Bendamustine–PAMAM Conjugates for Improved Apoptosis, Efficacy, and in Vivo Pharmacokinetics: A Sustainable Delivery Tactic

• DOI: 10.1021/acs.molpharmaceut.7b00625
• Publication Date: 2017-12-02T00:08:02Z
• Authors: Avinash Gothwal; Iliyas Khan; Pramod Kumar; Kaisar Raza; Ankur Kaul; Anil Kumar Mishra; Umesh Gupta
• Keywords: Bendamustine; Conjugate

Successful delivery of a chemotherapeutic agent like bendamustine still remains challenge in clinical conditions chronic lymphatic leukemia (CLL), non-Hodgkin lymphoma (NHL), and multiple myeloma. We have conjugated to polyamidoamine (PAMAM) dendrimers after conjugating with N-(hydroxyethyl)maleimide (spacer) via an ester bond. The particle size PAMAM-bendamustine conjugate was 49.8 ± 2.5 nm. In vitro drug release resulted sustained improved solution stability up 72 h. 24 h cytotoxicity study by MTT assay against human monoblastic cells (THP-1), the IC50 value for 32.1 4.8 μM compared 50.42 3.4 2303 106.5 PAMAM dendrimer, respectively. Significantly higher cell uptake apoptosis were observed THP-1 which confirmed flow cytometry confocal laser scanning microscopy. Preliminary vivo studies undertaken included pharmacokinetics studies, organ distribution tumor inhibition studies. healthy Wistar rat model (1CBM IV push model), pharmacokinetic revealed that bioavailability t1/2 increased significantly, i.e., almost 8.5-fold (193.8 1.116 vs 22.8 0.158 μg mL-1/h) 5.1-fold (0.75 0.005 3.85 0.015 h), respectively, pure ( p < 0.05), however, clearance volume found be decreased those free drug. suggests not only stable longer period but also least toxic highly taken exert anticancer effect at reduced dose. Tumor biodistribution tumor-bearing BALB/c mice more effective than showed accumulation tumor.