Gemcitabine and nab-paclitaxel (Abraxane®) is a standard of care chemotherapy combination used in the treatment of patients with advanced pancreatic cancer. While the combination has shown a survival benefit when compared to gemcitabine monotherapy, it is associated with significant off-target toxicity. Ultrasound targeted microbubble destruction (UTMD) has emerged as an effective strategy for the site-specific deposition of drug-payloads. However, loading a single microbubble formulation with two drug payloads can be challenging and often involves several manipulations post-microbubble preparation that can be cumbersome and generally results in low / inconsistent drug loadings. In this manuscript, we report the one-pot synthesis of a gemcitabine functionalised phospholipid and use it to successfully generate stable microbubble formulations loaded with gemcitabine (Lipid-Gem MB) or a combination of gemcitabine and paclitaxel (Lipid-Gem-PTX MB). Efficacy of the Lipid-Gem MB and Lipid-Gem-PTX MB formulations, following ultrasound (US) stimulation, was evaluated in a three-dimensional (3D) PANC-1 spheroid model of pancreatic cancer and a mouse model bearing ectopic BxPC-3 tumours. The results demonstrated a significant reduction in the cell viability in spheroids for both formulations reducing from 90 ± 10% to 62 ± 5% for Lipid-Gem MB and 84 ± 10% to 30 ± 6% Lipid-Gem-PTX MB following US irradiation. When compared with a clinically relevant dose of free gemcitabine and paclitaxel (i.e. non-particle bound) in a BxPC-3 murine pancreatic tumour model, both formulations also improved tumour growth delay with tumours 40 ± 20% and 40 ± 30% smaller than the respective free drug formulation when treated with Lipid-Gem MB and Lipid-Gem-PTX MB respectively, at the conclusion of the experiment. These results highlight the potential of UTMD mediated Gem / PTX as a treatment for pancreatic cancer and the facile preparation of Lipid-Gem-PTX MBs using a gemcitabine functionalised lipid should expedite clinical translation of this technology.
|Number of pages||9|
|Journal||European Journal of Pharmaceutics and Biopharmaceutics|
|Early online date||24 May 2021|
|Publication status||Published (in print/issue) - 31 Aug 2021|
Bibliographical noteFunding Information:
KAL thanks the Department of the Economy in Northern Ireland for a PhD studentship. JFC thanks Norbrook Laboratories Ltd for an endowed chair. The raw/processed data required to reproduce these findings cannot be shared at this time due to technical limitations. However, any specific file(s) can be made available on request.
© 2021 Elsevier B.V.
- pancreatic cancer
- Pancreatic cancer
- Drug Carriers/chemistry
- Drug Liberation/radiation effects
- Pancreatic Neoplasms/drug therapy
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Ultrasonic Waves
- Deoxycytidine/administration & dosage
- Xenograft Model Antitumor Assays
- Albumins/administration & dosage
- Paclitaxel/administration & dosage
- Cell Line, Tumor
- Drug Compounding/methods