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L-Asparaginase Immobilization in Supramolecular Nanogels of Peg-Grafted Poly Hpma and Bis(Α-Cyclodextrin) to Enhance Pharmacokinetics and Lower Enzyme Antigenicity Publisher Pubmed



Monajati M1, 2 ; Tamaddon AM1, 2, 3 ; Abolmaali SS1, 2 ; Yousefi G2, 3 ; Javanmardi S2 ; Borandeh S2 ; Heidari R4 ; Azarpira N5 ; Dinarvand R6
Authors
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Authors Affiliations
  1. 1. Department of Pharmaceutical Nanotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
  2. 2. Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran
  3. 3. Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
  4. 4. Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  5. 5. Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  6. 6. Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 1417614315, Iran

Source: Colloids and Surfaces B: Biointerfaces Published:2023


Abstract

L-asparaginase (ASNase) enzyme has limited therapeutic use due to its poor pharmacokinetics and immunogenicity. To overcome these obstacles, we immobilized ASNase in biocompatible poly hydroxypropyl methacrylamide (P(HPMA))-based nanogels simply formed through the host-guest inclusion complex of ASNase-conjugated random copolymer of HPMA and polyethylene glycol (PEG) acrylate (P(HPMA-MPEGA)) and α-cyclodextrin dimer (bisCD) using cystamine as a linker. The effects of bisCD and polymer concentrations on particle size, gelation time, and recovery of enzyme activity were investigated. The ASNase-conjugated bisCD nanogels were discrete, homogeneous, and spherical with a mean projected diameter of 148 ± 41 nm. ASNase immobilized in the bisCD nanogels caused cytotoxicity on HL-60 cell line with IC50 of 3 IU/ml. In-vivo rat study revealed that the immobilized ASNase reduced the enzyme antigenicity and resulted in 8.1 folds longer circulation half-life than the native enzyme. Conclusively, immobilization of ASNase in P(HPMA-MPEGA) and bisCD supramolecular nanogels could enhance the therapeutic value of ASNase in cancer chemotherapy. © 2023