Bendamustine–PAMAM Conjugates for Improved Apoptosis, Efficacy

Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan , Bandarsindri, Ajmer , Rajasthan 305817 , India...
0 downloads 0 Views 3MB Size
Subscriber access provided by READING UNIV

Article

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

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Molecular Pharmaceutics is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 47 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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

Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 47

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