Anticancer Drug Irinotecan Research Articles

The preventive effects of diosmin alone or combined with irinotecan on 1,2-dimethylhydrazine-induced colon cancer in rats.

Colorectal cancer, one of the most frequently diagnosed cancers worldwide, has a high mortality rate. Thus, our research aims to examine the preventive effects of diosmin (DIO) alone and in conjunction with the anti-cancer drug irinotecan (camptothecin-11, CPT-11), on 1,2-dimethylhydrazine (DMH)-induced colon cancer (CC) in male Wistar rats. Fifty adult male Wistar rats were categorized into five groups. Group I (Normal) received saline 0.9 orally % as a vehicle once a week for 14 weeks. Group II (DMH) received DMH (20 mg/kg/week) orally dissolved in 0.9% saline for 14 weeks and 1% carboxymethylcellulose (CMC) every other day for the final 10 weeks. Group III (DMH+DIO) received DMH orally for 14 weeks and DIO (10 mg/kg, suspended in 1% CMC) every other day for the final 10 weeks. Group IV (DMH+CPT-11) received DMH orally for 14 weeks and intraperitoneal injection of CPT-11 (3 mg/kg) twice a week for the final 10 weeks. Group V (DMH+DIO+CPT-11) orally received DMH for 14 weeks and both DIO and CPT-11. All treated groups showed a significant reduction (p<0.05) in their elevated serum malondialdehyde levels and significant amelioration (p<0.05) of their lowered activities of colon glutathione-S-transferase (GST) and glutathione reductase (GR) as well as serum glutathione level (GSH). In addition, simultaneous treatment with DIO and CPT-11 led to a significant decrease (p<0.05) in the elevated serum levels of carcinoembryonic antigen (CEA) in rats administered with DMH, as well as a reduction in the colon expression levels of the inflammatory mediator (NF-κB), cell proliferator protein (Ki-67), and proapoptotic protein (p53). These findings suggest DIO, CPT-11, and their combination have anticarcinogenic effects against DMH-induced CC by suppressing oxidative stress, simulating the antioxidant defense system, attenuating the inflammatory effects, and reducing cell proliferation.

Engineering stable and non-immunogenic immunoenzymes for cancer therapy via in situ generated prodrugs

Engineering human enzymes for therapeutic applications is attractive but introducing new amino acids may adversely affect enzyme stability and immunogenicity. Here we used a mammalian membrane-tethered screening system (ECSTASY) to evolve human lysosomal beta-glucuronidase (hBG) to hydrolyze a glucuronide metabolite (SN-38G) of the anticancer drug irinotecan (CPT-11). Three human beta-glucuronidase variants (hBG3, hBG10 and hBG19) with 3, 10 and 19 amino acid substitutions were identified that display up to 40-fold enhanced enzymatic activity, higher stability than E. coli beta-glucuronidase in human serum, and similar pharmacokinetics in mice as wild-type hBG. The hBG variants were two to three orders of magnitude less immunogenic than E. coli beta-glucuronidase in hBG transgenic mice. Intravenous administration of an immunoenzyme (hcc49-hBG10) targeting a sialyl-Tn tumor-associated antigen to mice bearing human colon xenografts significantly enhanced the anticancer activity of CPT-11 as measured by tumor suppression and mouse survival. Our results suggest that genetically-modified human enzymes represent a good alternative to microbially-derived enzymes for therapeutic applications.

Ultrasound-activated prodrug-loaded liposome for efficient cancer targeting therapy without chemotherapy-induced side effects.

Off-targeted distribution of chemotherapeutic drugs causes severe side effects, further leading to poor prognosis and patient compliance. Ligand/receptor-mediated targeted drug delivery can improve drug accumulation in the tumor but it always attenuated by protein corona barriers. To address these problems, a radically different strategy is proposed that can leave the off-targeted drugs inactive but activate the tumor-distributed drugs for cancer-targeting therapy in a tumor microenvironment-independent manner. The feasibility and effectiveness of this strategy is demonstrated by developing an ultrasound (US)-activated prodrug-loaded liposome (CPBSN38L) comprising the sonosensitizer chlorin e6 (Ce6)-modified lipids and the prodrug of pinacol boronic ester-conjugated SN38 (PBSN38). Once CPBSN38L is accumulated in the tumor and internalized into the cancer cells, under US irradiation, the sonosensitizer Ce6 rapidly induces extensive production of intracellular reactive oxygen species (ROS), thereby initiating a cascade amplified ROS-responsive activation of PBSN38 to release the active SN38 for inducing cell apoptosis. If some of the injected CPBSN38L is distributed into normal tissues, the inactive PBSN38 exerts no pharmacological activity on normal cells. CPBSN38L exhibited strong anticancer activity in multiple murine tumor models of colon adenocarcinoma and hepatocellular carcinoma with no chemotherapy-induced side effects, compared with the standard first-line anticancer drugs irinotecan and topotecan. This study established a side-effect-evitable, universal, and feasible strategy for cancer-targeting therapy.

Mitochondrial topoisomerase 1 targeted anticancer therapy using irinotecan encapsulated mesoporous MIL-101(Fe) synthesized via a vapour assisted method.

Mitochondrial topisomerase 1 (Top1mt) is critical for mtDNA replication, transcription, and energy production. Here, we investigate the carrier-mediated targeted delivery of the anticancer drug irinotecan into the mitochondria to selectively trap Top1mt covalent complexes (Top1mtcc) and its role in anticancer therapeutics. We have designed a biocompatible mesoporous metal-organic framework (MOF) material, namely MIL-101(Fe), as the drug delivery carrier that selectively localizes inside mitochondria. In contrast to the traditional way of synthesising MOFs, here we have employed a vapour-assisted solvothermal method for the synthesis of MIL-101(Fe) using terephthalic acid as the organic linker and Fe(III) as the metal source. The advantage of this method is that it recycles the excess solvent (DMF) and reduces the amount of washing solvent. We demonstrate that MIL-101(Fe)-encapsulated irinotecan (MIL-Iri) was selectively targeted towards the mitochondria to poison Top1mtcc in a dose-dependent manner and was achieved at a low nanomolar drug concentration. We provide evidence that Top1mtcc generated by MIL-Iri leads to mtDNA damage in human colon and breast cancer cells and plays a significant role in cellular toxicity. Altogether, this study provides evidence for a new and effective strategy in anticancer chemotherapy.

Utilizing the Hofmeister Effect to Induce Hydrogelation of Nonionic Supramolecular Polymers into a Therapeutic Depot

AbstractNonionic hydrogels are of particular interest for long‐term therapeutic implantation due to their minimal immunogenicity relative to their charged counterparts. However, in situ formation of nonionic supramolecular hydrogels under physiological conditions has been a challenging task. In this context, we report on our discovery of salt‐triggered hydrogelation of nonionic supramolecular polymers (SPs) formed by self‐assembling prodrug hydrogelators (SAPHs) through the Hofmeister effect. The designed SAPHs consist of two SN‐38 units, which is an active metabolite of the anticancer drug irinotecan, and a short peptide grafted with two or four oligoethylene glycol (OEG) segments. Upon self‐assembly in water, the resultant nonionic SPs can be triggered to gel upon addition of phosphate salts. Our 1H NMR studies revealed that the added phosphates led to a change in the chemical shift of the methylene protons, suggestive of a disruption of the water‐ether hydrogen bonds and consequent reorganization of the hydration shell surrounding the SPs. This deshielding effect, commensurate with the amount of salt added, likely promoted associative interactions among the SAPH filaments to percolate into a 3D network. The formed hydrogels exhibited a sustained release profile of SN‐38 hydrogelator that acted potently against cancer cells.

Utilizing the Hofmeister Effect to Induce Hydrogelation of Nonionic Supramolecular Polymers into a Therapeutic Depot.

Nonionic hydrogels are of particular interest for long-term therapeutic implantation due to their minimal immunogenicity relative to their charged counterparts. However, in situ formation of nonionic supramolecular hydrogels under physiological conditions has been a challenging task. In this context, we report on our discovery of salt-triggered hydrogelation of nonionic supramolecular polymers (SPs) formed by self-assembling prodrug hydrogelators (SAPHs) through the Hofmeister effect. The designed SAPHs consist of two SN-38 units, which is an active metabolite of the anticancer drug irinotecan, and a short peptide grafted with two or four oligoethylene glycol (OEG) segments. Upon self-assembly in water, the resultant nonionic SPs can be triggered to gel upon addition of phosphate salts. Our 1 H NMR studies revealed that the added phosphates led to a change in the chemical shift of the methylene protons, suggestive of a disruption of the water-ether hydrogen bonds and consequent reorganization of the hydration shell surrounding the SPs. This deshielding effect, commensurate with the amount of salt added, likely promoted associative interactions among the SAPH filaments to percolate into a 3D network. The formed hydrogels exhibited a sustained release profile of SN-38 hydrogelator that acted potently against cancer cells.

Crystalline Nanoparticles of Water-Soluble Covalent Basket Cages (CBCs) for Encapsulation of Anticancer Drugs.

We herein describe the preparation, assembly, recognition characteristics, and biocompatibility of novel covalent basket cage CBC-11, composed of four molecular baskets linked to four trivalent aromatic amines through amide groups. The cage is tetrahedral in shape and similar in size to small proteins (Mw =8637 g/mol) with a spacious nonpolar interior for accommodating multiple guests. While 24 carboxylates at the outer surface of CBC-11 render it soluble in aqueous phosphate buffer (PBS) at pH=7.0, the amphiphilic nature prompts its assembly into nanoparticles (d=250 nm, DLS). Cryo-TEM examination of nanoparticles revealed their crystalline nature with wafer-like shapes and hexagonally arranged cages. Nanoparticulate CBC-11 traps anticancer drugs irinotecan and doxorubicin, with each cage binding up to four drug molecules in a non-cooperative manner. The inclusion complexation resulted in nanoparticles growing in size and precipitating. In media containing mammalian cells (HCT 116, human colon carcinoma), the IC50 value of CBC-11 was above 100 μM. While this work presents the first example of a large covalent organic cage operating in water at the physiological pH and forming crystalline nanoparticles, it also demonstrates its biocompatibility and potential to act as a polyvalent binder of drugs for their sequestration or delivery.

Crystalline Nanoparticles of Water‐Soluble Covalent Basket Cages (CBCs) for Encapsulation of Anticancer Drugs

AbstractWe herein describe the preparation, assembly, recognition characteristics, and biocompatibility of novel covalent basket cage CBC‐11, composed of four molecular baskets linked to four trivalent aromatic amines through amide groups. The cage is tetrahedral in shape and similar in size to small proteins (Mw=8637 g/mol) with a spacious nonpolar interior for accommodating multiple guests. While 24 carboxylates at the outer surface of CBC‐11 render it soluble in aqueous phosphate buffer (PBS) at pH=7.0, the amphiphilic nature prompts its assembly into nanoparticles (d=250 nm, DLS). Cryo‐TEM examination of nanoparticles revealed their crystalline nature with wafer‐like shapes and hexagonally arranged cages. Nanoparticulate CBC‐11 traps anticancer drugs irinotecan and doxorubicin, with each cage binding up to four drug molecules in a non‐cooperative manner. The inclusion complexation resulted in nanoparticles growing in size and precipitating. In media containing mammalian cells (HCT 116, human colon carcinoma), the IC50 value of CBC‐11 was above 100 μM. While this work presents the first example of a large covalent organic cage operating in water at the physiological pH and forming crystalline nanoparticles, it also demonstrates its biocompatibility and potential to act as a polyvalent binder of drugs for their sequestration or delivery.

Design, synthesis, and biological evaluation studies of novel carboxylesterase 2 inhibitors for the treatment of irinotecan-induced delayed diarrhea

Human carboxylesterase 2 (hCES2A), one of the most important serine hydrolases distributed in the small intestine and colon, plays a crucial role in the hydrolysis of various prodrugs and esters. Accumulating evidence has demonstrated that the inhibition of hCES2A effectively alleviate the side effects induced by some hCES2A-substrate drugs, including delayed diarrhea caused by the anticancer drug irinotecan. Nonetheless, there is a scarcity of selective and effective inhibitors that are suitable for irinotecan-induced delayed diarrhea. Following screening of the in-house library, the lead compound 01 was identified with potent inhibition on hCES2A, which was further optimized to obtain LK-44 with potent inhibitory activity (IC50 = 5.02 ± 0.67 μM) and high selectivity on hCES2A. Molecular docking and molecular dynamics simulations indicated that LK-44 can formed stable hydrogen bonds with amino acids surrounding the active cavity of hCES2A. The results of inhibition kinetics studies unveiled that LK-44 inhibited hCES2A-mediated FD hydrolysis in a mixed inhibition manner, with a Ki value of 5.28 μM. Notably, LK-44 exhibited low toxicity towards HepG2 cells according to the MTT assay. Importantly, in vivo studies showed that LK-44 significantly reduced the side effects of irinotecan-induced diarrhea. These findings suggested that LK-44 is a potent inhibitor of hCES2A with high selectivity against hCES1A, which has potential as a lead compound for the development of more effective hCES2A inhibitors to mitigate irinotecan-induced delayed diarrhea.

Synthesis and biological evaluation of theranostic Trastuzumab–SN38 conjugate for Near-IR fluorescence imaging and targeted therapy of HER2+ breast cancer

Here, we report on the design, synthesis, and biological evaluation of a new theranostic antibody drug conjugate (ADC), Cy5-Ab-SS-SN38, that consists of the HER2-specific antibody trastuzumab (Ab) connected to the near infrared (NIR) pentamethine cyanine dye Cy5 and SN38, which is a bioactive metabolite of the anticancer drug irinotecan. SN38 is bound to an antibody through a glutathione-responsive self-immolative disulfide carbamate linker. For the first time, we explored this linker in ADC and found that it to reduce the drug release rate, which is important for safe drug delivery. The developed ADC exhibited specific accumulation and nanomolar anti-breast cancer activity on HER2-positive (HER2+) cell lines but no effect on HER2-. Animals treated with this ADC exhibited good tolerance. In vivo studies have shown that the ADC had good targeting ability for HER2+ tumors with much higher anticancer potency than trastuzumab itself or a mixture of trastuzumab with SN38. Side-by-side HER2+/HER2-xenograft at the 10 mg/kg dose exhibited specific accumulation and reduction of HER2+ tumor but not accumulation or growth inhibition of HER2-counterpart. The self-immolative disulfide linker implemented in this study was proven to be successful, broadening its utilization with other antibodies for targeted anticancer therapy in general. We believe that the theranostic ADCs comprising the glutathione-responsive self-immolative disulfide carbamate linker are applicable for the treatment and fluorescent monitoring of malignancies and anticancer drug delivery.

Enhanced degradation mechanism of anticancer drug irinotecan through low-frequency ultrasound assisted reactive electrochemical membrane

The effect of low-frequency ultrasound (US, 20 kHz, 104 W) on the degradation of anticancer drug irinotecan (IRI) using reactive electrochemical membrane (REM) was investigated. Results demonstrated that higher k value (0.103 min−1) and mineralization efficiency (94.6%) as well as lower energy consumption (0.906 Wh L−1) were observed in US-REM system. The effects of influence factors including US power, volume flow rate, current density and initial IRI concentration on the degradation of IRI were studied in US-REM system. The relative contributions of •OH, SO4•− and O2•− (indirect oxidation) to IRI degradation using REM were all increased with the assistance of US. The production rate of •OH using US-REM increased by 19.7% compared with that using REM. Seven intermediates of IRI degradation using both REM and US-REM were identified, and the main degradation pathways of IRI were hydroxylation, oxidation and ring cleavage. The enhanced degradation and mineralization of IRI in US-REM system could mainly be attributed to higher •OH production and higher contribution of free radicals.

Dutch pharmacogenetics working group (DPWG) guideline for the gene-drug interaction between UGT1A1 and irinotecan.

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of the anti-cancer drug irinotecan to decrease the risk of severe toxicity, such as (febrile) neutropenia or diarrhoea. Uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1 encoded by the UGT1A1 gene) enzyme deficiency increases risk of irinotecan-induced toxicity. Gene variants leading to UGT1A1 enzyme deficiency (e.g. UGT1A1*6, *28 and *37) can be used to optimize an individual's starting dose thereby preventing carriers from toxicity. Homozygous or compound heterozygous carriers of these allele variants are defined as UGT1A1 poor metabolisers (PM). DPWG recommends a 70% starting dose in PM patients and no dose reduction in IM patients who start treatment with irinotecan. Based on the DPWG clinical implication score, UGT1A1 genotyping is considered "essential", indicating that UGT1A1 testing must be performed prior to initiating irinotecan treatment.

Covalent CES2 Inhibitors Protect against Reduced Formation of Intestinal Organoids by the Anticancer Drug Irinotecan.

Irinotecan is widely used to treat various types of solid and metastatic cancer. It is an ester prodrug and its hydrolytic metabolite (SN-38) exerts potent anticancer activity. Irinotecan is hydrolyzed primarily by carboxylesterase-2 (CES2), a hydrolase abundantly present in the intestine such as the duodenum. We have identified several potent and covalent CES2 inhibitors such as remdesivir and sofosbuvir. Remdesivir is the first small molecule drug approved for COVID-19, whereas sofosbuvir is a paradigm-shift medicine for hepatitis C viral infection. Irinotecan is generally well-tolerated but associated with severe/life-threatening diarrhea due to intestinal accumulation of SN-38. This study was to test the hypothesis that remdesivir and sofosbuvir protect against irinotecan-induced epithelial injury associated with gastrointestinal toxicity. To test this hypothesis, formation of organoids derived from mouse duodenal crypts, a robust cellular model for intestinal regeneration, was induced in the presence or absence of irinotecan +/- pretreatment with a CES2 drug inhibitor. Irinotecan profoundly inhibited the formation of intestinal organoids and the magnitude of the inhibition was greater with female crypts than their male counterparts. Consistently, crypts from female mice had significantly higher hydrolytic activity toward irinotecan. Critically, remdesivir and sofosbuvir both reduced irinotecan hydrolysis and reversed irinotecan-reduced formation of organoids. Human duodenal samples robustly hydrolyzed irinotecan, stable CES2 transfection induced cytotoxicity and the cytotoxicity was reduced by CES2 drug inhibitor. These findings establish a therapeutic rationale to reduce irinotecan-gastrointestinal injury and serve as a cellular foundation to develop oral formulations of irinotecan with high safety.

Lanthanide (Eu3+/Tb3+)-Loaded γ-Cyclodextrin Nano-Aggregates for Smart Sensing of the Anticancer Drug Irinotecan.

The clinical use of anticancer drugs necessitates new technologies for their safe, sensitive, and selective detection. In this article, lanthanide (Eu3+ and Tb3+)-loaded γ-cyclodextrin nano-aggregates (ECA and TCA) are reported, which sensitively detects the anticancer drug irinotecan by fluorescence intensity changes. Fluorescent lanthanide (Eu3+ and Tb3+) complexes exhibit high fluorescence intensity, narrow and distinct emission bands, long fluorescence lifetime, and insensitivity to photobleaching. However, these lanthanide (Eu3+ and Tb3+) complexes are essentially hydrophobic, toxic, and non-biocompatible. Lanthanide (Eu3+ and Tb3+) complexes were loaded into naturally hydrophilic γ-cyclodextrin to form fluorescent nano-aggregates. The biological nontoxicity and cytocompatibility of ECA and TCA fluorescent nanoparticles were demonstrated by cytotoxicity experiments. The ECA and TCA fluorescence nanosensors can detect irinotecan selectively and sensitively through the change of fluorescence intensity, with detection limits of 6.80 μM and 2.89 μM, respectively. ECA can safely detect irinotecan in the cellular environment, while TCA can detect irinotecan intracellularly and is suitable for cell labeling.

Covalent CES2 Inhibitors Protect against Reduced Formation of Intestinal Organoids by the Anticancer Drug Irinotecan

Covalent CES2 Inhibitors Protect against Reduced Formation of Intestinal Organoids by the Anticancer Drug Irinotecan

Abstract 934: Identification of a GPC3 specific RNA aptamer and its use in cell specific targeted killing of GPC3 expressing tumors

Abstract Aptamers are short oligonucleotides that recognize specific molecular targets due to their folded three-dimensional structures. Aptamers are generated against a target molecule using a process called SELEX. This method allows the in vitro evolution of nucleic acid molecules with highly specific binding to target molecules. Here we describe a nuclease stable, fully modified 2'OMethyl aptamer that recognizes Glypican-3 (GPC3) with high affinity and specificity. GPC3 is a heparan sulfate proteoglycan and cell surface oncofetal protein which is highly expressed on a variety of liver cancers, but not in healthy adult tissues. A conjugate comprising a GPC3 aptamer and Drug Maytansinoid (DM1), a membrane-permeable inhibitor of tubulin which can prevent cell division, is used to specifically target GPC3 expressing cells in vitro and in vivo. The aptamer-drug conjugate (GRX54) is capable of selectively killing a variety of GPC3 expressing liver cells in vitro and has significantly less toxicity in cells not expressing GPC3. The anti-tumor effect of GRX54 was tested in several tumor xenograft mouse models: Hep3B xenograft, Balb/c nude mice and NCI-H446 xenograft, Balb/c nude mice. GRX54 was administered at different doses via intraperitoneal injection (IP). For each group, mice were administered with vehicle or GRX54 once a day (QD) for 3, 5 or 7 days. Tumor weight and growth were measured. An anti-cancer drug Sorafenib Tosylate (30mg/kg, oral administration, once a day - Hep3B xenograft mouse model) or irinotecan (40mg/kg, i.p. twice a day for 4 days - NCI-H446 xenograft mouse model) were used as positive controls. GRX54 decreases Hep3B tumor volume in a Balb/c nude mouse xenograft model by ~30-45% depending on treatment schedule and NCI-H446 tumor volume by ~45-90% depending on treatment schedule. Together, our data show that GRX54 is a novel GPC3-targeting molecule capable of reducing tumor size with IP injection. Citation Format: Kristin M. Thompson, Christina McGuire, Jin Yuan, Aaron Ball, Justin Sonberg, Yuxun Wang, Shuhao Zhu. Identification of a GPC3 specific RNA aptamer and its use in cell specific targeted killing of GPC3 expressing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 934.

Synthesis and characterization of magnetic nanocomposite for in vitro evaluation of irinotecan using human cell lines.

In this study, magnetic O-carboxymethyl chitosan (MOCC) nanocomposite was synthesized and characterized as a drug delivery system for loading the anticancer drug irinotecan (CPT-11). To increase the drug loading capacity, MOCC was synthesized by linking the carboxyl group functionally to chitosan. Also, several critical factors such as concentration, the dose of MOCC, and contact time for optimum drug loading condition were investigated. The loading capacity of CPT-11 onto MOCC was calculated as 5.6 mg/g, and the loaded drug concentration was calculated as 0.04787 mM at pH value of 5. Besides, the cytotoxic properties of MOCC, CPT- 11 loaded MOCC (MOCC-CPT-11), and free CPT-11 were studied on glioblastoma multiforme cell lines, including U87 and U373. According to the results, the MOCC-CPT-11 showed at least as toxic effect as free CPT-11 even at very low concentrations, while the MOCC showed slight toxicity (cell viability of 96% to 78%) on U373 cell lines at all concentrations and for 24 h and 48 h incubation times. Moreover, the results showed that the MOCC indicated significant toxicity in increasing concentrations and incubation times, and the MOCC-CPT-11 is as toxic as free CPT-11 on U87 cells at all concentrations and incubation times.

Quantitative Investigation of Irinotecan Metabolism, Transport, and Gut Microbiome Activation.

The anticancer drug irinotecan shows serious dose-limiting gastrointestinal toxicity regardless of intravenous dosing. Although enzymes and transporters involved in irinotecan disposition are known, quantitative contributions of these mechanisms in complex in vivo disposition of irinotecan are poorly understood. We explained intestinal disposition and toxicity of irinotecan by integrating 1) in vitro metabolism and transport data of irinotecan and its metabolites, 2) ex vivo gut microbial activation of the toxic metabolite SN-38, and 3) the tissue protein abundance data of enzymes and transporters relevant to irinotecan and its metabolites. Integration of in vitro kinetics data with the tissue enzyme and transporter abundance predicted that carboxylesterase (CES)-mediated hydrolysis of irinotecan is the rate-limiting process in the liver, where the toxic metabolite formed is rapidly deactivated by glucuronidation. In contrast, the poor SN-38 glucuronidation rate as compared with its efficient formation by CES2 in the enterocytes is the key mechanism of the intestinal accumulation of the toxic metabolite. The biliary efflux and organic anion transporting polypeptide-2B1-mediated enterocyte uptake can also synergize buildup of SN-38 in the enterocytes, whereas intestinal P-glycoprotein likely facilitates SN-38 detoxification in the enterocytes. The higher SN-38 concentration in the intestine can be further nourished by β-d-glucuronidases. Understanding the quantitative significance of the key metabolism and transport processes of irinotecan and its metabolites can be leveraged to alleviate its intestinal side effects. Further, the proteomics-informed quantitative approach to determine intracellular disposition can be extended to determine susceptibility of cancer cells over normal cells for precision irinotecan therapy. SIGNIFICANCE STATEMENT: This work provides a deeper insight into the quantitative relevance of irinotecan hydrolysis (activation), conjugation (deactivation), and deconjugation (reactivation) by human or gut microbial enzymes or transporters. The results of this study explain the characteristic intestinal exposure and toxicity of irinotecan. The quantitative tissue-specific in vitro to in vivo extrapolation approach presented in this study can be extended to cancer cells.

A covalent triazine-based framework containing hydrogen-bonding for highly drug loading and pH-responsive release

A porous covalent triazine-based organic framework (CTF) containing amide hydrogen-bonding was synthesized using Pigment Orange 71 under Lewis acidic (ZnCl2) conditions at 400 °C. The novel CTF material shows excellent chemical and thermal stability with 10% weight loss temperature up to 465 °C and owns a high surface area (960 m2 g−1) and a total pore volume of 0.48 cm3 g−1. The pore size distribution calculated by the non-local density functional theory shows the single micropores center at about 1.5 nm. The CTF particles have an average size of 374 nm and display excellent size-selective adsorption performance, high anticancer drug Irinotecan (CPT-11) loading (27.9 wt%) capacity and outstanding pH-responsive release.

Development and validation of a selective SPR aptasensor for the detection of anticancer drug irinotecan in human plasma samples.

In this work, a surface plasmon resonance (SPR)-based assay for the quantification of antineoplastic drug irinotecan in human plasma samples has been developed for the first time. The selective binding of irinotecan with an aptamer receptor, operating in human plasma, allowed to set-up a novel analytical methodology to detect the drug in the analytical range of interest by using SPR as detection technique. After hybridizing the aptamer to the sensing platform and optimizing the sample preparation procedure, a quantitative assay was validated according to FDA regulatory guidelines. The analytical working range was found between 100 and 7500ngmL-1 with negligible interferences from plasma components and co-medication associated with the administration of irinotecan. The utility of the new SPR assay was confirmed by analyzing plasma samples in parallel with LC-MS as reference technique, providing a new analytical tool for the therapeutic drug monitoring of irinotecan in patients under chemotherapy regimens.