ABSTRACT
Hydrogels are widely studied as drug delivery system. In this work we propose the employment of tetrakis(hydroxymethyl)phosphonium chloride as crosslinking agent to obtain covalent hydrogels based on chitosan. These hydrogels are obtained by Mannich reaction between the amino groups of chitosan with the hydroxymethyl groups of the crosslinker molecule. They show a pH sensitive second order swelling kinetic, have low toxicity, are biocompatible, mucoadhesive and allow a modified release of the encapsulated drug, camptothecin, for 48â¯h. This antitumor drug has been studied as a drug of interest to develop oral chemotherapy administration strategies. According to the obtained results, oral administration of camptothecin through hydrogels would provide low concentrations of drug at the absorption site, avoiding carrier saturation and reducing its intestinal toxicity.
Subject(s)
Camptothecin/administration & dosage , Chitosan/administration & dosage , Cross-Linking Reagents/administration & dosage , Drug Delivery Systems/methods , Hydrogel, Polyethylene Glycol Dimethacrylate/administration & dosage , Organophosphorus Compounds/administration & dosage , Administration, Oral , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacokinetics , Caco-2 Cells , Camptothecin/chemistry , Camptothecin/pharmacokinetics , Chitosan/chemistry , Chitosan/pharmacokinetics , Cross-Linking Reagents/chemistry , Cross-Linking Reagents/pharmacokinetics , Dose-Response Relationship, Drug , Drug Carriers/administration & dosage , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Humans , Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry , Hydrogel, Polyethylene Glycol Dimethacrylate/pharmacokinetics , Male , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacokinetics , Rats , Rats, WistarABSTRACT
In this work, 6-phosphogluconic trisodium salt (6-PG-Na+) is introduced as a new aqueous and nontoxic cross-linking agent to obtain ionic hydrogels. Here, it is shown the formation of hydrogels based on chitosan cross-linked with 6-PG-Na+. This formulation is obtained by ionic interaction of cationic groups of polymer with anionic groups of the cross-linker. These hydrogels are nontoxic, do not cause dermal irritation, are easy to extend, and have an adequate adhesion force to be applied as polymeric film over the skin. This formulation exhibits a first order release kinetic and can be applied as drug vehicle for topical administration or as wound dressing for wound healing. The primary goal of this communication is to report the identification and utility of 6-phosphogluconic trisodium salt (6-PG-Na+) as a nontoxic cross-linker applicable for cationic polymers.
Subject(s)
Chitosan/chemistry , Drug Delivery Systems , Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry , Wound Healing/drug effects , Administration, Topical , Chitosan/administration & dosage , Cross-Linking Reagents/chemistry , Gluconates/administration & dosage , Gluconates/chemistry , Humans , Hydrogel, Polyethylene Glycol Dimethacrylate/administration & dosage , Kinetics , Polymers/chemistry , Sodium , Wound Closure TechniquesABSTRACT
Oral administration of camptothecin (CPT) derivatives and other antitumoral agents is being actively developed in order to improve the quality of life of patients with cancer. Though several lipophilic derivatives of CPT have shown interesting oral bioavailability in preclinical and clinical studies, only Topotecan has been approved for this route of administration. Semisynthesis, antitumor activity, biological inhibition mechanism, and in situ intestinal permeability of 9, 10-[1,3]-Dioxinocamptothecin (CDiox), an unexplored CPT derivative, have been studied in this paper. The hexacyclic analog was as effective as Topotecan and CPT in different tumor cell lines, showing an expected similar apoptosis cell mechanism and high ability to inhibit DNA synthesis in HeLa, Caco-2, A375 and MDA-MB-231 cell lines. Furthermore, in vitro and in situ pharmacokinetics transport values obtained for CDiox displayed more favorable absorption profile than CPT and Topotecan.
Subject(s)
Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Camptothecin/metabolism , Camptothecin/pharmacology , Intestinal Mucosa/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biological Transport , Camptothecin/analogs & derivatives , Camptothecin/chemical synthesis , Cell Line, Tumor , Chemistry Techniques, Synthetic , Humans , Permeability , RatsABSTRACT
Despite that 9-substituted camptothecins are promising candidates in cancer therapy, the limited accessibility to this position has reduced the studies of these derivatives to a few standard modifications. We report herein a novel semisynthetic route based on the Tscherniac-Einhorn reaction to synthesize new lipophilic camptothecin derivatives with amidomethyl and imidomethyl substitutions in position 9. Compounds were evaluated for their antiproliferative activity, topoisomerase I inhibition, and oral availability. Preliminary data demonstrated that bulky imidomethyl modification is an appropriate lipophilic substitution for an effective oral administration relative to topotecan. In addition, this general procedure paves the way for obtaining new camptothecin derivatives.
