Nanomedicines achieve tumor-targeted delivery mainly through enhanced permeability and retention (EPR) effect following intravenous (IV) administration. Unfortunately, the EPR effect is severely compromised in pancreatic cancer due to hypovascularity and dense desmoplastic stroma. Intraperitoneal (IP) administration may be an effective EPR-independent local delivery approach to target peritoneal tumors. Besides improved delivery, effective combination delivery strategies are needed to improve pancreatic cancer therapy by targeting both cancer cells and cellular interactions within the tumor stroma. Here, we described simple cholesterol-modified polymeric CXCR4 antagonist (PCX) nanoparticles (to block cancer-stroma interactions) for codelivery of anti-miR-210 (to inactivate stroma-producing pancreatic stellate cells (PSCs)) and siKRAS G12D (to kill pancreatic cancer cells). IP administration delivered the nanoparticles to an orthotopic syngeneic pancreatic tumors as a result of preferential localization to the tumors and metastases with disrupted mesothelium and effective tumor penetration. The local IP delivery resulted in nearly 15-fold higher tumor accumulation than delivery by IV injection. Through antagonism of CXCR4 and downregulation of miR-210/KRAS G12D , the triple-action nanoparticles favorably modulated desmoplastic tumor microenvironment via inactivating PSCs and promoting the infiltration of cytotoxic T cells. The combined therapy displayed improved therapeutic effect when compared with individual therapies as documented by the delayed tumor growth, depletion of stroma, reduction of immunosuppression, inhibition of metastasis, and prolonged survival. Overall, we present data that a local IP delivery of a miRNA/siRNA combination holds the potential to improve pancreatic cancer therapy.

Key Points Question What are the morbidity and mortality of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) compared with other major oncologic surgical procedures? Findings In this cohort study of 1822 patients who received CRS/HIPEC compared with patients who received other high-risk surgical oncology procedures, overall 30-day mortality was lower in CRS/HIPEC (1.1%) compared with pancreaticoduodenectomy (2.5%), right lobe hepatectomy (2.9%), esophagectomy (3.0%), and trisegmental hepatectomy (3.9%). Meaning Comparative analysis revealed CRS/HIPEC to be safe across the spectrum of National Surgical Quality Improvement Project safety metrics when compared with oncologic procedures with similar inherent risk.

Hydroxychloroquine (HCQ) has been shown to disrupt autophagy and sensitize cancer cells to radiation and chemotherapeutic agents. However, the optimal delivery method, dose, and tumor concentrations required for these effects are not known. This is in part due to a lack of sensitive and reproducible analytical methods for HCQ quantitation in small animals. As such, we developed and validated a selective and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method for simultaneous quantitation of hydroxychloroquine and its metabolites in mouse blood and tissues. The chromatographic separation and detection of analytes were achieved on a reversed phase Thermo Aquasil C (50×4.6mm, 3μ) column, with gradient elution using 0.2% formic acid and 0.1% formic acid in methanol as mobile phase at a flow rate of 0.5mL/min. Simple protein precipitation was utilized for extraction of analytes from the desired matrix. Analytes were separated and quantitated using MS/MS with an electrospray ionization source in positive multiple reaction monitoring (MRM) mode. The MS/MS response was linear over the concentration range from 1 to 2000ng/mL for all analytes with a correlation coefficient (R) of 0.998 or better. The within- and between-day precision (relative standard deviation, % RSD) and accuracy were within the acceptable limits per FDA guidelines. The validated method was successfully applied to a preclinical pharmacokinetic mouse study involving low volume blood and tissue samples for hydroxychloroquine and metabolites.

Chloroquine (CQ) is a widely used antimalarial drug with emerging potential in anticancer therapies due to its apparent inhibitory effects on CXCR4 chemokine receptor, autophagy, and cholesterol metabolism. This study reports on polymeric CQ (pCQ) as a macromolecular drug with antimetastatic activity. The pCQ polymers were synthesized by copolymerization of methacryloylated hydroxy-CQ (HCQ) and N-(2-hydroxypropyl)methacrylamide (HPMA). The results show that pCQ is significantly more effective in inhibiting cancer cell migration and invasion when compared with the parent HCQ. The proposed mechanism of action at least partially relies on the ability of pCQ to inhibit cell migration mediated by the CXCR4/CXCL12 pathway. The pCQ also demonstrates superior inhibitory activity over HCQ when tested in a mouse model of experimental lung metastasis. Lastly, pCQ shows the ability to efficiently translocate to the cytoplasm while exhibiting lower cytotoxicity than HCQ. Overall, this study supports pCQ as a promising polymeric drug platform suitable for use in combination antimetastatic strategies and potential use in cytoplasmic drug delivery.

In the USA, MPM is treated using a wide variety of strategies. Many factors impact the type of treatment delivered, including age, sociodemographics, geography, histology, and facility type. Although these data do not imply causation, combined-modality management seems associated with the longest OS.

BackgroundKMT2/MLL proteins are commonly overexpressed or mutated in cancer and have been shown to support cancer maintenance. These proteins are responsible for methylating histone 3 at lysine 4 and promoting transcription and DNA synthesis; however, they are inactive outside of a multi-protein complex that requires WDR5. WDR5 has been implicated in cancer for its role in the COMPASS complex and its interaction with Myc; however, the role of WDR5 in colon cancer has not yet been elucidated.MethodsWDR5 expression was evaluated using RT-qPCR and western blot analysis. Cell viability and colony forming assays were utilized to evaluate the effects of WDR5 depletion or inhibition in colon cancer cells. Downstream effects of WDR5 depletion and inhibition were observed by western blot.ResultsWDR5 is overexpressed in colon tumors and colon cancer cell lines at the mRNA and protein level. WDR5 depletion reduces cell viability in HCT116, LoVo, RKO, HCT15, SW480, SW620, and T84 colon cancer cells. Inhibition of the WDR5:KMT2/MLL interaction using OICR-9429 reduces cell viability in the same panel of cell lines albeit not to the same extent as RNAi-mediated WDR5 depletion. WDR5 depletion reduced H3K4Me3 and increased phosphorylation of H2AX in HCT116, SW620, and RKO colon cancer cells; however, OICR-9429 treatment did not recapitulate these effects in all cell lines potentially explaining the reduced toxicity of OICR-9429 treatment as compared to WDR5 depletion. WDR5 depletion also sensitized colon cancer cells to radiation-induced DNA damage.ConclusionsThese data demonstrate a clear role for WDR5 in colon cancer and future studies should examine its potential to serve as a therapeutic target in cancer. Additional studies are needed to fully elucidate if the requirement for WDR5 is independent of or consistent with its role within the COMPASS complex. OICR-9429 treatment was particularly toxic to SW620 and T84 colon cancer cells, two cell lines without mutations in WDR5 and KMT2/MLL proteins suggesting COMPASS complex inhibition may be particularly effective in tumors lacking KMT2 mutations. Additionally, the ability of WDR5 depletion to amplify the toxic effects of radiation presents the possibility of targeting WDR5 to sensitize cells to DNA-damaging therapies.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4580-6) contains supplementary material, which is available to authorized users.

No abstract

Hydroxyethyl starch (HES) is a clinically used polysaccharide colloidal plasma volume expander. The goal of this study was to synthesize HES modified with hydroxychloroquine (HCQ) as a novel polymeric drug with the ability to inhibit the invasive character of pancreatic cancer (PC) cells. HES was conjugated with HCQ using a simple carbonyldiimidazole coupling to prepare Chloroquine-modified HES (CQ-HES). CQ-HES with various degrees of HCQ substitution were synthesized and characterized. Atomic force microscopy was used to demonstrate a pH-dependent assembly of CQ-HES into well-defined nanoparticles. In vitro studies in multiple PC cell lines showed CQ-HES to have a similar toxicity profile as HCQ. Confocal microscopy revealed the propensity of CQ-HES to localize to lysosomes and mechanistic studies confirmed the ability of CQ-HES to inhibit autophagy in PC cells. Further studies demonstrated a greatly enhanced ability of CQ-HES to inhibit the migration and invasion of PC cells when compared with HCQ. The enhanced inhibitory actions of CQ-HES compared to HCQ appeared to arise in part from the increased inhibition of ERK and Akt phosphorylation. We found no significant HCQ release from CQ-HES, which confirmed that the observed activity was due to the action of CQ-HES as a polymeric drug. Due to its promising ability to block cancer cell invasion and the ability to form nanoparticles, CQ-HES has the potential as a drug delivery platform suitable for future development with chemotherapeutics to establish novel antimetastatic treatments.