Long-circulating magnetoliposomes as surrogates for assessing pancreatic tumour permeability and nanoparticle deposition

Nanocarriers are candidates for cancer chemotherapy delivery, with growing numbers of clinically-approved nano-liposomal formulations such as Doxil® and Onivyde® (liposomal doxorubicin and irinotecan) providing proof-of-concept. However, their complex biodistribution and the varying susceptibility of individual patient tumours to nanoparticle deposition remains a clinical challenge. Here we describe the preparation, characterisation, and biological evaluation of phospholipidic structures containing solid magnetic cores (SMLs) as an MRI-trackable surrogate that could aid in the clinical development and deployment of nano-liposomal formulations. Through the sequential assembly of size-defined iron oxide nanoparticle clusters with a stabilizing anionic phospholipid inner monolayer and an outer monolayer of independently-selectable composition, SMLs can mimic physiologically a wide range of nano-liposomal carrier compositions. In patient-derived xenograft models of pancreatic adenocarcinoma, similar tumour deposition of SML and their nano-liposomal counterparts of identical bilayer composition was observed in vivo, both at the tissue level (fluorescence intensities of 1.5 × 108 ± 1.8 × 107 and 1.2 × 108 ± 6.3 × 107, respectively; ns, 99% confidence interval) and non-invasively using MR imaging. We observed superior capabilities of SML as a surrogate for nano-liposomal formulations as compared to other clinically-approved iron oxide nano-formulations (ferumoxytol). In combination with diagnostic and therapeutic imaging tools, SMLs have high clinical translational potential to predict nano-liposomal drug carrier deposition and could assist in stratifying patients into treatment regimens that promote optimal tumour deposition of nanoparticulate chemotherapy carriers. Statement of significance: Solid magnetoliposomes (SMLs) with compositions resembling that of FDA-approved agents such as Doxil® and Onivyde® offer potential application as non-invasive MRI stratification agents to assess extent of tumour deposition of nano-liposomal therapeutics prior to administration. In animals with pancreatic adenocarcinoma (PDAC), SML-PEG exhibited (i) tumour deposition comparable to liposomes of the same composition; (ii) extended circulation times, with continued tumour deposition up to 24 hours post-injection; and (iii) MRI capabilities to determine tumour deposition up to 1 week post-injection, and confirmation of patient-to-patient variation in nanoparticulate deposition in tumours. Hence SMLs with controlled formulation are a step towards non-invasive MRI stratification approaches for patients, enabled by evaluation of the extent of deposition in tumours prior to administration of nano-liposomal therapeutics.Science Foundation IrelandIrish Research CouncilNational Cancer InstituteU.S. National Inst. of Health/NCIFulbright Commission of Ireland Student AwardEuropean Association for Cancer ResearchRoyal Society of Chemistr

Dual-hit strategy for therapeutic targeting of pancreatic cancer in patient-derived xenograft tumors

PurposeParacrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) “primes” PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial–mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters.Experimental designAnimals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key “nodes” responsible for EMT induction.ResultsMultiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect.ConclusionsThis dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical–translational requirement for patient stratification.<br/