O-P05 Gemcitabine and paclitaxel loaded microbubbles for the treatment of pancreatic cancer

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Abstract

Background: Ultrasound targeted microbubble destruction (UTMD) has emerged as an effective strategy for the delivery of drug payloads to solid tumours. However, loading a single microbubble (MB) formulation with two drug payloads is challenging and often involves several manipulations post-MB preparation to enable attachment of drug payloads which can be cumbersome and generally results in low / inconsistent drug loading. Here we report a one-step synthesis of a gemcitabine-functionalised phospholipid and its subsequent incorporation into a stable MB formulation co-loaded with paclitaxel (PTX). The efficacy of the MB conjugate was determined in a Panc-1 spheroid model and ectopic BxPC-3 tumour model of pancreatic cancer. Methods Gemcitabine-modified phospholipid (Lipid-Gem MB) was prepared from 1,2-dibehenoyl-sn-glycero-3-phosphocholine (DBPC) though a transphosphatidylation reaction using gemcitabine (Gem) as the acceptor alcohol. Lipid-Gem MB and Lipid-Gem-PTX MB were prepared from Lipid-Gem MB and/or PTX using a standard thin-film hydration technique followed by sonication in the presence of PFB gas. In vitro efficacy of Lipid-Gem MB and Lipid-Gem-PTX MB were determined in Panc-1 spheroids using an MTT assay. The in vivo effectiveness was determined in BxPC-3 tumour bearing mice following IV administration of either Lipid-Gem MB or Lipid-Gem-PTX MB plus ultrasound (US). Free Gem, free Gem + PTX and untreated mice were used for comparative purposes. Results Spheroids treated with Lipid-Gem MB +US or Lipid-Gem-PTX MB +US were significantly reduced relative to spheroids treated with US alone (p = 0.033 and p = 0.0031 respectively) or with the respective MB formulation alone (i.e. no US) (p = 0.0336 and p = 0.0037 respectively). Furthermore, cell viability for spheroids treated with Lipid-Gem-PTX MB +US was significantly reduced compared with spheroids treated with Lipid-Gem MB +US (p = 0.0077) (Figure a). Mice treated with Lipid-Gem MB +US or Lipid-Gem-PTX MB +US showed an average change in tumour volume of + 7 ± 7% and -10 ± 10 % respectively compared with +45 ±10% and +30 ± 10% for free gem and free gem + PTX respectively (Figure b). Conclusions A Gem-modified lipid was succesfully synthesised using a single step reaction and was subsequently incorporated into MBs containging PTX, eliminating the need for cumbersome drug conjgation methods. UTMD mediated treatment of Panc-1 spheroids and BxPC-3 tumours demonstrated the efficacy and tolerability of the formulations. Given that all components of this formulation are already clinicaly apporved, UTMD using Lipid-Gem-PTX MB offers a promising alternative to existing treatments
Original languageEnglish
Pages (from-to)ix18-ix19
Number of pages2
JournalBritish Journal of Surgery
Volume108
Issue numberSupplement_9
DOIs
Publication statusPublished - 15 Dec 2021

Keywords

  • Surgery

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