Polycation fluorination improves intraperitoneal siRNA delivery in metastatic pancreatic cancer

H, Yu; Tang, Siyuan; Tang, Weimin; Větvička, David; Zhang, Chuhan; Xie, Ying; Yu, Fang; Yu, Ao; Sil, Diptesh; Li, Jing; Singh, Rakesh K.; Oupický, David

doi:10.1016/j.jconrel.2021.03.028

Cited by 21 publications

(13 citation statements)

References 57 publications

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“…This is likely because the conjugation of cholesterol decreases the exposed positive charges that could interact with cell membranes and cause damage . PAMD-CHOL showed CXCR4 antagonism in a dose-dependent manner with an EC 50 of 0.12 μg/mL, well below its toxic concentration …”

Section: Resultsmentioning

confidence: 99%

“…37 PAMD-CHOL showed CXCR4 antagonism in a dose-dependent manner with an EC 50 of 0.12 μg/mL, well below its toxic concentration. 34 The effect of CXCR4 inhibition with PAMD-CHOL on the migration of the two PDAC cell lines was tested using CXCL12 as the chemoattractant (Figure 1). PAMD-CHOL effectively inhibited migration of both the mouse KPC8060 and human S2-013 cells.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Polymer Synthesis and Characterization. PAMD and PAMD-CHOL were synthesized as previously described 32,34 by Michael-type polyaddition. AMD3100 and HMBA in an equal molar ratio were dissolved in 70% MeOH (v/v) and reacted for 3 days at 37 °C under nitrogen.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

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Intraperitoneal siRNA Nanoparticles for Augmentation of Gemcitabine Efficacy in the Treatment of Pancreatic Cancer

Tang

Ding

et al. 2021

Mol. Pharmaceutics

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Pancreatic ductal adenocarcinoma is a deadly disease with limited treatment options due to late diagnosis and resistance to conventional chemotherapy. Among emerging therapeutic targets, the CXCR4 chemokine receptor and polo-like kinase 1 (PLK1) play critical roles in the progression, metastasis, and chemoresistance of pancreatic cancer. Here, we tested the hypothesis that combining CXCR4 inhibition by a polymeric CXCR4 antagonist PAMD-CHOL with PLK1 knockdown by siRNA will enhance the therapeutic effect of gemcitabine (GEM) in the orthotopic model of metastatic pancreatic cancer. We formulated nanoparticles with cholesterol-modified PAMD and siPLK1 and found strong synergism when combined with GEM treatment in vitro in both murine and human pancreatic cancer cell lines. The biodistribution of the nanoparticles in orthotopic pancreatic cancer models revealed strong accumulation in primary and metastatic tumors, with limited hepatic disposition. The cholesterol-containing nanoparticles showed not only increased tumor accumulation than the cholesterol-lacking control but also deeper penetration into the tumors. In a therapeutic study in vivo, the triple combination of PAMD-CHOL/siPLK1 and GEM showed superior anticancer activity when compared with single and dual combination controls. In conclusion, PAMD-CHOL/siPLK1 nanoparticles synergistically enhance anticancer activity of GEM in pancreatic cancer and represent a promising addition to the treatment arsenal.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

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Intraperitoneal siRNA Nanoparticles for Augmentation of Gemcitabine Efficacy in the Treatment of Pancreatic Cancer

Tang

Ding

et al. 2021

Mol. Pharmaceutics

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“…As hypothesized above, we believe that the observed tumor penetration of the nanoemulsions is a cell-mediated process. The interactions between P@P EPs and the tumor cells or other cells, such as infiltrating macrophages, are complex and likely to contribute to the delivery efficacy . To evaluate if the penetration mechanism of P@P EPs in vivo follows the one proposed in our in vitro study, we have treated the tumor-bearing mice with IP injection of EXO-1 prior to administration of the P@P EPs.…”

Section: Resultsmentioning

confidence: 99%

Nanoemulsion-Assisted siRNA Delivery to Modulate the Nervous Tumor Microenvironment in the Treatment of Pancreatic Cancer

Ding

Tang

et al. 2022

ACS Appl. Mater. Interfaces

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Pancreatic cancer (PC) is a fatal human cancer, whose progression is highly dependent on the nervous tumor microenvironment. In the present study, cationic perfluorocarbon nanoemulsions were employed as an intraperitoneal delivery platform to facilitate the delivery and penetration of a therapeutic small interfering RNA (siRNA) to orthotopic pancreatic tumors. The nanoemulsion was used to silence the expression of the nerve growth factor (NGF) as a way of favorably modulating the tumor–neuronal interactions in pancreatic tumors. The nanoemulsions exhibited deep tumor penetration that was dependent on exocytosis and enhanced NGF gene silencing in vitro and in vivo when compared with control polycation/siRNA polyplexes, leading to the effective and safe suppression of tumor growth in orthotopic PC. Overall, emulsion-assisted delivery of NGF siRNA is a promising treatment approach for PC by targeting the interactions between the tumor cells and the nervous microenvironment.

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“…PEI and synthesized polymers were fluorescently labeled by reacting with N-hydroxysuccinimide activated Cy3 (Cy3-NHS). 43 Briefly, 50 mg of the polymer was dissolved in 5 mL of deionized water, then 0.5 mg of Cy3-NHS in dimethyl sulfoxide (DMSO) was added to the polymer solution, followed by overnight stirring at room temperature in the dark. The reaction mixture was then dialyzed for 7 days to remove the unconjugated Cy3.…”

Section: Methodsmentioning

confidence: 99%

Study of Renal Accumulation of Targeted Polycations in Acute Kidney Injury

et al. 2022

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Acute kidney injury (AKI) is a global healthcare burden characterized by rapid loss of renal function and high morbidity and mortality. Chemokine receptor CXCR4 participates in the renal infiltration of immune cells following injury and in local inflammatory enhancement. Injured renal tubule cells overexpress CXCR4, which could be used as a target for improved drug delivery in AKI. Plerixafor is a small-molecule CXCR4 antagonist that has shown beneficial effects against AKI and has been previously developed into a polymeric analog (polymeric plerixafor, PP). With the goal of gaining a better understanding of how overall charge and hydrophilicity affect renal accumulation of PP, we have synthesized PP copolymers containing hydroxyl, carboxyl, primary amine, and alkyl moieties using Michael-type addition copolymerization. All synthesized copolymers showed excellent CXCR4-binding and inhibiting ability in vitro and improved cellular uptake in hypoxia-reoxygenation stimulated mouse tubule cells. Analysis of serum protein binding revealed that polymers with hydroxyl group modification showed the least amount of protein binding. Biodistribution of the polymers was tested in a unilateral ischemia reperfusion-induced AKI mouse model. The results showed significant differences in accumulation in the injured kidneys depending on the net charge and hydrophilicity of the polymers. The findings of this study will guide the development of polymeric drug carriers for targeted delivery to injured kidneys for better AKI therapy.

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Polycation fluorination improves intraperitoneal siRNA delivery in metastatic pancreatic cancer

Cited by 21 publications

References 57 publications

Intraperitoneal siRNA Nanoparticles for Augmentation of Gemcitabine Efficacy in the Treatment of Pancreatic Cancer

Intraperitoneal siRNA Nanoparticles for Augmentation of Gemcitabine Efficacy in the Treatment of Pancreatic Cancer

Nanoemulsion-Assisted siRNA Delivery to Modulate the Nervous Tumor Microenvironment in the Treatment of Pancreatic Cancer

Study of Renal Accumulation of Targeted Polycations in Acute Kidney Injury

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