PMID- 34812000 OWN - NLM STAT- MEDLINE DCOM- 20211124 LR - 20220915 IS - 1872-2059 (Electronic) IS - 1000-8713 (Print) IS - 1000-8713 (Linking) VI - 39 IP - 12 DP - 2021 Dec TI - [Pharmacokinetics and tissue distribution characteristics of the novel photosensitizer 3(2)-(4-methoxyphenyl)-15(2)-aspartyl-chlorin e6]. PG - 1291-1297 LID - 10.3724/SP.J.1123.2021.01010 [doi] AB - Photodynamic therapy (PDT) has garnered immense research interest. PDT can directly kill the cells via a combination of photosensitizer, light, and molecular oxygen. It has emerged as a promising therapeutic option for cancer treatment owing to its advantages such as minimized systemic toxicity, minimal invasiveness, high therapeutic efficacy, and potential for developing antitumor immunity. The novel photosensitizer 3(2)-(4-methoxyphenyl)-15(2)-aspartyl-chlorin e6 (DYSP-C34) was synthesized by introducing a 3(2)-aryl substitution and amino acid substituent of the Chenghai chlorin (CHC). Briefly, 3(2)-(4-methoxyphenyl) substitution was achieved via olefin metathesis reactions. The aspartic acid side chain was introduced regioselectively at C-15(2), followed by hydrolysis to yield the target DYSP-C34. CHC with the same chemical structure as chlorin e6 was prepared from chlorophyll a, which was extracted from Spirulina powders derived from Chenghai Lake in the Yunnan province of China. This strategy successfully endowed the resultant photosensitizer with better cellular permeability and increased water solubility. In addition, the photodynamic antitumor effects of PDT largely depend on the dose of photosensitizer used, time between photosensitizer administration and light exposure, and possibly other still poorly known variables. Determination of optimal conditions for PDT requires a coordinated interdisciplinary effort. Therefore, the pharmacokinetics and tissue distribution of DYSP-C34 in vivo are critical for the efficacy and safety of PDT. Herein, a high performance liquid chromatography-ultraviolet (HPLC-UV) detection method was established for the determination of the new photosensitizer DYSP-C34 in rat plasma. The sample preparation involved a protein-precipitation and liquid-liquid extraction method. Methanol was used to precipitate proteins and chloroform was used to extract chlorins. Then, DYSP-C34 was separated on a Unitary C(18) column (250 mmx4.6 mm, 5 mum) with a mobile phase comprising methanol and 5 mmol/L tetrabutylammonium phosphate buffer solution (70ratio30, v/v). The flow rate was 1.0 mL/min with UV detection using a wavelength of 400 nm at 40 ℃. Results showed that DYSP-C34 and chlorin e6 trimethyl ester (IS) were well separated under these conditions. The method was sensitive and sufficiently precise with a good linear relationship (determination coefficient (r(2))=0.9941) over the range of 1-200 mug/mL in rat plasma. At three spiked levels (8, 40, and 120 mug/mL), the average recoveries were 74.39%, 69.71%, and 65.89%, respectively. The intra-day and inter-day relative standard deviations (RSDs) were lower than 5%. The precision met the requirements of biological sample determination. Furthermore, DYSP-C34 was stable in rat plasma under various storage conditions at room temperature, three freeze-thaw cycles, and long-term cryopreservation. The validated method was successfully applied to the pharmacokinetic study of DYSP-C34 after intravenous injection of a single dose in rat plasma. The pharmacokinetic parameters after intravenous injection of DYSP-C34 (16 mg/kg) were calculated. The plasma half-life (t(1/2z)) was 6.98 h, the area under the plasma concentration-time curve AUC((0-infinity)) was 1025.01 h.mg/L and the mean retention time MRT((0-infinity)) was 9.19 h. In addition, the results of DYSP-C34 distribution in tumor-bearing mice showed that DYSP-C34 could accumulate in tumor tissues, with higher concentrations in liver and kidney tissues, and lower concentrations in heart, spleen, and lung tissues. In summary, a specific, simple, and accurate HPLC-UV method was developed and validated for the determination of DYSP-C34 in rat plasma and tumor-bearing mouse tissues. The pharmacokinetics of DYSP-C34 after intravenous administration in rats and the tissue distribution characteristics of tumor-bearing mice were clarified for the first time. It is significant for clinical rational drug use and pharmacodynamic research. Therefore, choosing an appropriate time for light treatment time can achieve the best photodynamic effect. The results of pharmacokinetics and tissue distribution of DYSP-C34 provide vital guidance for subsequent pharmacodynamic research and further clinical trials in terms of dosage, light time, light toxicity and side effects. FAU - Wang, Liu AU - Wang L AD - College of Chemical Engineering, Faculty of Chemical, Environment and Biological Science and Technology, Dalian University of Technology, Dalian 116024, China. FAU - Dong, Yi AU - Dong Y AD - College of Chemical Engineering, Faculty of Chemical, Environment and Biological Science and Technology, Dalian University of Technology, Dalian 116024, China. FAU - Cao, Lei AU - Cao L AD - College of Chemical Engineering, Faculty of Chemical, Environment and Biological Science and Technology, Dalian University of Technology, Dalian 116024, China. FAU - Sun, Yuming AU - Sun Y AD - Chemical Analysis and Research Center, Dalian University of Technology, Dalian 116024, China. FAU - Li, Yueqing AU - Li Y AD - College of Chemical Engineering, Faculty of Chemical, Environment and Biological Science and Technology, Dalian University of Technology, Dalian 116024, China. FAU - Zhao, Weijie AU - Zhao W AD - College of Chemical Engineering, Faculty of Chemical, Environment and Biological Science and Technology, Dalian University of Technology, Dalian 116024, China. AD - State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China. LA - chi PT - Journal Article PL - China TA - Se Pu JT - Se pu = Chinese journal of chromatography JID - 9424804 RN - 0 (Chlorophyllides) RN - 0 (Photosensitizing Agents) RN - 0 (Porphyrins) RN - 5S2CCF3T1Z (phytochlorin) RN - YF5Q9EJC8Y (Chlorophyll A) SB - IM MH - Animals MH - China MH - Chlorophyll A MH - Chlorophyllides MH - Chromatography, High Pressure Liquid MH - Mice MH - *Photosensitizing Agents MH - Porphyrins MH - Rats MH - Reproducibility of Results MH - Tissue Distribution PMC - PMC9404104 OTO - NOTNLM OT - chlorins OT - high performance liquid chromatography-ultraviolet (HPLC-UV) detection OT - pharmacokinetics OT - photosensitizer OT - tissue distribution OT - tumor-bearing mice EDAT- 2021/11/24 06:00 MHDA- 2021/11/25 06:00 PMCR- 2021/12/08 CRDT- 2021/11/23 07:00 PHST- 2021/11/23 07:00 [entrez] PHST- 2021/11/24 06:00 [pubmed] PHST- 2021/11/25 06:00 [medline] PHST- 2021/12/08 00:00 [pmc-release] AID - 1000-8713-39-12-1291 [pii] AID - 10.3724/SP.J.1123.2021.01010 [doi] PST - ppublish SO - Se Pu. 2021 Dec;39(12):1291-1297. doi: 10.3724/SP.J.1123.2021.01010.