Search

Background/Objectives: In addition to oncological applications, poly(ADP-ribose) polymerase (PARP) inhibitors have potential as anti-inflammatory agents. Colon-targeted delivery of PARP inhibitors has been evaluated as a pharmaceutical strategy to enhance their safety and therapeutic efficacy against gut inflammation. Methods: Colon-targeted PARP inhibitors 5-aminoisoquinoline (5-AIQ) and 3-aminobenzamide (3-AB) were designed and synthesized by azo coupling with salicylic acid (SA), yielding 5-AIQ azo-linked with SA (AQSA) and 3-AB azo-linked with SA (ABSA). Additional conjugation of AQSA with acidic amino acids yielded glutamic acid-conjugated AQSA (AQSA-Glu) and aspartic acid-conjugated AQSA, which further increased the hydrophilicity of AQSA. Results: The distribution coefficients of PARP inhibitors were lowered by chemical modifications, which correlated well with drug permeability via the Caco-2 cell monolayer. All derivatives were effectively converted to their corresponding PARP inhibitors in the cecal contents. Compared with observations in the oral administration of PARP inhibitors, AQSA-Glu and ABSA resulted in the accumulation of much greater amounts of each PARP inhibitor in the cecum. ABSA accumulated mesalazine (5-ASA) in the cecum to a similar extent as sulfasalazine (SSZ), a colon-targeted 5-ASA prodrug. In the DNBS-induced rat colitis model, AQSA-Glu enhanced the anticolitic potency of 5-AIQ. Furthermore, ABSA was more effective against rat colitis than SSZ or AQSA-Glu, and the anticolitic effects of AQSA-Glu were augmented by combined treatment with a colon-targeted 5-ASA prodrug. In addition, the colon-targeted delivery of PARP inhibitors substantially reduced their systemic absorption. Conclusions: Colon-targeted PARP inhibitors may improve the therapeutic and toxicological properties of inhibitors and synergize the anticolitic effects of 5-ASA. [ABSTRACT FROM AUTHOR]

Background/Objectives: Owing to the growing resistance of methicillin-resistant Staphylococcus aureus (MRSA) to conventional antibiotics, the development of innovative therapeutic strategies for the treatment of MRSA-infected cutaneous wounds poses a significant challenge. Methods: Here, by using polyhydroxyalkanoates (PHA), emerging biodegradable and biocompatible polymers naturally produced by various microorganisms, we developed clindamycin-loaded PHA nanoparticles (Cly-PHA NPs) as a novel approach for the treatment of MRSA-infected cutaneous wounds. Results: Cly-PHA NPs were characterized in terms of mean particle size (216.2 ± 38.9 nm), polydispersity index (0.093 ± 0.03), zeta potential (11.3 ± 0.5 mV), and drug loading (6.76 ± 0.19%). Owing to the sustained release of clindamycin over 2 days provided by the PHA, Cly-PHA NPs exhibited potent antibacterial effects against MRSA. Furthermore, Cly-PHA NPs significantly facilitated wound healing in a mouse model of MRSA-infected full-thickness wounds by effectively eradicating MRSA from the wound bed. Conclusions: Therefore, our results suggest that Cly-PHA NPs offer a promising approach for combating MRSA infections and accelerating cutaneous wound healing. [ABSTRACT FROM AUTHOR]

We designed colon-targeted trans-cinnamic acid (tCA) and synthesized its conjugates with glutamic acid (tCA-GA) and aspartic acid (tCA-AA). We evaluated the anti-colitic activity of colon-targeted tCA using a dinitrobenzenesulfonic acid-induced rat colitis model. The conjugates lowered the distribution coefficient and Caco-2 cell permeability of tCA and converted to tCA in the cecum, with higher rates and percentages with tCA-GA than with tCA-AA. Following oral gavage, tCA-GA delivered a higher amount of tCA to the cecum and exhibited better anti-colitic effects than tCA and sulfasalazine (SSZ), which is the current treatment for inflammatory bowel disease. In the cellular assay, tCA acted as a full agonist of GPR109A (EC50: 530 µM). The anti-colitic effects of tCA-GA were significantly compromised by the co-administration of the GPR109A antagonist, mepenzolate. Collectively, colon-targeted tCA potentiated the anti-colitic activity of tCA by effectively activating GPR109A in the inflamed colon, enabling tCA to elicit therapeutic superiority over SSZ. [ABSTRACT FROM AUTHOR]

Targeting celecoxib to the ileo-colonic region could be beneficial for the treatment and prevention of colon cancer. Ileo-colonic targeting can be achieved by using pH-dependent coating systems such as ColoPulse. Celecoxib has poor aqueous solubility, which may jeopardize optimal treatment. Therefore, we combined a pH-dependent coating with self-emulsifying drug delivery systems (SEDDS) or with solid dispersion systems (SD); two approaches that are often used to improve the dissolution behavior of lipophilic drugs. The dissolution behavior of various formulations of both systems was investigated. Optimized formulations with and without precipitation inhibitors were coated with the ColoPulse and the release of celecoxib was tested under non-sink conditions using an in vitro dissolution system, simulating the pH gradient of the gastrointestinal tract. The dissolution behavior of SDs with and without precipitation inhibitor (sodium dodecyl sulfate) and the SEDDS without precipitation inhibitor was negatively impacted by the coating. Control experiments indicated that components of the coating released in the dissolution medium acted as precipitation mediators. However, the SEDDS formulation with HPMC 4000 cps as a precipitation inhibitor showed excellent dissolution behavior. We hypothesize that HPMC accumulates at the oil/water interface of the emulsion thereby stabilizing the emulsion resulting in maintenance of the supersaturated state. [ABSTRACT FROM AUTHOR]

The neurotensin is a tridecapeptide involved in the proliferation of colon cancer, the overexpression of neurotensin receptors occurring at an early stage development of many tumours. Targeting neurotensin receptors by using the same biological active molecule is an effective approach for both imaging quantification and treatment. The present work aimed to demonstrate the ability of radiolabelled neurotensin to specifically target colon cancer cells, and substantiate its usefulness in targeted imaging and radiotherapy, depending on the emission of the coupled radioisotope. Syntheses of 68Ga–DOTA–NT and 177Lu–DOTA–NT were developed to obtain a level of quality suitable for preclinical use with consistent high synthesis yields. Radiochemical purity meets the pharmaceutical requirements, and it is maintained 4 h for 68Ga–DOTA–NT and 48 h for 177Lu–DOTA–NT. Extensive in vitro studies were conducted to assess the uptake and retention of 68Ga–DOTA–NT, the amount of non-specific binding of neurotensin and the effect of 177Lu–DOTA–NT on HT–29 cells. In vivo biodistribution of 68Ga–DOTA–NT revealed significant uptake at the tumour site, along with fast clearance evidenced by decreasing activity in kidneys and blood after 60 min p.i. 177Lu–DOTA–NT exhibited similar uptake in the tumour, but also a significant uptake at 14 days p.i. in the bone marrow was reported. These results successfully demonstrated the potential of neurotensin to deliver imaging/therapeutic 68Ga/177Lu radioisotopes pair, but also the need for further evaluation of the possible radiotoxicity effects on the liver, kidneys or bone marrow. [ABSTRACT FROM AUTHOR]

Anti-cancer therapies that integrate smart nanomaterials are the focus of cancer research in recent years. Here, we present our results with PEGylated nanographene oxide particles (nGO-PEG) and have studied their combined effect with near-infrared (NIR) irradiation on low and high invasive colorectal carcinoma cells. The aim is to develop nGO-PEG as a smart nanocarrier for colon cancer-targeted therapy. For this purpose, nGO-PEG nanoparticles' size, zeta potential, surface morphology, dispersion stability, aggregation, and sterility were determined and compared with pristine nGO nanoparticles (NPs). Our results show that PEGylation increased the particle sizes from 256.7 nm (pristine nGO) to 324.6 nm (nGO-PEG), the zeta potential from −32.9 to −21.6 mV, and wrinkled the surface of the nanosheets. Furthermore, nGO-PEG exhibited higher absorbance in the NIR region, as compared to unmodified nGO. PEGylated nGO demonstrated enhanced stability in aqueous solution, improved dispensability in the culture medium, containing 10% fetal bovine serum (FBS) and amended biocompatibility. A strong synergic effect of nGO-PEG activated with NIR irradiation for 5 min (1.5 W/cm−2 laser) was observed on cell growth inhibition of low invasive colon cancer cells (HT29) and their wound closure ability while the effect of NIR on cellular morphology was relatively weak. Our results show that PEGylation of nGO combined with NIR irradiation holds the potential for a biocompatible smart nanocarrier in colon cancer cells with enhanced physicochemical properties and higher biological compatibility. For that reason, further optimization of the irradiation process and detailed screening of nGO-PEG in combination with NIR and chemotherapeutics on the fate of the colon cancer cells is a prerequisite for highly efficient combined nanothermal and photothermal therapy for colon cancer. [ABSTRACT FROM AUTHOR]