Development of a multifunctional platform for near-infrared imaging and targeted radionuclide therapy for tumors

Nowadays, cancer remains the main death cause of people around the world. It is urgent to develop efficient strategies to conquer cancer. To cure the cancer, precise diagnosis and effective treatment are both needed. In general, a successful therapeutic regimen should be established based on accurate diagnosis, especially early diagnosis. To improve the early diagnosis level of tumor, it is necessary to enhance the specificity and sensitivity of agents, which is helpful for distinguishing tumor cells from normal cells. As well known, rapid proliferation is a typical characteristic of tumor cells. Therefore, tumor cells need more nutrients to sustain their rapid proliferation. It is acknowledged that biotin is an essential vitamin for cell growth, and biotin demand is much higher in tumor cells than normal cells [1]. On the other hand, biotin receptor (BR) is overexpressed on the surface of several kinds of tumor cells, such as ovarian, colon, lung and breast tumor cells [2]. Therefore, BR has become an important biomarker for tumor diagnosis and treatment [3]. Recently, a large number of BR-targeted agents have been developed, including diagnostic probes and therapeutic drugs [1], [3].

For tumor diagnosis, molecular imaging techniques, such as optical imaging, magnetic resonance imaging (MRI) and positron emission tomography (PET), have been emerged as a powerful tool in this field [4], [5]. Molecular imaging can detect pathological changes in living bodies at the cellular or sub-cellular level, which is helpful to improve the level of tumor early diagnosis [5], [6]. In particular, optical imaging has drawn much attention in tumor diagnosis due to its characteristics of low cost and high spatial resolution [7], [8]. Near-infrared (NIR) light within 700–1000 nm has low absorption in tissues, but displays deep tissue penetration and low auto-fluorescence [9], [10]. Therefore, NIR imaging has great application potential for real-time detection of tumor. Furthermore, NIR imaging has been applied as a navigation tool during the tumor surgery [11]. In the tumor surgery, it is essential to precisely distinguish tumor areas for complete resection of cancerous tissues. However, it is very difficult to identify the margin of tumor tissue only by naked eyes. Intraoperative NIR imaging can highlight the tumor tissues, which can improve surgical success rate and patient survival rate. Considering the overexpression of BR in several kinds of cancer cell lines, various BR-targeted NIR probes have been developed and applied in molecular imaging [12], [13], [14], [15].

For tumor treatment, surgery, chemotherapy and radiotherapy are commonly used in clinic. However, chemotherapy usually suffers from several side effects [16], while surgery and external irradiation radiotherapy are not effective in treating metastatic tumors [17]. Recently, targeted radionuclide therapy (TRT) has been widely used in the treatment of inoperable and metastatic tumors [17], which employs the carrier with strong target specificity to deliver radionuclides to tumors [17], [18]. Compared with traditional external irradiation radiotherapy, TRT can specifically deliver therapeutic radionuclides to tumors, affording systemic therapy to tumors [19]. 131I, a β-emitting radionuclide with a long physical half-life of 8.02 d, is one of the most used therapeutic radionuclides in clinic due to its suitable radiochemical properties, low cost and easy availability [20]. As BR is overexpressed in several kinds of cancers [1], 131I-labeling BR-targeted pharmaceuticals can serve as a powerful weapon for TRT of cancers.

In clinical practice, a multifunctional platform that can be used in both tumor diagnosis and treatment is preferable. Cyanine molecules are widely used in medical researches as fluorescent groups [21], [22], due to their advantages such as large molar absorption coefficient, high photon yield, convenient preparation, and easy modification [23], [24]. Both the excitation wavelength and emission wavelength of cyanine dyes can be adjusted by varying the length of polymethine chain [25]. Hence, cyanine dyes emitting light within the NIR region are widely used to develop NIR probes [26]. Recently, we designed a biotin-tagged cyanine probe G1 [27], which possessed good NIR fluorescence properties and specifically targeted BR-positive tumors with large tumor-to-muscle (T/M) ratio. More importantly, the probe G1 displayed long retention time (about 7 d) in the tumor, which could serve as a proper tumor-targeted carrier in designing therapeutic drugs. To achieve satisfactory therapeutic effect of TRT agents, the half-life of radionuclide should match the pharmacokinetics of delivery carriers [20]. In this work, taking advantage of the characteristics of biotin-tagged cyanine probe G1 and radioisotope 131I, a multifunctional cyanine derivative (RT-H2) was developed for NIR imaging and 131I-based TRT. On one hand, RT-H2 itself can serve as a NIR probe for diagnosing BR-overexpressed tumors; on the other hand, after labeling with 131I, [131I]I-RT-H2 could serve as a TRT agent to achieve superior therapeutic effect on BR-positive tumors. A series of in vitro and in vivo experiments were carried out to systematically evaluate the application value of RT-H2 and [131I]I-RT-H2.

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