Manju Kanamala1, Brian D Palmer2, Stephen Mf Jamieson2, William R Wilson2, Zimei Wu1. 1. School of Pharmacy, Auckland Cancer Society Research Centre, Faculty of Medical & Health Sciences, University of Auckland, Auckland 1142, New Zealand. 2. Auckland Cancer Society Research Centre, Faculty of Medical & Health Sciences, University of Auckland, Auckland 1142, New Zealand.
Abstract
Aim: pH-sensitive liposomes (pSL) have emerged as promising nanocarriers due to their endo/lysosome-escape abilities, however, their pH sensitivity is compromised by poly(ethylene glycol) (PEG) coating. This study investigates whether an intracellular PEG-detachment strategy can overcome this PEG dilemma. Materials & methods: First, PEG2000 was conjugated with a phospholipid via an acid-labile hydrazide-hydrazone bond (-CO-NH-N = CH-), which was postinserted into pSL, forming PEG-cleavable pSL (CL-PEG-pSL). Their endo/lysosomal-escape abilities in MIA PaCa-2 cells, pharmacokinetics and tumor accumulation abilities were studied using PEG-pSL as reference. Results: CL-PEG-pSL showed rapid endo/lysosome-escape abilities in the cancer cells and higher tumor accumulation in MIA PaCa-2 xenograft model in contrast to PEG-pSL. Conclusion: Cleavable PEGylation is an efficient strategy to ameliorate the PEG dilemma of pSL for cancer drug delivery.
Aim: pH-sensitive liposomes (pSL) have emerged as promising nanocarriers due to their endo/lysosome-escape abilities, however, their pH sensitivity is compromised by poly(ethylene glycol) (PEG) coating. This study investigates whether an intracellular PEG-detachment strategy can overcome this PEG dilemma. Materials & methods: First, PEG2000 was conjugated with a phospholipid via an acid-labile hydrazide-hydrazone bond (-CO-NH-N = CH-), which was postinserted into pSL, forming PEG-cleavable pSL (CL-PEG-pSL). Their endo/lysosomal-escape abilities in MIA PaCa-2 cells, pharmacokinetics and tumor accumulation abilities were studied using PEG-pSL as reference. Results:CL-PEG-pSL showed rapid endo/lysosome-escape abilities in the cancer cells and higher tumor accumulation in MIA PaCa-2 xenograft model in contrast to PEG-pSL. Conclusion: Cleavable PEGylation is an efficient strategy to ameliorate the PEG dilemma of pSL for cancer drug delivery.
Entities:
Keywords:
MIA PaCa-2; PEG dilemma; PEG shedding; PEG-detachment; dual pH-sensitive liposomes; endosome escape; live cell imaging; pharmacokinetics; tumor distribution
Authors: Joy N Reginald-Opara; Darren Svirskis; Song Yee Paek; Mingtan Tang; Simon J O'Carroll; Justin M Dean; Lawrence W Chamley; Zimei Wu Journal: Mater Today Bio Date: 2022-02-05
Authors: Mimi M Yang; Sasi Bhushan Yarragudi; Stephen M F Jamieson; Mingtan Tang; William R Wilson; Zimei Wu Journal: Pharm Res Date: 2022-02-28 Impact factor: 4.580