Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study

Nanoparticle drug delivery systems have been used in the clinic since the early 1990's. Since that time, the field of nanomedicine has evolved alongside growing technological needs to improve the delivery of various therapeutics. Over these past decades, newer generations of nanoparticles have emerged that are capable of performing additional delivery functions that can enable treatment via new therapeutic modalities. In the current clinical landscape, many of these new generation nanoparticles have reached clinical trials and have been approved for various indications. In the first issue of Bioengineering & Translational Medicine in 2016, we reviewed the history, current clinical landscape, and clinical challenges of nanoparticle delivery systems. Here, we provide a 3 year update on the current clinical landscape of nanoparticle drug delivery systems and highlight newly approved nanomedicines, provide a status update on previous clinical trials, and highlight new technologies that have recently entered the clinic.

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“…NCT02369198 (Ph I): Published study demonstrates that TargomiRs were well‐tolerated by refractory malignant pleural mesothelioma patients …”

Section: Update On Previous Trialsmentioning

confidence: 99%

Nanoparticles in the clinic: An update

Anselmo

Mitragotri

2019

Bioengineering & Transla Med

1,351

1,044

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“…For targeted drug delivery and gene silencing, complex particle vehicles are needed to overcome extracellular and intracellular barriers. While smaller nanoparticles have been the preferred size for approaches such as gene therapy, there are examples of larger nanoparticles (400 nm) and MPs (>1 μm) being used . For example, our previous preclinical work and clinical trial in mesothelioma patients used bacterial minicells of 400 nm in diameter to deliver miRNA mimics to patients.…”

Section: Discussionmentioning

confidence: 99%

Covalent binding of molecules to plasma immersion ion implantation‐activated microparticles for delivery into cells

Kruse

Tran

Zandwijk

et al. 2020

Engineering Reports

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Delivery of biomolecules to target cells is an essential step in gene therapy, targeted drug delivery, and cell imaging, and can be achieved by encapsulation or conjugation to micro‐ or nanoparticles. For successful systemic delivery, these complexes must be stable under physiological conditions and prevent leakage of the cargo. Covalent binding of the active agent to a carrier is one‐way to facilitate this stability but frequently requires several steps. Here we show that plasma immersion ion implantation (PIII) treatment can activate the surface of paramagnetic polystyrene microparticles (MPs), increasing autofluorescence and allowing conjugation of biological molecules in a single‐step. Using PIII‐activated MPs, we demonstrate covalent binding of therapeutically relevant payloads including antibodies (Abs) and small‐interfering RNAs (siRNAs). The PIII‐activated magnetic particles were actively taken up by the cells, were nontoxic, and could be visualized due to increased autofluorescence induced by the PIII treatment. Ab and siRNA were effectively conjugated simultaneously to the active surface, and these functionalized MPs were also taken up by cells. This simple PIII‐based activation system has the potential to be applied to many different therapeutic approaches.

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“…For other diseases, miRNA‐infusion‐based therapies are proven feasible and already are in clinical trials. For example, miR‐16‐loaded minicells (TargomiRs) are currently being assessed for their safety and optimal dosing in a phase I trial in patients with malignant pleural mesothelioma . A similarly designed trial was recently set for a cohort of patients with advanced solid tumors refractory to standard treatment .…”

Section: Discussionmentioning

confidence: 99%

Adipose may actively delay progression of NAFLD by releasing tumor‐suppressing, anti‐fibrotic miR‐122 into circulation

2018

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Summary Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology. Here we propose tissue‐cooperative, homeostatic model of NAFLD. During early stages of NAFLD the intrahepatic production of miR‐122 falls, while the secretion of miRNA‐containing exosomes by adipose increases. Bloodstream carries exosome to the liver, where their miRNA cargo is released to regulate their intrahepatic targets. When the deterioration of adipose catches up with the failing hepatic parenchyma, the external supply of liver‐supporting miRNAs gradually tapers off, leading to the fibrotic decompensation of the liver and an increase in hepatic carcinogenesis. This model may explain paradoxical observations of the disease‐associated decrease in intrahepatic production of certain miRNAs with an increase in their levels in serum. Infusions of miR‐122 and, possibly, some other miRNAs may be efficient for preventing NAFLD‐associated hepatocellular carcinoma. The best candidates for exosome‐wrapped miRNA producer are adipose tissue‐derived mesenchymal stem cells (MSCs), known for their capacity to shed large amounts of exosomes into the media. Notably, MSC‐derived exosomes with no specific loading are already tested in patients with liver fibrosis. Carrier exosomes may be co‐manufactured along with their cargo. Exosome‐delivered miRNA cocktails may augment functioning of human organs suffering from a variety of chronic diseases.

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Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study

Cited by 542 publications

References 37 publications

Nanoparticles in the clinic: An update

Nanoparticles in the clinic: An update

Covalent binding of molecules to plasma immersion ion implantation‐activated microparticles for delivery into cells

Adipose may actively delay progression of NAFLD by releasing tumor‐suppressing, anti‐fibrotic miR‐122 into circulation

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