What is it about?
Camptothecin (CPT) was first extracted from the Chinese tree Camptotheca acuminata and was used in traditional Chinese medicine. It was discovered to be a potent agent with antitumor and antibiotic activities that acted by inhibiting DNA topoisomerase I (Topo I), an essential enzyme that can release DNA supercoiling during transcription and replication.1 CPT binds to the Topo I-DNA intermediate, holding the single- and double-stranded DNA breaks unligated, and the resulting complex can induce DNA damage and initiate cellular apoptosis, which is programmed cell death.2 In particular, CPT is specific to the S-phase of the cell cycle; thus, it is highly toxic to rapidly replicate cells like cancerous cells
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Why is it important?
Recently, our group has designed and developed a series of advanced molecular carriers that contain carbohydrates as a scaffold. For example, monosaccharides (e.g., glucose, mannose, allose, and galactose), disaccharides (e.g., lactose and trehalose), stereoisomers of inositols, and sorbitol were utilized as scaffolds.24–28 Similar to CPP, multiple guanidine units were attached to the carbohydrate scaffold via linkers to facilitate cell membrane penetration. Furthermore, these synthetic carbohydrate-based molecular carriers demonstrated their greatest utility in delivering diverse cargoes into mammalian tissues and organs. To date, small molecules such as paclitaxel, ibuprofen, and AZT, as well as larger sized substances such as proteins and nanoparticles were readily delivered to targets by these molecular carriers.29–34 Therefore, to make CPT a more potent drug and to treat colon cancer efficiently with lower doses of CPT, the need for an efficient drug delivery vector is straightforward. We herein synthesized a CPT-conjugated molecular transporter, studied its cell membrane permeability, and measured its anticancer activity.
Perspectives
Although CPT is known to have an anticancer effect, there are many challenges in using CPT as a chemotherapy drug. For the purpose of improving drug delivery issue of CPT, we designed and synthesized a CPT-conjugated molecular transporter that included eight guanidines, which are essential for cell internalization. A fluorescent probe was also attached to the conjugate to allow imaging. Using confocal microscopy, the conjugate was confirmed to internalize rapidly into HeLa cells and target the mitochondria. The conjugate showed preference to kidney, lung, and spleen. The cytotoxicity of the conjugate was quantified by MTT assay, and the resulting IC50 values of the conjugate in SW480 and HT-29 cells were much lower than those of CPT. Therefore, we confirmed that the drug efficacy of the conjugate was well maintained after internalization. Further studies are underway to exploit the conjugate in other in vivo experiments and to demonstrate the potentiating effect of CPT on cancer treatment.
TEJINDER SINGH
Soonchunhyang University
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This page is a summary of: Preparation of a Camptothecin‐conjugated Molecular Carrier and its Cytotoxic Effect Toward Human Colorectal Carcinoma
In Vitro, Bulletin of the Korean Chemical Society, November 2018, Wiley,
DOI: 10.1002/bkcs.11611.
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