title: Nanosized complexation assemblies housed inside reverse micelles churn out monocytic delivery cores for bendamustine hydrochloride.
abstract: OBJECTIVE
  We explore a plausible method of targeting bendamustine hydrochloride (BM) to circulatory monocytes by exploiting their intrinsic endocytic/phagocytic capability.
  
  
  METHODS
  We do so by complexation of sodium alginate and chitosan inside dioctyl sulfo succinate sodium (AOT) reverse micelles to form bendamustine hydrochloride loaded nanoparticles (CANPs). Dynamic light scattering, electrophoretic mobility and UV spectroscopy were used to detail intra-micellar complexation dynamics and to prove that drug was co-captured during interaction of carbohydrate polymers. A fluorescent conjugate of drug (RBM) was used to trace its intracellular fate after its loading into nanoparticles.
  
  
  RESULTS
  CANPs were sized below 150nm, had 75% drug entrapment and negative zeta potential (-30mV). Confocal microscopy demonstrated that developed chitosan alginate nanoparticles had the unique capability to carry BM specifically to its site of action. Quantitative and mechanism based cell uptake studies revealed that monocytes had voracious capacity to internalize CANPs via simultaneous scavenger receptor based endocytic and phagocytic mechanism. Comparative in vitro pharmacokinetic studies revealed obtainment of significantly greater intracellular drug levels when cells were treated with CANPs. This caused reduction in IC50(22.5±2.1μg/mL), enhancement in G2M cell cycle arrest, greater intracellular reactive oxygen species generation, and increased apopotic potential of bendamustine hydrochloride in THP-1 cells.
  
  
  CONCLUSIONS
  Selective monocytic targeting of bendamustine hydrochloride using carbohydrate constructs can prove advantageous in case of leukemic disorders displaying overabundance of such cells.
authors.affiliation: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Yuvraj
authors.initials: Y
authors.lastname: Singh
authors.affiliation: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Anumandla
authors.initials: A
authors.lastname: Chandrashekhar
authors.affiliation: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Jaya Gopal
authors.initials: JG
authors.lastname: Meher
authors.affiliation: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: K K
authors.initials: KK
authors.lastname: Durga Rao Viswanadham
authors.affiliation: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Vivek K
authors.initials: VK
authors.lastname: Pawar
authors.affiliation: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Kavit
authors.initials: K
authors.lastname: Raval
authors.affiliation: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Komal
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Animesh
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India. Electronic address: manish_chourasia@cdri.res.in.
authors.forename: Manish K
authors.initials: MK
authors.lastname: Chourasia
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000069461:Bendamustine Hydrochloride / Q000008:administration & dosage* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D004337:Drug Carriers; D004705:Endocytosis / Q000187:drug effects; D005456:Fluorescent Dyes; D006801:Humans; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D010587:Phagocytosis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004337:Drug Carriers; D005456:Fluorescent Dyes; D008823:Micelles; D017382:Reactive Oxygen Species; D000069461:Bendamustine Hydrochloride
keywords: AOT; Bendamustine hydrochloride; Cell uptake; DLS; Monocyte targeting; Reverse micelle