valent transition metals (e.g., Cu2+, Fe3+, and Mn4+) possess reversible redox characteristic, thereby they can be utilized in the removal of the reducing species. Subsequently, the reduced transition metal ions can be employed in Fenton/Fenton-like reactions. It is worth noting that Cu+-catalyzed Fenton-like reaction can occur in a favorable reaction condition (neutral and weakly acidic condition). Cu+-catalyzed Fenton-like reaction exhibits a maximum rate of ·OH generation 160 times higher than that of Fe2+-catalyzed one, thereby it is capable of greatly enhancing the CDT effect and preventing the growth and progression of tumor tissues [31]. Therefore, it is urgent to develop a novel inorganic agent with excellent PCE and superior target ability to cancer cells for NIR-II-mediated PA imaging and PTT/CDT, which is pivotal for advancing both scientific research and clinical applications.
如今,化學動力學療法(CDT)已成為基於芬頓/類芬頓反應的有效治療抗癌方法。與透過雷射照射活化產生活性氧(ROS)的光動力療法相比,CDT是一種持久性癌症治療方法,直接利用內源性化學能在缺氧條件下觸發ROS產生[16] , [29] 。多價過渡金屬,特別是鐵、銅和錳,參與芬頓/芬頓樣反應,可以提高腫瘤組織中細胞內ROS的含量[30] 。具體地,高價過渡金屬(例如Cu 2+ 、Fe 3+和Mn 4+ )具有可逆的氧化還原特性,因此它們可以用來去除還原物質。隨後,還原的過渡金屬離子可用於芬頓/類芬頓反應。值得注意的是,Cu +催化的類芬頓反應可以在有利的反應條件(中性和弱酸性條件)下發生。 Cu +催化的類 Fenton 反應最大·OH 生成速率比 Fe 2+催化的高 160 倍,因此能夠大大增強 CDT 效果,阻止腫瘤組織的生長和進展[31] 。 因此,迫切需要開發一種具有優異PCE和對癌細胞具有優異靶向能力的新型無機製劑,用於NIR-II介導的PA成像和PTT/CDT,這對於推進科學研究和臨床應用至關重要。
如今,化學動力學療法(CDT)已成為基於芬頓/類芬頓反應的有效治療抗癌方法。與透過雷射照射活化產生活性氧(ROS)的光動力療法相比,CDT是一種持久性癌症治療方法,直接利用內源性化學能在缺氧條件下觸發ROS產生[16] , [29] 。多價過渡金屬,特別是鐵、銅和錳,參與芬頓/芬頓樣反應,可以提高腫瘤組織中細胞內ROS的含量[30] 。具體地,高價過渡金屬(例如Cu 2+ 、Fe 3+和Mn 4+ )具有可逆的氧化還原特性,因此它們可以用來去除還原物質。隨後,還原的過渡金屬離子可用於芬頓/類芬頓反應。值得注意的是,Cu +催化的類芬頓反應可以在有利的反應條件(中性和弱酸性條件)下發生。 Cu +催化的類 Fenton 反應最大·OH 生成速率比 Fe 2+催化的高 160 倍,因此能夠大大增強 CDT 效果,阻止腫瘤組織的生長和進展[31] 。 因此,迫切需要開發一種具有優異PCE和對癌細胞具有優異靶向能力的新型無機製劑,用於NIR-II介導的PA成像和PTT/CDT,這對於推進科學研究和臨床應用至關重要。
In previous studies, mesoporous silica has conventionally served as a drug carrier [32]. However, compared to mesoporous silica, mesoporous platinum nanoparticle (MPNP) has been explored for biomedical applications recently. MPNP has several advantages as drug carrier [33], [34], [35], [36], including superior photothermal conversion efficiency, photothermal stability [36], and excellent biocompatibility and low cytotoxicity due to their inertia-driven reactivity in vivo and in vitro [37]. In this study, MPNP with mesoporous structure and large surface area synthesized using Pluronic F-127 (PF-127) can serve as carrier for other nanomaterials, paving the way for cancer theranostics.
在先前的研究中,介孔二氧化矽通常用作藥物載體[32] 。然而,與介孔二氧化矽相比,介孔鉑奈米顆粒(MPNP)最近已被探索用於生物醫學應用。 MPNP作為藥物載體具有多種優勢[33] 、 [34] 、 [35] 、 [36] ,包括優異的光熱轉換效率、光熱穩定性[36] ,以及由於其慣性驅動的體內反應性而具有優異的生物相容性和低細胞毒性。在這項研究中,使用Pluronic F-127(PF-127)合成的具有介孔結構和大表面積的MPNP可以作為其他奈米材料的載體,為癌症治療鋪平了道路。
在先前的研究中,介孔二氧化矽通常用作藥物載體[32] 。然而,與介孔二氧化矽相比,介孔鉑奈米顆粒(MPNP)最近已被探索用於生物醫學應用。 MPNP作為藥物載體具有多種優勢[33] 、 [34] 、 [35] 、 [36] ,包括優異的光熱轉換效率、光熱穩定性[36] ,以及由於其慣性驅動的體內反應性而具有優異的生物相容性和低細胞毒性。在這項研究中,使用Pluronic F-127(PF-127)合成的具有介孔結構和大表面積的MPNP可以作為其他奈米材料的載體,為癌症治療鋪平了道路。
The AS1411 aptamer, a G-rich quadruplex 26-mer DNA sequence, has the ability to targeting nucleolin which is overexpressed on the cell membrane of 4T1 tumor cells [38], [39]. AS1411 is one of the most advanced single-stranded DNA aptamers that has selected in clinical trials and showed selective cellular uptake towards tumor cells [40]. The AS1411 with low cytotoxicity has broad potential applications in drug delivery for cancer therapy [41], [42]. Previous studies have shown that AS1411-modified nanomaterials can specifically target 4T1 cancer cells, leading to enhanced targeting ability and therapeutic effect [43], [44], [45]. Thus, the design and application of AS1411-modified nanomaterials with superior targeting ability offers a promising avenue for developing NIR-II PA imaging-guided PTT/CDT agent.
AS1411 適體是一種富含 G 的四鏈體 26 聚體 DNA 序列,能夠靶向在 4T1 腫瘤細胞細胞膜上過度表現的核仁素[38] 、 [39] 。 AS1411是最先進的單股DNA適配體之一,已在臨床試驗中選擇並顯示對腫瘤細胞的選擇性攝取[40] 。具有低細胞毒性的AS1411在癌症治療的藥物傳遞方面具有廣泛的潛在應用[41] , [42] 。先前的研究表明,AS1411修飾的奈米材料可以特異性靶向4T1癌細胞,從而增強靶向能力和治療效果[43] , [44] , [45] 。因此,具有優異標靶能力的AS1411修飾奈米材料的設計和應用為開發NIR-II PA成像引導的PTT/CDT試劑提供了有前景的途徑。
AS1411 適體是一種富含 G 的四鏈體 26 聚體 DNA 序列,能夠靶向在 4T1 腫瘤細胞細胞膜上過度表現的核仁素[38] 、 [39] 。 AS1411是最先進的單股DNA適配體之一,已在臨床試驗中選擇並顯示對腫瘤細胞的選擇性攝取[40] 。具有低細胞毒性的AS1411在癌症治療的藥物傳遞方面具有廣泛的潛在應用[41] , [42] 。先前的研究表明,AS1411修飾的奈米材料可以特異性靶向4T1癌細胞,從而增強靶向能力和治療效果[43] , [44] , [45] 。因此,具有優異標靶能力的AS1411修飾奈米材料的設計和應用為開發NIR-II PA成像引導的PTT/CDT試劑提供了有前景的途徑。
In this work, we developed a tumor-targeting flower-like nanocomposite, MPNPs@Cu2-xSe-AS1411 (MPCSA) with superior tumor ablation capability and excellent biocompatibility. The synthesis protocol and application of this nanocomposite is depicted in Scheme 1. The MPNPs synthesized with PF-127 possess larger specific surface area. Building upon this advantage, Cu2-xSe nanosheets were in-situ synthesized and self-assembled on MPNPs, yielding MPNPs@Cu2-xSe (MPCS) with uniform flower-like morphology. Cu2-xSe, an intrinsic p-type semiconductor, possesses high density of free charge-carriers and demonstrates strong LSPR in the biological NIR-II window, thereby significantly enhancing the PCE and PA imaging signal. Notably, the in vitro photothermal property study showed that MPCSA could reach 70 °C within 1 min and possessed a remarkable PCE of 82.33 % upon 1064 nm laser irradiation. Therefore, the three-dimensional MPCS nano-flowers can be readily prepared, resulting in greater specific surface area, stronger PA signal, enhanced PCE owing to MPNPs and the LSPR effect caused by the copper vacancies and higher tumor accumulation efficiency. By utilizing the AS1411-NH2 nucleolin aptamer for targeting nucleolin on the surface of 4T1 tumor cells, MPCS conjugated with AS1411-NH2 aptamer rapidly accumulated at the tumor site in 4T1 tumor-bearing mice. Finally, MPCSA nanocomposites were degraded into metal ions and eliminated from mice body through metabolism. Our work offers a feasible approach for enhancing the antitumor effects of MPCSA nanocomposites by integrating functionalities of NIR-II PA imaging and PTT/CDT effects.
在這項工作中,我們開發了一種腫瘤靶向花狀奈米複合材料MPNPs@Cu 2- x Se-AS1411(MPCSA),具有卓越的腫瘤消融能力和優異的生物相容性。此奈米複合材料的合成方案與應用如方案1所示。用PF-127合成的MPNPs具有較大的比表面積。基於此優勢,Cu 2- x Se奈米片被原位合成並在MPNPs上自組裝,產生具有均勻花狀形態的MPNPs@Cu 2- x Se(MPCS)。 Cu 2- x Se 是一種本徵 p 型半導體,具有高密度的自由載流子,在生物 NIR-II 視窗中表現出強局部表面等離子體共振,從而顯著增強 PCE 和 PA 成像訊號。值得注意的是,體外光熱性能研究表明,MPCSA可以在1分鐘內達到70°C,並且在1064 nm雷射照射下具有高達82.33%的PCE。因此,可以輕鬆製備三維MPCS奈米花,從而產生更大的比表面積、更強的PA訊號、MPNPs增強的PCE和銅空位引起的LSPR效應以及更高的腫瘤累積效率。透過利用AS1411-NH 2核仁素適體標靶4T1腫瘤細胞表面的核仁素,與AS1411-NH 2適體綴合的MPCS在4T1荷瘤小鼠的腫瘤部位快速累積。最後,MPCSA奈米複合材料被降解為金屬離子並透過代謝從小鼠體內消除。 我們的工作透過整合 NIR-II PA 成像和 PTT/CDT 效應的功能,為增強 MPCSA 奈米複合材料的抗腫瘤效果提供了可行的方法。
在這項工作中,我們開發了一種腫瘤靶向花狀奈米複合材料MPNPs@Cu 2- x Se-AS1411(MPCSA),具有卓越的腫瘤消融能力和優異的生物相容性。此奈米複合材料的合成方案與應用如方案1所示。用PF-127合成的MPNPs具有較大的比表面積。基於此優勢,Cu 2- x Se奈米片被原位合成並在MPNPs上自組裝,產生具有均勻花狀形態的MPNPs@Cu 2- x Se(MPCS)。 Cu 2- x Se 是一種本徵 p 型半導體,具有高密度的自由載流子,在生物 NIR-II 視窗中表現出強局部表面等離子體共振,從而顯著增強 PCE 和 PA 成像訊號。值得注意的是,體外光熱性能研究表明,MPCSA可以在1分鐘內達到70°C,並且在1064 nm雷射照射下具有高達82.33%的PCE。因此,可以輕鬆製備三維MPCS奈米花,從而產生更大的比表面積、更強的PA訊號、MPNPs增強的PCE和銅空位引起的LSPR效應以及更高的腫瘤累積效率。透過利用AS1411-NH 2核仁素適體標靶4T1腫瘤細胞表面的核仁素,與AS1411-NH 2適體綴合的MPCS在4T1荷瘤小鼠的腫瘤部位快速累積。最後,MPCSA奈米複合材料被降解為金屬離子並透過代謝從小鼠體內消除。 我們的工作透過整合 NIR-II PA 成像和 PTT/CDT 效應的功能,為增強 MPCSA 奈米複合材料的抗腫瘤效果提供了可行的方法。
2. Experimental section 2.實驗部分
2.1. Materials 2.1.材料
All chemicals and reagents utilized in this study were of analytical grade and utilized as received without any further purification. Polyvinylpyrrolidone (PVP), selenium dioxide (SeO2), copper (II) chloride dihydrate (CuCl2·2H2O), potassium bromide (KBr), chloroplatinic acid hexahydrate (H2PtCl6·6H2O), ethanol, hydrochloric acid (HCl), 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB), and 3,3′,5,5′-tetramethylbienzidine (TMB) were purchased from Aladdin Reagent Co., Ltd.. Ascorbic acid (AA) was purchased from Xilong Scientific Co., Ltd.. AS1411-NH2-3′ was purchased from Sangon Biotech Co., Ltd.. Cell counting kit-8 (CCK-8) assay kit was procured from Solarbio Science & Technology Co., Ltd.. PF-127, Calcein-AM, propidium iodide (PI), 2-(4-amidinophenyl)-6- indolecarbamidine dihydrochloride (DAPI) and 2′,7′-dichloro-fluorescin diacetate (DCFH-DA) were procured from Beyotime Biotechnology Co., Ltd..
本研究中使用的所有化學品和試劑均為分析級,按原樣使用,無需任何進一步純化。聚乙烯吡咯烷酮 (PVP)、二氧化硒 (SeO 2 )、二水合氯化銅 (II) (CuCl 2 ·2H 2 O)、溴化鉀 (KBr)、六水合氯鉑酸 (H 2 PtCl 6 · 6H 2 O)、乙醇、鹽酸抗壞血酸(HCl)、5,5'-二硫代雙(2-硝基苯甲酸)(DTNB)及3,3',5,5'-四甲基聯苯胺( TMB)購自阿拉丁試劑有限公司。自索拉生物科技有限公司。 ',7'-二氯螢光素二乙酸酯
購自碧陽天生物科技有限公司。
Type | Sequence |
---|---|
AS1411 | 5′-(GGTGGTGGTGGTTGTGGTGGTGGTGG)-3′ |
AS1411-NH2-3′ | 5′-(GGTGGTGGTGGTTGTGGTGGTGGTGG)–NH2-3′ |
本研究中使用的所有化學品和試劑均為分析級,按原樣使用,無需任何進一步純化。聚乙烯吡咯烷酮 (PVP)、二氧化硒 (SeO 2 )、二水合氯化銅 (II) (CuCl 2 ·2H 2 O)、溴化鉀 (KBr)、六水合氯鉑酸 (H 2 PtCl 6 · 6H 2 O)、乙醇、鹽酸抗壞血酸(HCl)、5,5'-二硫代雙(2-硝基苯甲酸)(DTNB)及3,3',5,5'-四甲基聯苯胺( TMB)購自阿拉丁試劑有限公司。自索拉生物科技有限公司。 ',7'-二氯螢光素二乙酸酯
( | DCFH |
---|---|
- | DA |
) | ) |
-(GGTGGTGGTGGTTGTGGTGGTGGTGG)–NH 2 -3′ |
2.2. Characterization 2.2.表徵
Transmission electron microscopy (TEM) images, elemental mapping, and size distribution were conducted on an FEI Talos 200S TEM (Thermo Fisher Scientific Inc.) with an accelerating voltage of 200 kV. The hydrodynamic diameter and Zeta potential values were recorded on a Nano Zetasizer (Malvern Panalytical Ltd.). Ultraviolet–visible-near infrared (UV–Vis–NIR) absorption spectra were recorded on an Agilent CARY 60 spectrometer (Agilent Technologies) at room temperature. The CCK-8 assay was tested by an EL800