Ultrasound-mediated delivery of miRNA-122 and anti-miRNA-21 therapeutically immunomodulates murine hepatocellular carcinoma in vivo

Wischhusen, Jennifer; Chowdhury, Sayan Mullick; Lee, Taehwa; Wang, Huaijun; Bachawal, Sunitha V.; Devulapally, Rammohan; Afjei, Rayhaneh; Sukumar, Uday Kumar; Paulmurugan, Ramasamy

doi:10.1016/j.jconrel.2020.01.051

Cited by 47 publications

(32 citation statements)

References 49 publications

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“…A consistent pattern of elevated cytokines accompanied by increased prevalence of CD8+ T cell in US treated tumor tissue hints to a hallmark signaling cascade for “cold‐to‐hot” tumor transition. In one of our recent work, we reported such immunomodulatory effects in mouse xenograft HCC tumor treated with similar strategy [ 63 ] (Figure 5). With growing evidence along this line, exploiting antitumoral immune effects could enhance the therapeutic efficacy of the proposed combination therapy for HCC.…”

Section: Resultsmentioning

confidence: 63%

“…This observation is consistent with our earlier study, where we reported that US targeted MB destruction in HCC mouse xenografts triggered a 189 ± 33% increase in TNF‐α (in 0.5 h post treatment). [ 63 ] Since TNF‐α is an inflammatory cytokine predominantly secreted by activated leukocytes in blood stream, and it is plausible that the observed surge in TNF‐α is an outcome of US‐MB treatment mediated recruitment and activation of leucocytes in HCC. The recruitment of tumor infiltrating leukocytes (T lymphocyte) in the tumor milieu primes the switch from “cold” HCC tumor into “hot” tumor to augment therapeutic miRNA combination therapy against HCC.…”

Section: Resultsmentioning

confidence: 99%

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Acoustically Driven Microbubbles Enable Targeted Delivery of microRNA‐Loaded Nanoparticles to Spontaneous Hepatocellular Neoplasia in Canines

Sukumar

Telichko

Hyun

et al. 2020

Advanced Therapeutics

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Spatially localized microbubble cavitation by ultrasound offers an effective means of altering the permeability of natural barriers (i.e., blood vessels and cell membranes) in favor of nanomaterial accumulation in target sites. In this study, a clinically relevant, minimally invasive ultrasound guided therapeutic approach is investigated for the targeted delivery of anticancer microRNA loaded PLGA-b-PEG nanoparticles to spontaneous hepatocellular neoplasia in a canine model. Quantitative assessment of the delivered microRNAs reveals a prominent and consistent increase in microRNAs levels (1.5-to 2.3-fold increase [p < 0.001]) in ultrasound treated tumor regions compared to untreated control regions. The immunohistology of ultrasound treated tumor tissue presents clear evidence for a higher amount of nanoparticle extravasation from the blood vessels. A distinct pattern of cytokine expression supporting a CD8+ T cells mediated "cold-to-hot" tumor transition is evident in all patients. This proposed platform can enhance delivery of microRNA-loaded nanoparticles to deeply located visceral tumors in large animals to enhance chemotherapy.

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Section: Resultsmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Acoustically Driven Microbubbles Enable Targeted Delivery of microRNA‐Loaded Nanoparticles to Spontaneous Hepatocellular Neoplasia in Canines

Sukumar

Telichko

Hyun

et al. 2020

Advanced Therapeutics

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“…We also observed in our earlier study that immune cytokines levels are significantly altered upon US‐MB mediated delivery of miRNA loaded PLGA‐PEG NPs. [ 31 ] Hence, we chose immunocompetent BALB/c mice to establish 4T1 syngeneic tumor for evaluation of therapeutic efficacy in this study. The study was designed to evaluate two different hypotheses: 1) US‐MB treatment improves delivery of TK‐p53‐NTR and/or miRNAs into the tumor, and 2) to evaluate miRNA combination therapy improves therapeutic outcome of TK‐p53‐NTR suicide gene therapy in the presence of prodrugs.…”

Section: Resultsmentioning

confidence: 99%

Ultrasound Triggered Co‐Delivery of Therapeutic MicroRNAs and a Triple Suicide Gene Therapy Vector by Using Biocompatible Polymer Nanoparticles for Improved Cancer Therapy in Mouse Models

Sukumar

Telichko

Natarajan

et al. 2021

Advanced Therapeutics

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Microbubbles (MBs) exhibit cavitation upon exposure to ultrasound (US), which creates opportunities to adopt them in new therapeutic approaches. The present study reports an efficient, translatable approach to precisely control the spaciotemporal delivery of therapeutic microRNAs (AmiR‐21 and miR‐100) and TK‐p53‐NTR triple therapeutic gene, co‐loaded in PLGA‐PEG‐PEI polymer nanoparticles (NPs) to tumor models of triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) using US‐mediated targeted destruction of BR38 MBs. PLGA‐PEG‐PEI conjugated triblock co‐polymer NPs are synthesized and characterized for their physicochemical properties, and optimized for co‐loading of miRNAs and TK‐p53‐NTR. Quantitative in vivo imaging and ex vivo tissue analysis of 4T1 (TNBC) subcutaneous tumors in BALB/c mice reveal 19 ± 0.5% (p < 0.01) increase in delivery of miRNAs, and 48 ± 1.79% (p < 0.001) increase in delivery of TK‐p53‐NTR upon US treatment, which results to 48 ± 6.98% (p < 0.01) reduction in tumor growth as compared to contralateral tumors without US. This significantly increases the survival rate of animals as compared to pDNA control group. Similar treatment effects are observed in both TNBC and HCC tumor models. This novel combined therapeutic approach, entailing both miRNAs and suicide gene therapy has strong potential for future applications in cancer therapy.

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“…114 Ultrasound-targeted microbubble destruction (UTMD)− miRNA combination therapy, which uses UTMD for local delivery of nanoparticle-loaded miRNA-122 and anti-miRNA-21, alters the immune microenvironment in Hepa1-6 tumors by modulating cytokine expression, improving the response of HCC to chemotherapy by eliminating drug resistance. 115 Triple-action nanoparticles acting via CXCR4 antagonism and miR-210/KRAS G12D downregulation improved pancreatic cancer therapeutic effects, as revealed by delayed tumor growth, stromal depletion, reduced immunosuppression, inhibited metastasis, and prolonged survival. 116 In addition to nanoparticle-based delivery, an RNA micelle platform can be used to deliver anti-miRNA agents.…”

Section: Mir-451mentioning

confidence: 99%

Expression, regulation, and function of exosome‐derived miRNAs in cancer progression and therapy

et al. 2021

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Exosomes are a novel class of intercellular signal modulators that contain a wide range of molecules and deliver information between cells and tissues. MicroRNAs (miRNAs), a type of regulatory non-coding RNA, are often incorporated into exosomes as signaling molecules. In this review, we discuss the expression of exosomal miRNAs from diverse origins such as tumor cells, solid tumor tissue, and biological fluids in various cancers (lung, breast, colorectal, liver, stomach, and pancreatic). We address the biological functions of exosome-derived miRNAs in processes such as tumor-cell proliferation, angiogenesis, metastasis, and chemoresistance in the tumor microenvironment. In particular, we discuss three oncogenic miRNAs, miR-21, miR-141, and miR-451, which occur within exosomes, in terms of gene regulation and intercellular communication. We consider therapeutic miRNA-based nanoparticles, which are widely expressed in tumors and show promise in drug therapy. The review assesses the wide-ranging evidence for using exosomal miRNAs as tumor markers in molecular diagnosis. Further, we consider the use of nanoparticle platforms to transport miRNAs, in the targeted treatment of disease and tumors.

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Ultrasound-mediated delivery of miRNA-122 and anti-miRNA-21 therapeutically immunomodulates murine hepatocellular carcinoma in vivo

Cited by 47 publications

References 49 publications

Acoustically Driven Microbubbles Enable Targeted Delivery of microRNA‐Loaded Nanoparticles to Spontaneous Hepatocellular Neoplasia in Canines

Acoustically Driven Microbubbles Enable Targeted Delivery of microRNA‐Loaded Nanoparticles to Spontaneous Hepatocellular Neoplasia in Canines

Ultrasound Triggered Co‐Delivery of Therapeutic MicroRNAs and a Triple Suicide Gene Therapy Vector by Using Biocompatible Polymer Nanoparticles for Improved Cancer Therapy in Mouse Models

Expression, regulation, and function of exosome‐derived miRNAs in cancer progression and therapy

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