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Bendamustine-PAMAM Conjugates for the Improved Apoptosis, Efficacy and in vivo Pharmacokinetics: A Sustainable Delivery Tactic Avinash Gothwal, Iliyas Khan, Pramod Kumar, Kaisar Raza, Ankur Kaul, Anil Kumar Mishra, and Umesh Gupta Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b00625 • Publication Date (Web): 01 Dec 2017 Downloaded from http://pubs.acs.org on December 2, 2017
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Molecular Pharmaceutics
BendamustineBendamustine-PAMAM Conjugates for the Improved Apoptosis, Efficacy and in vivo Pharmacokinetics: A Sustainable Delivery Tactic
Avinash Gothwal1, Iliyas Khan1, Pramod Kumar1, Kaisar Raza1, Ankur Kaul2, Anil Kumar Mishra and Umesh Gupta1*
2
1Department
of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, Ajmer, Rajasthan 305817 India 2Division
of Cyclotron And Radiopharmaceutical sciences, Institute of Nuclear Medicine and Allied Sciences, New Delhi, India 110054
*Corresponding author Dr. Umesh Gupta Department of Pharmacy School of Chemical Sciences and Pharmacy Central University of Rajasthan Bandarsindri, Ajmer, Rajasthan-305817, India
[email protected];
[email protected] (U. Gupta)
1 ACS Paragon Plus Environment
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Abstract Successful delivery of chemotherapeutic agent like bendamustine still remains a challenge in the clinical conditions like Chronic lymphatic leukemia (CLL), Non-Hodgkin lymphoma (NHL) and multiple myeloma. We have conjugated bendamustine to Polyamidoamine (PAMAM) dendrimers after conjugating with N-hydroxyethylmaleimide (spacer) via an ester bond. The particle size of PAMAMbendamustine conjugate was 49.8±2.5 nm. In vitro drug release resulted in sustained release with improved solution stability of drug up to 72 h. In 24 h cytotoxicity study by MTT assay against human monoblastic leukemia cells (THP-1), the IC50 value for PAMAM-bendamustine was 32.1±4.8 µM compared to 50.42±3.4 µM and 2303±106.5 µM for bendamustine and PAMAM dendrimer, respectively. Significantly higher cell uptake and apoptosis were observed in THP-1 cells by PAMAM-bendamustine conjugate which was confirmed by flow cytometry and confocal laser scanning microscopy. Preliminary in vivo studies undertaken includes- pharmacokinetics studies, organ distribution studies, and tumor inhibition studies. In healthy Wistar rat model (1CBM IV push model), the pharmacokinetic studies revealed that bioavailability and t1/2 increased significantly, i.e. almost 8.5 (193.8±1.116 vs. 22.8±0.158 µg mL-1/h) and 5.1 folds (0.75±0.005 vs. 3.85±0.015 h), respectively, for PAMAM-bendamustine conjugate compared to pure bendamustine (p
