本文關(guān)鍵詞：七甲川花菁類熒光小分子IR-780衍生物的合成、鑒定及其用于腫瘤靶向顯影與治療的實(shí)驗(yàn)研究，由筆耕文化傳播整理發(fā)布。

七甲川花菁類熒光小分子IR-780衍生物的合成、鑒定及其用于腫瘤靶向顯影與治療的實(shí)驗(yàn)研究

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摘要

研究背景與目的
     盡管近幾十年來人們對腫瘤的發(fā)生發(fā)展、轉(zhuǎn)移等機(jī)制研究獲得了重要進(jìn)展，但由于仍缺乏靈敏的早期診斷、高特異性的靶向治療以及實(shí)時(shí)有效的治療監(jiān)測，惡性腫瘤依然是目前嚴(yán)重威脅人類健康的重大疾病。腫瘤診斷治療學(xué)(Tumor theranostics)是近些年提出來的一種腫瘤診治新策略，其核心是將腫瘤治療與實(shí)時(shí)顯影有效結(jié)合，引導(dǎo)醫(yī)生及時(shí)調(diào)整治療方案，提高腫瘤病人的生存率和生活質(zhì)量，為腫瘤個(gè)體化治療提供一種新途徑。由于制備同時(shí)具有腫瘤特異顯影與靶向治療作用的診斷治療劑(Theranosticagents)是同步實(shí)現(xiàn)腫瘤診斷與治療的重要途徑，因此近兩年就該類多功能抗腫瘤藥物的研發(fā)已成為繼分子靶向藥物后的新研究熱點(diǎn)。
     目前對于診斷治療劑的制備主要是通過兩種策略：一是通過多步化學(xué)連接策略，將腫瘤靶向配體，如葉酸、多肽、抗體、核酸適配體等，分別與造影劑和抗腫瘤藥物進(jìn)行連接，從而同時(shí)實(shí)現(xiàn)腫瘤靶向顯影與治療作用；另一種是基于納米材料的特殊性質(zhì)，如利用尺寸依賴性的腫瘤組織增透與阻滯(EPR)效應(yīng)，或利用其比表面積大，易于表面修飾各種靶向配體的優(yōu)點(diǎn)，實(shí)現(xiàn)腫瘤藥物的被動(dòng)或主動(dòng)靶向遞送，同時(shí)利用納米材料自身顯影特性或進(jìn)一步偶聯(lián)顯影劑，實(shí)現(xiàn)腫瘤的靶向顯影與治療監(jiān)測。通過上述兩種策略，目前已經(jīng)獲得了一些具有潛在應(yīng)用價(jià)值的診斷治療劑。例如，99mTc標(biāo)記的阿霉素脂質(zhì)體已經(jīng)在進(jìn)入I期臨床試驗(yàn)，用于頭頸鱗癌病人的治療與監(jiān)測。
     然而，通過多步化學(xué)連接策略制備診斷治療劑，可能會(huì)導(dǎo)致腫瘤配體靶向性的降低、顯影劑成像能力的減弱，甚至藥物抗腫瘤活性的喪失。此外，多步化學(xué)反應(yīng)與分離純化，還可能增加制備成本。特別是基于多功能納米材料策略制備的診斷治療劑，容易在內(nèi)皮網(wǎng)狀系統(tǒng)，例如肝脾等組織器官沉積，存在制備復(fù)雜、成本較高、潛在毒性等缺點(diǎn)，其應(yīng)用也受到了很大限制。因此，優(yōu)化診斷治療劑的制備方法，或發(fā)展新的制備策略具有重要研究意義。
     七甲川花菁類化合物是一類兩端氮雜環(huán)中間含有多個(gè)次甲基長共軛鏈的花菁小分子，其具有摩爾吸光系數(shù)大、熒光量子產(chǎn)率高、穩(wěn)定性好等優(yōu)點(diǎn)，作為近紅外熒光探針，已經(jīng)被廣泛應(yīng)用于蛋白與核酸標(biāo)記、基因測序、動(dòng)物活體成像以及臨床造影等。其中，代表性分子吲哚菁綠(ICG)，已經(jīng)在臨床上廣泛用于心臟、肝臟、眼底血管顯影等。最近，我們課題組首次報(bào)道七甲川花菁熒光小分子IR-780，不需要化學(xué)連接腫瘤靶向配體，即在多種腫瘤細(xì)胞及其荷瘤模型上顯示出良好的腫瘤靶向近紅外熒光顯影特性。進(jìn)一步亞細(xì)胞器共定位實(shí)驗(yàn)結(jié)果表明， IR-780選擇性蓄積在腫瘤細(xì)胞的線粒體內(nèi)，其親脂性離域型陽離子特性可能與其靶向腫瘤細(xì)胞線粒體密切相關(guān)。
     由于IR-780具有良好的腫瘤選擇性和近紅外熒光顯影特性，其也為腫瘤靶向診斷治療藥物的研究提供了新的思路和途徑。基于課題組前期研究基礎(chǔ)，本研究設(shè)想：（1）IR-780能否作為抗腫瘤藥物的新型靶向載體，即通過化學(xué)連接策略，將抗腫瘤藥物與IR-780進(jìn)行共價(jià)連接，能否獲得同時(shí)具有腫瘤靶向近紅外顯影與治療作用的多功能化合物？（2）能否不經(jīng)過化學(xué)連接抗腫瘤藥物策略，直接通過對IR-780分子結(jié)構(gòu)進(jìn)行修飾，通過類似物的合成與篩選，獲得自身同時(shí)具有腫瘤靶向顯影與治療作用的新型多功能診斷治療劑，為腫瘤診斷治療劑探索新的制備策略，為腫瘤個(gè)體化治療提供新途徑。
     研究方法與結(jié)果
     為了驗(yàn)證上述假設(shè)，獲得同時(shí)具有腫瘤靶向、近紅外熒光顯影與治療作用的多功能七甲川花菁分子，本論文分三個(gè)部分開展研究，主要結(jié)果如下：
     1. IR-780羧基衍生物IR-808的合成及腫瘤近紅外熒光顯影特性的鑒定
     1.1首先建立并優(yōu)化了該類七甲川花菁類熒光小分子的合成方法，分別對合成該類七甲川花菁熒光小分子需要的三步反應(yīng)，即Vilsmeier-Haack甲�；-烷基化、縮合反應(yīng)進(jìn)行了改進(jìn)。與以往文獻(xiàn)中報(bào)道的常用合成方法相比，新建立的合成方法具有高效簡潔、易大量制備等優(yōu)點(diǎn)，為大量合成七甲川花菁熒光小分子、進(jìn)一步化學(xué)修飾與藥物連接奠定了基礎(chǔ)。
     1.2衍生合成了含有羧基官能團(tuán)的IR-780衍生物—IR-808。鑒于IR-780缺乏可供直接化學(xué)連接抗腫瘤藥物的活性反應(yīng)官能團(tuán)，需要對其進(jìn)行結(jié)構(gòu)修飾。本研究以6-溴己酸為原料，在合成IR-780的反應(yīng)原料中引入羧基活性反應(yīng)官能團(tuán)，成功合成了含有兩個(gè)羧基活性反應(yīng)官能團(tuán)的IR-780衍生物IR-808，并經(jīng)過核磁共振氫譜(1H-NMR)、碳譜(13C-NMR)、高分辨質(zhì)譜(HRMS)測試確證其結(jié)構(gòu)。
     1.3IR-808腫瘤靶向近紅外熒光顯影特性的鑒定。經(jīng)光譜測試發(fā)現(xiàn)，IR-808的最大吸收和發(fā)射波長均在700-900nm近紅外光譜區(qū)，具有近紅外顯影特性和良好的血清穩(wěn)定性。體內(nèi)實(shí)驗(yàn)表明，IR-808在rTDMCs、HeLa及LCC三種腫瘤細(xì)胞動(dòng)物荷瘤模型中均顯示出較好的腫瘤靶向性，提示其用于腫瘤特異性顯影與診斷具有潛在應(yīng)用前景。研究結(jié)果表明，IR-808不僅保留了良好的腫瘤靶向近紅外熒光顯影特性，同時(shí)還引入了兩個(gè)可供化學(xué)連接反應(yīng)的羧基官能團(tuán)，為進(jìn)一步化學(xué)修飾、藥物連接，或放射性核素標(biāo)記等奠定了基礎(chǔ)；為獲得同時(shí)具有腫瘤靶向顯影與治療作用的多功能分子，或經(jīng)放射性核素等標(biāo)記后用于深部組織腫瘤成像與診斷提供了可能性。
     2. IR-808與抗癌藥物的化學(xué)連接及其腫瘤顯影和殺傷活性的實(shí)驗(yàn)研究
     2.1成功地將IR-808與臨床上常用的三種抗腫瘤藥物進(jìn)行了共價(jià)連接。利用IR-808具有羧基活性反應(yīng)官能團(tuán)的結(jié)構(gòu)特性，選擇臨床上常用的分子量小、抗瘤譜廣、活性強(qiáng)但選擇性差的抗腫瘤藥物，包括美法侖(Melphalan)、5-氟尿嘧啶(5-Fu)、阿霉素(DOX)，分別與IR-808進(jìn)行化學(xué)連接，獲得與美法侖的連接物IR-808NM，與5-Fu的連接物IR-808-5Fu以及與阿霉素的共價(jià)連接物IR-808DOX。前兩者獲得純品化合物，其結(jié)構(gòu)經(jīng)過1H NMR及HRMS測試所確定。后者經(jīng)HRMS測試證明阿霉素與IR-808連接成功，但經(jīng)反復(fù)優(yōu)化反應(yīng)與純化條件，未獲得純品IR-808DOX。
     2.2對新合成的共價(jià)連接產(chǎn)物進(jìn)行腫瘤顯影與殺傷活性的評(píng)價(jià)。通過上述化學(xué)連接策略，將IR-808成功與抗腫瘤藥物連接并獲得純品的新共價(jià)連接物IR-808NM、IR-808-5Fu分別進(jìn)行評(píng)價(jià)。結(jié)果表明，IR-808NM保留較好的腫瘤靶向特性，但I(xiàn)R-808-5Fu則失去了腫瘤靶向性。進(jìn)一步應(yīng)用MG63骨肉瘤細(xì)胞和SW480結(jié)腸癌細(xì)胞進(jìn)行IR-808NM的抗腫瘤活性評(píng)價(jià)。結(jié)果顯示，IR-808NM對兩種細(xì)胞的生長抑制活性顯著高于對照藥美法侖。因此，通過化學(xué)連接策略，本研究成功獲得了同時(shí)具有腫瘤靶向顯影與治療作用的新型多功能熒光小分子IR-808NM，驗(yàn)證了IR-780類似熒光小分子可作為抗腫瘤藥物靶向載體的設(shè)想。
     3. IR-808酯化衍生物的合成與抗腫瘤活性研究
     鑒于我們的研究和相關(guān)文獻(xiàn)報(bào)道IR-780和某些花菁類分子在較高劑量時(shí)可表現(xiàn)出一定的線粒體毒性，本研究提出，通過對IR-808進(jìn)行酯化衍生化，以提高親脂性，使其更容易跨過磷脂雙層疏水性的線粒體膜，從而增大其在線粒體的濃度及毒性，可望獲得不需要化學(xué)連接抗腫瘤藥物，自身具有腫瘤靶向、近紅外熒光顯影與抗腫瘤活性的新型多功能小分子。
     3.1IR-808酯化衍生物的高效合成及其近紅外熒光顯影特性的鑒定。為了提高IR-808親脂性，顯著增強(qiáng)其進(jìn)入細(xì)胞及其線粒體的濃度與毒性，在IR-808的基礎(chǔ)上，設(shè)計(jì)合成四個(gè)IR-808親脂性強(qiáng)的酯化衍生物，包括丁酯(IR-808DB)、己酯(IR-808DH)、環(huán)己酯(IR-808DCH)、苯酚酯(IR-808DP)，均為全新結(jié)構(gòu)的化合物，未見文獻(xiàn)報(bào)道。所建立的合成方法具有高效、易于大量制備等優(yōu)點(diǎn)。四種IR-808酯類衍生物在甲醇、DMSO、血清中的最大吸收和發(fā)射波長均在近紅外區(qū)域，具有比ICG更高的摩爾吸光系數(shù)和熒光量子產(chǎn)率。
     3.2篩選獲得IR-808DB具有顯著抗腫瘤活性。應(yīng)用人肺癌細(xì)胞(A549)研究發(fā)現(xiàn)，IR-808丁酯衍生物(IR-808DB)具有最顯著的抗腫瘤活性(IC50值為0.43μM)。進(jìn)一步在乳腺癌細(xì)胞(MDA231、MCF-7)、肝癌細(xì)胞(SMMC-7721, HepG2)、肺癌細(xì)胞(NCIH-460)等多種人類腫瘤細(xì)胞模型中評(píng)價(jià)其抗腫瘤活性，結(jié)果顯示IR-808DB分子對多種腫瘤細(xì)胞均具有顯著的生長抑制作用(IC50<6μM)。通過荷瘤動(dòng)物體內(nèi)研究，發(fā)現(xiàn)IR-808DB在rTDMCs、Lewis、HeLa以及A549等四種腫瘤模型上，均顯示出較強(qiáng)的抗腫瘤活性。以20mg/kg臨床藥物環(huán)磷酰胺(CTX)為陽性對照，發(fā)現(xiàn)5mg/kg IR-808DB可以明顯抑制腫瘤的生長。治療過程中，荷瘤動(dòng)物的重量和生理狀態(tài)未見明顯異常，主要臟器的組織切片未見明顯病理改變。此外，通過荷瘤動(dòng)物體內(nèi)研究，比較IR-808DB和新合成的共價(jià)連接物IR-808NM的抗腫瘤活性，還發(fā)現(xiàn)IR-808DB的抗腫瘤活性顯著高于IR-808NM。
     3.3IR-808DB具有良好的腫瘤靶向顯影特性。近紅外熒光活體成像顯示，IR-808DB在大鼠rTDMCs荷瘤模型上顯示出腫瘤靶向特性；離體臟器和腫瘤組織的近紅外熒光成像進(jìn)一步證實(shí)其在腫瘤組織的選擇性蓄積。研究還表明，在荷瘤第4天肉眼未見明顯腫瘤包塊形成時(shí)，荷瘤部位即可顯示出近紅外熒光顯影；當(dāng)肉眼可見小于0.5cm的腫瘤包塊形成時(shí)，荷瘤部位即具有顯著的近紅外熒光顯影特性，提示IR-808DB在腫瘤早期識(shí)別與診斷中可能具有研究價(jià)值。
     結(jié)論與創(chuàng)新
     本研究首先建立并優(yōu)化了IR-780多種衍生物的化學(xué)合成方法，制備了含有羧基官能團(tuán)的IR-808，證明其具有良好的腫瘤靶向近紅外熒光顯影特性，為連接抗腫瘤藥物或放射性核素等顯影劑，制備可用于深部組織腫瘤成像和具有腫瘤治療作用的多功能分子奠定了基礎(chǔ)。進(jìn)而，利用IR-808具有羧基活性反應(yīng)官能團(tuán)的結(jié)構(gòu)特性，成功地與三種抗腫瘤藥物進(jìn)行共價(jià)連接，篩選獲得了同時(shí)具有腫瘤靶向顯影與殺傷作用的衍生物IR-808NM，驗(yàn)證了IR-780類似熒光小分子可作為抗腫瘤藥物靶向載體的設(shè)想。最后，通過對IR-808進(jìn)行酯化修飾，提高其親脂性，從而增強(qiáng)其線粒體毒性，制備獲得了不需要化學(xué)連接抗腫瘤藥物，自身具有腫瘤靶向、近紅外熒光顯影與抗腫瘤活性的新型化合物IR-808DB，為進(jìn)一步研發(fā)新型的腫瘤個(gè)體化診斷治療藥物提供了新的策略和途徑。目前，IR-808DB已獲得國家發(fā)明專利授權(quán)，其抗腫瘤機(jī)制與進(jìn)一步安全性評(píng)價(jià)等臨床前研究正在進(jìn)行中。
Background and Objectives：
     Despite recent research involving cancer development and metastasis has gainedsignificant progress, malignant tumor still remains one of the most deadly diseases in theworld, due to the inefficient early diagnosis, poor specificity of drugs resulting in severeadverse effects, and lack of sensitive and real-time modalities to monitor therapeuticresponse. Tuomr theranostics, a fusion of therapeutics and diagnostics for optimizingefficacy and safety in cancer treatment, has been considered as a significant alternativenessto overcome these challenges. This integration can monitor therapeutic efficacy followingtreatments which can expedite clinician’s individualized therapeutic decisions. Becausetheranostic agents are of importance to achieve the simultaneous multifunctionality oftumor targeting, imaging and therapy, their preparation has received a great deal of researchinterest in recent years.
     Currently, there are two main strategies explored for the obtainment of suchmultifunctional theranostic agents. One approach is through the multi-step chemicalconjugation of anticancer drugs and contrast agents with various cancer-targeted ligands,such as small molecules, antibodies, peptides, aptamers, etc. With the rapid development onadvanced multifunctional nanomaterials in nanomedicine, the other approach fordevelopment of cancer theranostic agents is based on nanoplatforms. They achievesimultaneous cancer specific detection and therapeutics by specifically delivering a highlypotent cytotoxic agent toward tumors either through the EPR effect of the tumormicrovasculature or through the conjugation of target ligands which can specifically bind tobiomakers highly associated with cancer cells. In many cases, advanced nanomaterialsendowed with imaging capability have been engineered to deliver and release drugsselectively toward tumor tissues. With the two strategies referred abrove, some cancer targeted therapeutic drugs are approved for clinical use or clinical trial. For example,99mTclabeing lipidosomes loaded with DOX has been approved to carry out clinic Phase I trial. Itachieves treatment of head and neck squamous carcinoma by SPECT imaging.
     However, the conjugation may alter the functional activities of tumor-targeted ligands,contrast agents or therapeutic agents. Multi-step chemical conjugation may lead to lowerthe specificity of tumor ligands, weaken the imaging intensity of contrast agents, or lose theantitumor activity of drugs. Meanwhile, additional reaction agents and purificationprocedure in the multi-step conjugation would require higher cost. In particular,nanoplatform-based strategy for the multifunctional nanotheranostic agents has been provenchallenging and is still at an early or proof-of-concept stage due to several fundamentalproblems and technical barriers, such as the lag effect from reticuloendothelial system (RES)and mononuclear phagocytic system, the difficulties in large scale preparation with highreproductivity, and the potential safe concerns for their long-term fate and toxicity. Thus,investigation of new strategy for obtainment of theranostic agents is high necessary.
     Heptamethine cyanine dyes with two terminal indole heterocyclic units linked by apolymethine bridge, characterized with high molar absorption coefficient and fluorescencequantum yield, good photostability, have been applied widely in labeling nucleic acids andproteins, gene sequencing, in vivo imaging animals. Of them, Indocyanine green (ICG)has been used in clinic extensively for visualizing tiny blood vessels of livers and eyes.Recently, our studies have characterized a heptamethine cyanine dye, IR-780with tumortargeting and NIR imaging properties without chemical conjugation of tumor target ligand.The targeting property of IR-780also has been confirmed in a broad spectrum of tumorcells and tumor xenografts, suggesting an attractive diagnostic agent for sensitive andnoninvasive tumor detection. The subcellular localization of IR-780in tumor cells furthershowed that the dye exclusively accumulated in the mitochondria of tumor cells. Theunique property of delocalized lipophilic cation, may give IR-780the ability to target andretain in mitochondria of tumor cells.
     Based on our previous findings on IR-780simultaneously with tumor targeting andNIR imaging properties, we hypothesized:(1) whether IR-780could be used as a carrier tochemically conjugate antitumor drugs for tumor targeted imaging and therapy;(2) whetherthe intrinsically multifunctional heptamethine cyanine dyes could be obtained by rational modification of IR-780without need of chemical conjugation of antitumor durgs. If thesedesigns mentioned above are proved, they would provide a valuable strategy for preparationof theranositc agents applied in cancer personalized therapy.
     Methods and Results：
     In order to verify the hypotheses referred above, and obtain multifunctionalheptamethine cyanine dyes with tumor targeted imaging and therapeutic properties, thisdissertation is divided into three chapters and main results are as follows:
     1. Synthesis and characterization of a carboxyl derivative of IR-780for tumortargeting and NIR imaging
     1.1A modified synthetic method for heptamethine cyanine dyes was established. Dueto low efficiency and small-scale limitation in preparing heptamethine cyanine dyes aspreviously reported in literatures, an improved synthetic method needs to be established.The synthetic routes of heptamethine cyanine dyes including Vilsmeier-Haack formylationreaction, N-alkylation reaction and condensation reaction, were optimized for theconditions of reaction and post-treatment, resulted in the improvement of syntheticefficiency with large-scale available preparation, providing a basis for further drugconjugation.
     1.2IR-808, a derivative of IR-780with two reactive carboxyl groups was synthesized.In order to obtain multifunctional heptamethine cyanine dyes simultaneously with tumortargeted imaging and antitumor activites, IR-780needs to chemically conjugate with anantitumor drug. However, IR-780is lack of available functional group in its structure forfurther conjugation. IR-808was synthesized by using6-bromo hexanoic acid as the startingmaterial to introduce a carboxyl group in a key raw material which was used to synthesizeIR-780. Its structure was comfirmed with Hydrogen nuclear magnetic resonance (1H-NMR),Carbon-nuclear magnetic resonance (13C-NMR) and High resolution mass spectrum(HRMS).
     1.3IR-808was identified with good tumor targeting and NIR imaging properties.After determining the spectra of IR-808, it was found the peak wavelength of absorbtionand emission was in the NIR region (700-900nm). IR-808exhibited NIR fluorescentimaging ability and pretty good stability in serum. The preferential in vivo tumoraccumulation of IR-808was comfirmed in rTDMCs, HeLa and LLC tumor xenografts, suggesting a prospective potential used for tumor specific imaging and diagnosis. Insummary, our results showed that IR-808with two reactive carboxyl groups exhibited thetumor targeting and NIR imaging properties, providing a basis for further drug conjugation.This finding also provides a possibility in developing a radionuclide-labelled heptamethinecyanine dyes for deep-tumor imaging and diagnosis.
     2. Conjugation of IR-808with antitumor drugs for tumor-targeted imaging andtreatment
     2.1Three clinically available antitumor drugs were covalently conjugated with IR-808.On the basis of the above studies, IR-808was further designed to conjugate with antitumordrugs. We successfully conjugated IR-808with Melphalan,5-Fluoro-2,4(1H,3H)pyrimidinedione (5-Fu), Doxorubicin(DOX), and obtained IR-808NM, IR-808-5Fu andIR-808DOX, respectively. IR-808NM and IR-808-5Fu were afforded with high purity, andtheir structures were comfirmed with1H NMR and HRMS. Successful conjugation of DOXwith IR-808was ensured by the testing report of HRMS. However, IR-808DOX wasafforded with a low pure complex even through continuously optimizing the conditions ofreaction and purification.
     2.2The tumor targeted imaging and antitumor activity of IR-808NM and IR-808-5Fuwere investigated. The two conjugations were injected into the rTDMCs tumor-bearingmice to evaluate their specificity for tumor imaging. In vivo NIR imaging showed thatIR-808NM remained the tumor-targeted NIR imaging ability while IR-808-5Fu failed. Then,the antitumor activity of IR-808NM was evaluated with MG63osteosarcoma cancer cellsand SW480colon cancer cells. It was found that IR-808NM inhibited the growth of cancercells efficiently. Its antitumor activity was significantly higher than that of Melphalan.These results supported that we successfully developed a multifunctional heptamethinecyanine dye with chemical conjugation strategy, and verify the hypothesis that this kind oftumor targeting NIR dyes can be used as a carrier of antitumor drugs for tumor targetedimaging and therapy.
     3. Synthesis of esterified derivatives of IR-808for tumor treatment
     According to our previous work and others, some caynine dyes, including IR-780would exhibit mitochondrial toxicity at higher concentration. Because mitochondria areencircled with two lipophilic membranes, lipophilic agents are more readily transported across bistratal membranes to reach a higher concentration. Basing on these investigations,we hypothesized that esterification of IR-808, would increase its lipophilicity greatly, aswell as its mitochondrial accumulation and potential toxicity. In this case, multifunctionalheptamethine cyanine dyes simultaneously with tumor targeted imaging and antitumoractivity would be obtained without need of chemical conjugation to tumor specific ligands.
     3.1Four esterified derivatives of IR-808were synthesized and characterized with NIRimaging property. In order to improve the lipophilicity of IR-808, and significantly enhancetheir accumulation and toxicity in tumor mitochondria, several esterified derivatives ofIR-808including butyl ester (IR-808DB), hexyl ester (IR-808DH), cyclohexyl ester(IR-808DCH), phenol ester (IR-808DP) were prepared with a highly efficient andlarge-scale available method. All these newly synthesized molecules have not been reportedpreviously. These molecules in methanol, DMSO and serum exhibited the maximumabsorption and emission wavelengths in the NIR region. Compared with ICG, esterderivatives of IR-808exhibited higher molar extinction coefficient and fluorescencequantum yields.
     3.2IR-808DB was characterized with significant antitumor effect. Cytotoxicity ofIR-808and its ester derivatives were performed on A549human lung cancer cells. Studiesshowed that these ester derivatives exhibited diverse anticancer activities on A549carcinoma cells. Of them, IR-808DB displayed most remarkable antitumor activity with anIC50of0.43μM. We further confirmed the antitumor effect of IR-808DB in other humancancer cell lines, including breast cancer cells (MDA231and MCF-7), hepatoma cells(SMMC-7721, HepG2), and non-small-cell lung cancer NCIH-460cells, demonstrating apotent antitumor activity of IR-808DB (IC50<6μM) on a broad spectrum of tumor cells. Invivo tumoricidal activities of IR-808DB were then evaluated in rTDMCs, A549, LLC, andHeLa tumor xenografts. Results revealed that5mg/kg IR-808DB inhibited tumor growthobviously as compared to20mg/kg Cyclophosphamide (CXT) group, a classic antitumordrug which has been widely applied in clinic. Laudable tumoricidal activities of IR-808DBwere observed in rTDMCs, A549, LLC and HeLa tumor xenografts, suggest the potentantitumor activity of IR-808DB in a variety of tumor xenografts. Meanwhile, the bodyweight and physical conditions of mice after treatment were not changed significantly. Inaddition, organs harvested from the mice with IR-808DB treatment were subjected to histopathological analysis and also showed no apparent abnormalities. The tumor growthinhibition of IR-808DB was also compared with IR-808NM, and results revealed thatIR-808DB displayed significantly higher tumor growth inhibition effect than IR-808NMdid.
     3.3IR-808DB was demonstrated with the ability of tumor-targeted imaging. In vivoNIR fluorescence imaging of athymic nude mice bearing with rTDMCs tumor xenograftsshowed IR-80DB with tumor targeting capability. The fluorescent intensity of the dissectedorgans and tumors further confirmed the preferential accumulation of IR-808DB in tumors.To evaluate its potential application in tumor early diagnosis,0.4mg/kg (imaging dosage)of IR-808DB was injected into the rats bearing rTDMCs tumors through tail vein and thefluorescent signals associated with tumor site were clearly detected even the tumor was notvisualized by eyes, indicating a potential used for tumor early identification and diagnosis.
     Conclusion and Innovation:
     In this dissertation, we initially established a modified synthetic method for IR-780and its derivatives, synthesized an analogue of IR-780with reactive carboxyl groups(IR-808) with tumor targeting and NIR imaging properties, providing a basis for furtherdrug conjugation. Next, IR-808was conjugated with three clinically available antitumordrugs respectively, and a multifunctional derivative of IR-808with tumor targeting andantitumor activity (IR-808NM) was successfully obtained. These results supported that wesuccessfully developed a multifunctional heptamethine cyanine dye with chemicalconjugation strategy, and verify the hypothesis that this kind of tumor targeting NIR dyescan be used as a carrier of antitumor drugs for tumor targeted imaging and therapy. Finally,by esterification of IR-808to increase its lipophilicity as well as its mitochondrialaccumulation and toxicity, we eventually obtained a multifunctional heptamethine cyaninedye (IR-808DB) intrinsically with tumor targeted imaging and antitumor effect withoutneed of chemical conjugation to tumor specific ligands. As a potential antitumor drug,IR-808DB has advantages of not only good tumor targeting, potent antitumor effect andfine NIR imaging, but also small molecular weight, low cost and large-scale availablepreparation. This multifunctional small molecule presents a valuable strategy forpreparation of new theranositc agents in cancer personalized therapy.

引文

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  本文關(guān)鍵詞：七甲川花菁類熒光小分子IR-780衍生物的合成、鑒定及其用于腫瘤靶向顯影與治療的實(shí)驗(yàn)研究，由筆耕文化傳播整理發(fā)布。