Surface-fill hydrogel attenuates the oncogenic signature of complex anatomical surface cancer in a single application

Our plain-English summary of Surface-fill hydrogel attenuates the oncogenic signature of complex anatomical surface cancer in a single application, by P. Majumder, A. Singh, Z. Wang, et al (Nature Nanotechnology, 2021).

The study

• Authors: P. Majumder, A. Singh, Z. Wang, K. Dutta, R. Pahwa, C. Liang, C. Andrews, N.L. Patel, J. Shi, N. de Val, S.T.R. Walsh, A.B. Jeon, B. Karim, C.D. Hoang, J.P. Schneider
• Journal: Nature Nanotechnology
• Published: 2021;16(11):1251-1259
• Cited by: 71 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Tumours growing in a sheet-like manner on the surface of organs and tissues with complex topologies represent a difficult-to-treat clinical scenario. Their complete surgical resection is difficult due to the complicated anatomy of the diseased tissue. Residual cancer often responds poorly to systemic therapy and locoregional treatment is hindered by the limited accessibility to microscopic tumour foci. Here we engineered a peptide-based surface-fill hydrogel (SFH) that can be syringe- or spray-delivered to surface cancers during surgery or used as a primary therapy. Once applied, SFH can shape change in response to alterations in tissue morphology that may occur during surgery. Implanted SFH releases nanoparticles composed of microRNA and intrinsically disordered peptides that enter cancer cells attenuating their oncogenic signature. With a single application, SFH shows efficacy in four preclinical models of mesothelioma, demonstrating the therapeutic impact of the local application of tumour-specific microRNA, which might change the treatment paradigm for mesothelioma and possibly other surface cancers.

© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

In plain English

This was a laboratory and preclinical animal study describing the engineering and testing of a peptide-based surface-fill hydrogel (SFH) designed to deliver microRNA to mesothelioma, described by the authors as an asbestos-related surface malignancy. Nanoparticles were made by condensing double-stranded miRNA mimics (miRNA-215 or miRNA-206) with an intrinsically disordered cationic peptide (Peptide 1) and were encapsulated in a fibrillar gel formed by a self-assembling peptide (Peptide 3). Particle charge could be varied from +20 to −17 mV, and 10:1 (N:P) particles averaged about 150 nm. In H2052 mesothelioma cells, the 10:1 particles entered cells, escaped endosomes and reduced expression of target genes, while scrambled-miRNA particles were non-cytotoxic and the miRNA particles did not significantly change viability of non-cancerous NP4 mesothelial cells. SFH could be sprayed or syringe-injected onto porcine lung; sprayed onto a glass surface it formed 200–250 micrometre films. A single application of SFH delivering miRNA-215 or miRNA-206, compared with empty SFH or SFH carrying scrambled miRNA, reduced growth of subcutaneous H2373 tumours, retarded progression and improved survival in intraperitoneal H2373 and intrapleural MB52 models, and limited recurrence after flank MB52 tumour resection. The authors presented this as proof-of-concept.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study: materials engineering and biophysical characterisation, in vitro cell experiments, ex vivo porcine lung models, and mouse xenograft experiments
• Who was studied: Human mesothelioma cell lines (H2052, H2373, MB52) and non-cancerous NP4 human pleural mesothelial cells; NSG, athymic nu/nu and C57BL/6J mice; pre-fixed porcine (swine) lung
• Exposure: Surface-fill hydrogel (SFH) made of self-assembling Peptide 3 encapsulating Peptide 1/miRNA nanoparticles carrying miRNA-215 or miRNA-206 mimics, with empty SFH and SFH with scrambled miRNA as controls; given as a single spray or syringe application, with 10 μg miRNA loaded per 100 μL of SFH in the orthotopic and resection studies
• Main results:
  • Peptide 1 (charge +9) bound FAM-labelled scrambled miRNA cooperatively with an EC50 of about 300 nM, and was selected for further study
  • Varying the amine:phosphate ratio changed particle charge from +20 to −17 mV; positively charged 10:1 (N:P) particles entered cells and escaped endosomes, whereas negatively charged 1:1 particles entered but did not escape
  • By cryo-EM, 10:1 (N:P) particles averaged about 150 nm (range about 100–200 nm) and 1:1 (N:P) particles about 50 nm (range 40–60 nm)
  • In H2052 mesothelioma cells, 10:1 nanoparticles carrying miRNA-215 silenced the target genes MDM2, CDC7, MAD2L1 and LMNB2, and miRNA-206 particles attenuated MET, KRAS, CCND1 and CDK4; silencing was comparable to Lipofectamine
  • Nanoparticles with miRNA-215 or miRNA-206 did not significantly change viability of the non-cancerous NP4 mesothelial cell line, and scrambled-miRNA nanoparticles were non-cytotoxic in H2052 cells
  • Spraying 0.2 mL of SFH onto a glass surface produced films 200–250 micrometres thick, measured by confocal z-stack imaging; separately, SFH was sprayed and syringe-injected onto porcine lung and spread-filled during lung inflation
  • Subcutaneously implanted SFH delivered Cy3-miRNA locally over two weeks, whereas a bolus of free miRNA was cleared within one day
  • In NSG mice with subcutaneous H2373 tumours of about 300 mm3 (n = 5 for therapeutic miRNA treated groups, n = 4 for the rest), a single peritumoral injection of SFH delivering miRNA-215 or miRNA-206 reduced tumour growth, with lower Ki-67 and, for miRNA-215, more TUNEL-positive apoptotic cells
  • In the disseminated intraperitoneal H2373 model, a single SFH application delivering miRNA-215 or miRNA-206 retarded tumour progression and increased survival
  • In the intrapleural MB52 model, a single injection of SFH delivering miRNA-215 or miRNA-206 reduced cancer progression and improved survival, with 21% of mice living well past the median overall survival timepoint
  • For the intrapleural MB52 model, the figure legend reports the day 14 statistics as p = 0.035 by one-way ANOVA and p = 0.045 by Tukey's multiple-comparisons test between the scrambled miRNA and miRNA-206 groups
  • In the bilateral flank MB52 resection model (n = 4 animals per group), sites treated with SFH containing miRNA-215 or miRNA-206 showed only faint tumour recurrence by bioluminescence at one month, while SFH-scrambled-treated sites showed bulky regrowth
  • Mice given subcutaneous, intraperitoneal or intrapleural SFH maintained bodyweight with no signs of toxicity on histopathology of vital organs
• The authors' conclusion: The authors concluded that their work provides proof-of-concept that mesothelioma can be affected by local delivery of tumour-specific miRNA using SFH, which they said lays a foundation to change the treatment paradigm for mesothelioma and other surface cancers

Topics

Medical terms in this study, explained in our Lexicon: Surgical Resection, Systemic Therapy, Mesothelioma.

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