Photosensitizer (PS)-cyanine dye (CD) conjugates: Impact of the linkers joining the PS and CD moieties and their orientation in tumor-uptake and photodynamic therapy (PDT) (original) (raw)
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Theranostics, 2013
Previous reports from our laboratory have shown that a bifunctional agent obtained by conjugating a photosensitizer (HPPH) to a cyanine dye (CD) can be used for fluorescence image-guided treatment of tumor by photodynamic therapy (PDT). However, the resulting HPPH-CD conjugate showed a significant difference between the tumor-imaging and therapeutic doses. It was demonstrated that the singlet oxygen (1 O 2 * , a key cytotoxic agent in PDT) produced by the conjugate upon excitation of the HPPH moiety was partially quenched by the CD-moiety; this resulted in a reduced PDT response when compared to HPPH-PDT under similar treatment parameters. To improve the therapeutic potential of the conjugate, we synthesized a series of dual functional agents in which one or two HPPH moieties were separately conjugated to three different dyes (Cypate, modified IR820 or modified IR783). The newly synthesized conjugates were compared with our lead compound HPPH-CD in terms of photophysical properties, in vitro and in vivo PDT efficacy, tumor uptake and imaging potential. Among the analogs investigated, the conjugate, in which two HPPH moieties were linked to the modified IR820 produced enhanced tumor uptake and tumor contrast in both Colon 26 (a murine Colon carcinoma) and U87 (a human glioblastoma) cell lines. The long-term PDT efficacy (cure) of this conjugate in BALB/c mice, bearing Colon 26 tumors was also enhanced; however, its efficacy in Nude mice bearing U87 tumors was slightly reduced. It was also found that in all the conjugates the singlet oxygen generation and, consequently, PDT efficacy were compromised by a competing pathway, whereby an electronic excitation of HPPH, the energy donor, is deactivated through an electronic excitation energy transfer (Forster Resonance Energy Transfer, FRET) to the CD fluorophore, the energy acceptor, resulting in overall reduction of the singlet oxygen production. Conjugates with increased FRET showed reduced singlet oxygen production and PDT efficacy. Among the conjugates investigated, the bifunctional agent in which two HPPH moieties were linked to the benzoindole-based cyanine dye 11 showed superiority over the lead candidate 9 (mono HPPH-cyanine dye).
Conjugated Photosensitizers for Imaging and PDT in Cancer Research
Journal of Medicinal Chemistry, 2020
Early cancer detection and perfect understanding of the disease are imperative towards efficient treatments. And it is straightforward that, for choosing a specific cancer treatment methodology, diagnostic agents undertake a critical role. Imaging is an extremely intriguing tool since it is not only assuming a follow up to treatments to survey the accomplishment of the treatment and to recognize any conceivable repeating injuries, but also it permits to analyze the disease, as well as to pursue treatment and monitor the possible changes that happen on the tumor. Likewise, it allows screening the adequacy of treatment and to visualize the state of the tumor. Additionally, when the treatment is finished, observing the patient is imperative to evaluate the treatment methodology and adjust the treatment if necessary. The goal of this review is to present an overview of conjugated photosensitizers for imaging and therapy.
Bioconjugate Chemistry, 2011
Purpurinimide methyl esters, bearing variable lengths of N-substitutions, were conjugated individually to a cyanine dye with a carboxylic acid functionality. The results obtained from in vitro and in vivo studies showed a significant impact of the linkers joining the phototherapeutic and fluorescence imaging moieties. The photosensitizer−fluorophore conjugate with a PEG linker showed the highest uptake in the liver, whereas the conjugate linked with two carbon units showed excellent tumor-imaging and PDT efficacy at 24 h postinjection. Whole body imaging and biodistribution studies at variable time points portrayed enhanced fluorescent uptake of the conjugates in the tumor compared to that in the skin. Interestingly, the conjugate with the shortest linker and the one joining with two carbon units showed faster clearance from normal organs, e.g., the liver, kidney, spleen, and lung, compared to that in tumors. Both imaging and PDT efficacy of the conjugates were performed in BALB/c mice bearing Colon26 tumors. Compared to the others, the short linker conjugate showed poor tumor fluorescent properties and as a corollary does not exhibit the dual functionality of the photosensitizer−fluorophore conjugate. For this reason, it was not evaluated for in vivo PDT efficacy. However, in Colon26 tumor cells (in vitro), the short linker was highly effective. Among the conjugates with variable linkers, the rate of energy transfer from the purpurinimide moiety to the cyanine moiety increased with deceasing linker length, as examined by femtosecond laser flash photolysis measurements. No electron transfer from the purpurinimide moiety to the singlet excited state of the cyanine moiety or from the singlet excited state of the cyanine moiety to the purpurinimide moiety occurred as indicated by a comparison of transient absorption spectra with spectra of the one-electron oxidized and one-electron reduced species of the conjugate obtained by spectroelectrochemical measurements.
European Journal of Medicinal Chemistry, 2019
Effective photosensitizers are particularly important factor in clinical photodynamic therapy (PDT). However, there is scarcity of photosensitizers for simultaneous cancer photo-diagnosis and targeted PDT. Herein, two novel dimethyl 2-(guanidinyl)ethylamino chlorin e6 photosensitizers were synthesized and their efficacy in PDT in A549 tumor was investigated. It was showed that compounds 3 and 4 have a long absorption wavelength in the near infrared region and strong fluorescence emission with slow photo-bleaching rate and markedly strong ability of 1 O2 generation. They exhibited lower cytotoxicity and higher photo-cytotoxicity in vitro compared to the known anticancer drug m-THPC in MTT assay in A549 lung cancer cell lines. Compound 4 exhibit better inhibition effect than compound 3 and the IC50 value of compound 4 was 0.197 μM/L under 2 J/cm 2 laser irradiation, while compound 3 showed better anti-tumor effects compared to compound 4 in vivo. Intracellular ROS generation was found to be responsible for apoptotic cell death in DCFDA assay. Subcellular localization confirmed the damage site of compounds 3 and 4 in PDT. These findings suggest that the two novel photosensitizers might serve as potential photosensitizers for improved therapeutic efficiency of PDT.
An updated overview on the development of new photosensitizers for anticancer photodynamic therapy
Acta Pharmaceutica Sinica B
Photodynamic therapy (PDT), based on the photoactivation of photosensitizers (PSs), has become a well-studied therapy for cancer. Photofrin ® , belonging to the first generation of PS, is still widely used for the treatment of different kinds of cancers; however, it has several drawbacks that significantly limit its general clinical use. Consequently, there has been extensive research on the design of PS molecules with optimized pharmaceutical properties, with aiming of overcoming the disadvantages of traditional PS, such as poor chemical purity, long half-life, excessive accumulation into the skin, and low attenuation coefficients. The rational design of novel PS with desirable properties has attracted considerable research in the pharmaceutical field. This review presents an overview on the classical photosensitizers and the most significant recent advances in the development of PS with regard to their potential application in oncology.
ChemistrySelect, 2017
Targeting peptides are very promising molecules to increase tumor selectivity of anticancer drugs. Herein, we report the synthesis of three complexes, which might act at the same time as photosensitizers (PSs) for cancer photodynamic therapy (PDT), as delivery systems of Re(I)/ 99m Tc(I) fragments into tumor cells as well as targeting agents for prostate cancer cells. To this aim, we designed a structure containing a PS such as a water soluble + 3-charged tris-methylpyridinium porphyrin or a fulleropyrrolidine derivative, a [1,4,7]-triazacyclononane (TACN) chelator suitable for coordination, and a bombesin BN[7-14] as a targeting peptide. Their syntheses were performed using two different approaches: the first one was based on a Cu(I)catalyzed azide-alkyne cycloaddition (CuAAC, "click reaction") in solution, that led to compound 1, and the second one based on coupling reactions on the solid phase, that led to compounds 2 and 3. We could successfully prepare molecules bearing tumor-targeting PSs and which are suitable for imaging applications. Overall, this work paves the way for the synthesis of theranostic complexes although the yields will need to be seriously improved and the synthetic process optimized.
Polymer Chemistry, 2013
A versatile approach is introduced for the synthesis of well-defined, biocompatible conjugates combining two-photon chromophores and hydrophilic multifunctional polymers synthesized by RAFT controlled radical polymerization. As an illustration, two different classes of conjugates carrying multiple fluorophores (based on an anthracene moiety, Anth) or photosensitizers (based on a dibromobenzene moiety, DBB) along the polymer chain were elaborated for bioimaging and photodynamic therapy (PDT) applications, respectively. In both cases, the polymer greatly improved the solubility in biorelevant media as well as the cell uptake. Anth conjugates provided high quality fluorescence microscopy images using both one-and two-photon excitation. DBB conjugates potently induced the death of cancer cells upon photoactivation. † Electronic supplementary information (ESI) available: Detailed synthesis of both TPA chromophores, complementary spectroscopic data, ow cytometry analyses, kinetics of cell uptake and cytotoxicity evaluation for 6Anth-H.
Current Advances in Photoactive Agents for Cancer Imaging and Therapy
Annual Review of Biomedical Engineering
Photoactive agents are promising complements for both early diagnosis and targeted treatment of cancer. The dual combination of diagnostics and therapeutics is known as theranostics. Photoactive theranostic agents are activated by a specific wavelength of light and emit another wavelength, which can be detected for imaging tumors, used to generate reactive oxygen species for ablating tumors, or both. Photodynamic therapy (PDT) combines photosensitizer (PS) accumulation and site-directed light irradiation for simultaneous imaging diagnostics and spatially targeted therapy. Although utilized since the early 1900s, advances in the fields of cancer biology, materials science, and nanomedicine have expanded photoactive agents to modern medical treatments. In this review we summarize the origins of PDT and the subsequent generations of PSs and analyze seminal research contributions that have provided insight into rational PS design, such as photophysics, modes of cell death, tumor-targeti...