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Christmas Tree-Shaped Microneedles as FOLFIRINOX Spatiotemporal Delivery System for Pancreatic Cancer Treatment.

ABSTRACT: As an effective combination chemotherapy, FOLFIRINOX regimen (fluorouracil, leucovorin, irinotecan, and oxaliplatin) has shown definite antitumor efficacy for treating pancreatic cancer (PC) nowadays. However, the traditional systematic administration of these chemotherapeutics limits the drug targeting and causes unwanted effects. Herein, we present a novel Christmas tree-shaped adhesive microneedle (MN) patch coloading fluorouracil, leucovorin, irinotecan, and oxaliplatin simultaneously to realize spatiotemporal FOLFIRINOX therapy in situ. Such MN patch was fabricated by using a layer-by-layer mold replication method, in which oxaliplatin and leucovorin are encapsulated in the top MNs, while irinotecan and fluorouracil are encapsulated in the bottom MNs. The multilayer structure imparts the MNs with enhanced adhesive ability and spatiotemporal drug release property, contributing to the antitumor effect on PC organoid models. Therefore, our Christmas tree-shaped MN patch represents an innovative approach for spatiotemporal multiple-drug delivering and realizes the combination chemotherapy for PC in a single platform.

SUBMITTER: Huang D

PROVIDER: S-EPMC9620638 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Christmas Tree-Shaped Microneedles as FOLFIRINOX Spatiotemporal Delivery System for Pancreatic Cancer Treatment.

Huang Danqing D Fu Xiao X Zhang Xiaoxuan X Zhao Yuanjin Y

Research (Washington, D.C.) 20221016

As an effective combination chemotherapy, FOLFIRINOX regimen (fluorouracil, leucovorin, irinotecan, and oxaliplatin) has shown definite antitumor efficacy for treating pancreatic cancer (PC) nowadays. However, the traditional systematic administration of these chemotherapeutics limits the drug targeting and causes unwanted effects. Herein, we present a novel Christmas tree-shaped adhesive microneedle (MN) patch coloading fluorouracil, leucovorin, irinotecan, and oxaliplatin simultaneously to rea ...[more]

PMID: 36340504

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Project description:PurposeEffective treatment of patients with locally advanced pancreatic cancer is a significant unmet clinical need. One major hurdle that exists is inadequate drug delivery due to the desmoplastic stroma and poor vascularization that is characteristic of pancreatic cancer. The local iontophoretic delivery of chemotherapies provides a novel way of improving treatment. With the growing practice of highly toxic combination therapies in the treatment of pancreatic cancer, the use of iontophoresis for local delivery can potentiate the anti-cancer effects of these therapies while sparing unwanted toxicity. The objective of this study was to investigate the impact of formulation on the electro-transport of the FOLFIRINOX regimen for the development of a new treatment for pancreatic cancer.MethodsThree formulations of the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) were generated at a fixed pH of 6.0 and were referred to as formulation A (single drug solution with all four drugs combined), formulation B (two drug solutions with two drugs per solution), and formulation C (four individual drug solutions). Anodic iontophoresis of the three different formulations was evaluated in orthotopic patient-derived xenografts of pancreatic cancer.ResultsIontophoretic transport of the FOLFIRINOX drugs was characterized according to organ exposure after a single device treatment in vivo. We report that the co-iontophoresis of two drug solutions, leucovorin + oxaliplatin and 5-fluorouracil + irinotecan, resulted in the highest levels of cytotoxic drugs in the tumor compared to drugs delivered individually or combined into one solution. There was no significant difference in plasma, pancreas, kidney, and liver exposure to the cytotoxic drugs delivered by the three different formulations. In addition, we found that reducing the duration of iontophoretic treatment from 10 to 5 min per solution resulted in a significant decrease in drug concentrations.ConclusionsUnderlying the difference in drug transport of the formulations was electrolyte concentrations, which includes both active and inactive components. Electrolyte concentrations can hinder or improve drug electro-transport. Overall, balancing electrolyte concentration is needed for optimal electro-transport.

Project description:BackgroundLarge pragmatic studies of patients who received 5-fluorouracil with leucovorin, irinotecan, and oxaliplatin ([m]FOLFIRINOX) as initial treatment for localized pancreatic ductal adenocarcinoma (PDAC) are lacking. This study aimed to provide realistic estimates of oncologic outcomes in these patients.MethodsThis international retrospective cohort study included all consecutive patients presenting with localized PDAC who received at least 1 cycle of (m)FOLFIRINOX as initial treatment in 5 referral centers from the United States and the Netherlands (2012-2019). Primary outcome was median overall survival (OS), calculated from the date of tissue diagnosis, assessed using Kaplan-Meier estimates. Log-rank test was used to compare OS between groups. A Cox proportional hazards regression model was used to assess prognostic baseline factors for OS. All statistical tests were 2-sided.ResultsOverall, 1835 patients were included, of whom 958 (52.2%) had locally advanced (LA), 531 (28.9%) had borderline resectable (BR), and 346 (18.9%) had potentially resectable (PR) PDAC. The median number of (m)FOLFIRINOX cycles was 6 (interquartile range = 4-8). Subsequent treatment included second chemotherapy (12.9%), radiotherapy (49.0%), and resection (37.9%). The resection rate was 17.6% for LA, 53.1% for BR, and 70.5% for PR PDAC (P < .001). The margin-negative resection rate (>1 mm) was 55.2% for LA, 62.6% for BR, and 79.2% for PR PDAC (P < .001). The median OS was 18.7 months (95% confidence interval [CI] = 17.7 to 19.9 months) for LA, 23.2 months (95% CI = 21.0 to 25.7 months) for BR, and 31.2 months (95% CI = 26.2 to 36.6 months) for PR PDAC (P < .001). The median OS for 695 patients who underwent a resection was 38.3 months (95% CI = 36.1 to 42.0 months). Independent prognostic factors at baseline for worse OS were more advanced stage, worse performance status, baseline carbohydrate antigen (CA) 19-9 > 500 U/mL, and body mass index ≤18.5 kg/m2.ConclusionsThis large international cohort study provides realistic estimates of resection rates and survival in patients with LA, BR, and PR PDAC who started (m)FOLFIRINOX treatment in PDAC referral centers.

Project description:IntroductionPancreatic adenocarcinoma (PDAC) is an aggressive tumor with limited response to both chemotherapy and immunotherapy. Pre-treatment tumor features within the tumor immune microenvironment (TiME) may influence treatment response. We hypothesized that the pre-treatment TiME composition differs between metastatic and primary lesions and would be associated with response to modified FOLFIRINOX (mFFX) or gemcitabine-based (Gem-based) therapy.MethodsUsing RNAseq data from a cohort of treatment-naïve, advanced PDAC patients in the COMPASS trial, differential gene expression analysis of key immunomodulatory genes in were analyzed based on multiple parameters including tumor site, response to mFFX, and response to Gem-based treatment. The relative proportions of immune cell infiltration were defined using CIBERSORTx and Dirichlet regression.Results145 samples were included in the analysis; 83 received mFFX, 62 received Gem-based therapy. Metastatic liver samples had both increased macrophage (1.2 times more, p < 0.05) and increased eosinophil infiltration (1.4 times more, p < 0.05) compared to primary lesion samples. Further analysis of the specific macrophage phenotypes revealed an increased M2 macrophage fraction in the liver samples. The pre-treatment CD8 T-cell, dendritic cell, and neutrophil infiltration of metastatic samples were associated with therapy response to mFFX (p < 0.05), while mast cell infiltration was associated with response to Gem-based therapy (p < 0.05). Multiple immunoinhibitory genes such as ADORA2A, CSF1R, KDR/VEGFR2, LAG3, PDCD1LG2, and TGFB1 and immunostimulatory genes including C10orf54, CXCL12, and TNFSF14/LIGHT were significantly associated with worse survival in patients who received mFFX (p = 0.01). There were no immunomodulatory genes associated with survival in the Gem-based cohort.DiscussionOur evidence implies that essential differences in the PDAC TiME exist between primary and metastatic tumors and an inflamed pretreatment TiME is associated with mFFX response. Defining components of the PDAC TiME that influence therapy response will provide opportunities for targeted therapeutic strategies that may need to be accounted for in designing personalized therapy to improve outcomes.

Dataset Information

Christmas Tree-Shaped Microneedles as FOLFIRINOX Spatiotemporal Delivery System for Pancreatic Cancer Treatment.

Publications

Christmas Tree-Shaped Microneedles as FOLFIRINOX Spatiotemporal Delivery System for Pancreatic Cancer Treatment.

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