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Synthesis, characterisation and evaluation of hyperbranched N-(2-hydroxypropyl) methacrylamides for transport and delivery in pancreatic cell lines in vitro and in vivo

Anane-Adjei, Akosua B.; Fletcher, Nicholas L.; Cavanagh, Robert J.; Houston, Zachary H.; Crawford, Theodore; Pearce, Amanda K.; Taresco, Vincenzo; Ritchie, Alison A.; Clarke, Phillip A.; Grabowska, Anna M.; Gellert, Paul R.; Ashford, Marianne B.; Kellam, Barrie; Thurecht, Kristofer J.; Alexander, Cameron

Synthesis, characterisation and evaluation of hyperbranched N-(2-hydroxypropyl) methacrylamides for transport and delivery in pancreatic cell lines in vitro and in vivo Thumbnail


Authors

Akosua B. Anane-Adjei

Nicholas L. Fletcher

Zachary H. Houston

Theodore Crawford

Amanda K. Pearce

Alison A. Ritchie

Phillip A. Clarke

ANNA GRABOWSKA ANNA.GRABOWSKA@NOTTINGHAM.AC.UK
Professor of Cancer Microenvironment

Paul R. Gellert

Marianne B. Ashford

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BARRIE KELLAM BARRIE.KELLAM@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistry

Kristofer J. Thurecht



Abstract

Hyperbranched polymers have many promising features for drug delivery, owing to their ease of synthesis, multiple functional group content, and potential for high drug loading with retention of solubility. Here we prepared hyperbranched N-(2-hydroxypropyl)methacrylamide (HPMA) polymers with a range of molar masses and particle sizes, and with attached dyes, radiolabel or the anticancer drug gemcitabine. Reversible addition-fragmentation chain transfer (RAFT) polymerisation enabled the synthesis of pHPMA polymers and a gemcitabine-comonomer functionalised pHPMA polymer pro-drug, with diameters of the polymer particles ranging from 7-40 nm. The non-drug loaded polymers were well-tolerated in cancer cell lines and macrophages, and were rapidly internalised in 2D cell culture and transported efficiently to the centre of dense pancreatic cancer 3D spheroids. The gemcitabine-loaded polymer pro-drug was found to be toxic both to 2D cultures of MIA PaCa-2 cells and also in reducing the volume of MIA PaCa-2 spheroids. The non-drug loaded polymers caused no short-term adverse effects in healthy mice following systemic injection, and derivatives of these polymers labelled with 89Zr-were tracked for their distribution in the organs of healthy and MIA PaCa-2 xenograft bearing Balb/c nude mice. Tumour accumulation, although variable across the samples, was highest in individual animals for the pHPMA polymer of ∼20 nm size, and accordingly a gemcitabine pHPMA polymer pro-drug of ∼18 nm diameter was evaluated for efficacy in the tumour-bearing animals. The efficacy of the pHPMA polymer pro-drug was very similar to that of free gemcitabine in terms of tumour growth retardation, and although there was a survival benefit after 70 days for the polymer pro-drug, there was no difference at day 80. These data suggest that while polymer pro-drugs of this type can be effective, better tumour targeting and enhanced in situ release remain as key obstacles to clinical translation even for relatively simple polymers such as pHPMA.

Journal Article Type Article
Acceptance Date Jan 6, 2022
Online Publication Date Apr 5, 2022
Publication Date May 7, 2022
Deposit Date Jan 10, 2022
Publicly Available Date Apr 6, 2023
Journal Biomaterials Science
Electronic ISSN 2047-4849
Peer Reviewed Peer Reviewed
Volume 10
Issue 9
Pages 2328-2344
DOI https://doi.org/10.1039/d1bm01548f
Keywords General Materials Science; Biomedical Engineering
Public URL https://nottingham-repository.worktribe.com/output/7220296
Publisher URL https://pubs.rsc.org/en/content/articlelanding/2022/bm/d1bm01548f

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