title: Trimethyl chitosan based conjugates for oral and intravenous delivery of paclitaxel.
abstract: Paclitaxel (PTX) conjugated trimethyl chitosan (TMC-PTX) and folic acid (FA) modified TMC-PTX (FA-TMC-PTX) were developed as polymer-drug conjugates for oral and intravenous delivery of PTX. As amphiphilic conjugates, TMC-PTX and FA-TMC-PTX containing approximately 11wt% PTX could self-assemble into spherical nanoparticles with average sizes of 170 and 187nm, respectively. The conjugates presented a sustained release of PTX and the release rate was positively correlated with the pH value of medium ranging from 1.2 to 7.4. TMC-PTX and FA-TMC-PTX possessed enhanced mucoadhesion compared with trimethyl chitosan, and promoted ex vivo intestinal transport of PTX in comparison to PTX solution by 15.5 and 18.8 folds, respectively. Hemolysis assessment confirmed the safety of TMC-PTX and FA-TMC-PTX, and FA modification alleviated protein adsorption of the conjugates. Prolonged blood retention and increased PTX accumulation in the tumor were achieved for orally and intravenously administered conjugates. In H22 tumor-bearing mice, TMC-PTX delivered via oral or intravenous route showed superior tumor retardation and survival rate compared with intravenously injected PTX, and FA-TMC-PTX further enhanced the antitumor efficacy. Overall, the trimethyl chitosan based drug conjugates may have potential applications as a promising candidate for cancer therapy.
  
  
  
  In the current study, PTX conjugated trimethyl chitosan (TMC-PTX) and folic acid (FA) modified TMC-PTX (FA-TMC-PTX) were developed as the polymer-drug conjugates for oral and intravenous delivery of PTX. By exploiting advantages with respect to improved solubility of drugs, controlled release behavior of covalently linked drugs, and enhanced targeting effect towards tumors, improved tumor growth inhibition efficacy and prolonged survival time were achieved for TMC-PTX as compared with free PTX, and FA modification further enhanced the in vivo antitumor efficacy. Overall, the self-assembled nanoplatform of trimethyl chitosan based drug conjugates may have potential applications as a promising candidate for tumor therapy via different administration routes.
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Rui
authors.initials: R
authors.lastname: He
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai 200433, China. Electronic address: chyin@fudan.edu.cn.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D048271:Chitosan / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000138:chemical synthesis*; D004058:Diffusion; D005260:Female; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism; D005492:Folic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry / Q000648:ultrastructure; D058726:Nanoconjugates / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; D058973:Folate Receptors, GPI-Anchored; C118071:N-trimethyl chitosan chloride; D053769:Nanocapsules; D058726:Nanoconjugates; D048271:Chitosan; D005492:Folic Acid; D017239:Paclitaxel
keywords: Antitumor efficacy; Intravenous injection; Oral administration; Paclitaxel; Polymer-drug conjugate; Trimethyl chitosan