Chris Butch

Strategic Timing of Gene Silencing: Cellular Kinetics-Based Administration of siRNA for Optimized Photothermal Cancer Treatment

Full open access paper here: doi.org/10.1002/advs.202510802.

(8/8)

This establishes that when you deliver siRNA matters just as much as what you deliver - a principle with broad applications across combination therapies.

Would love input from oncology and nanomedicine communities.

#siRNA #CancerResearch #GeneTherapy #CancerTherapy #BreastCancer #Medsky (7/8)

Results in mouse TNBC models show this temporally optimized approach achieves 86% improved tumor reduction compared to conventional single-treatment protocols. When we tested different timing intervals, the 36-hour window consistently outperformed other schedules by significant margins. (6/8)

The key finding: a critical 36-hour window when siRNA-mediated HSP70 suppression maximally sensitizes cancer cells to subsequent thermal stress. This timing optimization is what enables effective therapy at milder temperatures while maintaining the reduced side-effect profile. (5/8)

To conduct this work, we built a 3-in-1 nanoparticle with light-absorbing dye(ICG-II), immune-derived targeting membrane (via integrin α4/VCAM-1 interactions), and HSP70-blocking siRNA, which allowed precise control of siRNA delivery and release. (4/8)

While previous studies showed siRNA could sensitize tumors to photothermal therapy, siRNA timing remained under-explored. We conducted systematic temporal analysis of HSP70 expression dynamics following siRNA delivery - mapping exactly when cells are most vulnerable to thermal stress. (3/8)

This work addresses the problem of thermoresistance in mild-temperature photothermal therapy (MPTT). Cancer cells rapidly express Heat shock protein 70 (HSP70) to survive thermal stress, limiting treatment effectiveness especially in aggressive cancers like triple-negative breast cancer. (2/8)

Infographic for our Advanced Science paper showing how timing transforms gene therapy. Standard photothermal therapy is limited by heat shock proteins, but with siRNA delivered in a nanoparticle and precisely timed at a 36-hour window, HSP resistance is suppressed and tumor ablation is nearly doubled, achieving 86% greater reduction in triple-negative breast cancer models.

Excited to share the latest work by my students Tianliang Fang and Li Li in Advanced Science demonstrating the critical importance of siRNA timing in photothermal therapy showing how precisely timed siRNA delivery nearly doubles efficacy. 🧪 #PrecisionMedicine #Oncology #Nanomedicine (1/8)

Recent advances of engineering cell membranes for nanomedicine delivery across the blood–brain barrier - Journal of Nanobiotechnology The blood-brain barrier (BBB) poses a major challenge to the effective delivery of therapeutic agents for the treatment of central nervous system (CNS) disorders. The integration of cell membrane engi...

We also discuss the assay, modelling, and data integration strategies that will be necessary to drive the transition to clinic given the compositional heterogeneity and complexity of these particles. (4/4)

Full Paper (Open Access): jnanobiotechnology.biomedcentral.com/articles/10....

Shengnan does an excellent job synthesizing experimental data available on several membrane types (red blood cells, platelets, tumor cells, macrophages, neutrophils, and NK cells) which will be invaluable to any young researchers starting in this area. (3/4)

Engineered cell membranes are an exciting new approach to evade the body's natural clearance responses allowing more targeted drug delivery. They are an especially attractive option for brain cancers due to innate BBB permeability of many immune cells. (2/4)

Also out last week: I contributed to a review in J. Nanobiotechnology lead by Shengnan Yuan and Zonghai Sheng of the Shenzhen Institute of Advanced Techology on engineered cell membranes for drug delivery across the blood brain barrier.

🧪 #nanomedicine #drugdelivery #braintumor #biomimetics (1/4)

The current patches are only suitable to near surface cancers - skin, some head/neck, and maybe some superficial breast cancers - experimental evidence for those other cancers is one of the directions we are moving with this.

Great question! We believe the personalized approach using autologous tumor cells should work for any solid tumor, but the microneedle delivery system needs to be altered or replaced for internal usage. The immune activation mechanisms should be cancer-agnostic

ACT-Vac Paper Page Figure 1 -  The schematic illustration of ACT-vac(TVA)patch antitumor immune responses. A) preparation process of the ACT-vac(TV) and ACT-vac(A) loading into microneedle patch. B) engineered...

The published paper is available here:
advanced.onlinelibrary.wiley.com/doi/abs/10.1...

The accepted preprint can be viewed on my website:
butchresearch.com/actvac.html

(8/8)

Our results show a 93% reduction in tumor regrowth compared to no treatment. Importantly, when a distant second tumor is implanted to simulate an existing metastasis, the growth rate of this second tumor is drastically reduced as well, indicating a strong systemic immune effect. (7/8)

This attack is bolstered by the co-administered polyarginine which is converted to NO by elevated iNOS expression, inducing a strong pyroptotic response that further amplifies immunity. (6/8)

Exposure to the VNP2009 infected tumor cells triggers M2 to M1 macrophage conversion via the NF-κB pathway, breaking down the tumor immune cloaking mechanisms and reactivating immune cells to attack the cancer. (5/8)

This method resembles tumor infiltrating lymphocyte (TIL) therapies, which harvest and expand immune cells from resected tumors. Unlike TILs, which take 6-8 weeks to culture, our method completes in under 72 hours, relying on conversion of existing immune cells rather than culturing new ones. (4/8)

The main advancement in Tianliang's work is combining ex vivo infection of tumor cells with VNP20009 for more effective antigen presentation, along with combination with polyarginine during administration using a microneedle patch. (3/8)

This work addresses the problem of incomplete surgical resection of solid tumors which frequently leads to recurrence and metastasis. Therapeutic vaccines aim to reduce these occurrences by retraining the immune system to attack any residual cancer cells, preventing future malignancy. (2/8)

Depiction of vaccine synthesis methodology.

I'm a bit late on this one due to some travel, but I want to congratulate my student Tianliang Fang on her recent publication in Advanced Functional Materials demonstrating a new technique for the rapid synthesis of personalized therapeutic cancer vaccines.

🧪 #cancer #vaccines (1/8)

Hello, I am a biomedical engineer working in cancer therapy. Could you add me please?

scholar.google.com/citations?us...

I haven't been good about sharing my science, so here's to the start of a new trend.
(7/7)

Signal-to-Noise Ratio Imaging and Real-Time Sharpening of Tumor Boundaries for Image-Guided Cancer Surgery Fluorescence-guided cancer surgery is of considerable current interest in bioanalytical chemistry, engineering, and medicine, but its clinical utility is still hampered by the diffusive (scattering) nature of human tissues and large variations among different patients. Here, we report a new method based on signal-to-noise (contrast-to-noise) ratio (SNR or CNR) imaging for real-time delineation and sharpening of tumor boundaries during image-guided cancer surgery. In particular, we show that in vivo tumor fluorescence signals (both intensity and standard deviation) are strongly correlated with those of the surrounding tissue of the same tissue type and that this relationship is maintained as a function of time for fluorescent tracers such as indocyanine green. This dynamic relationship permits a precise removal of nonspecific background fluorescence from tumor fluorescence. As a result, single-pixel SNR values have been calculated, mapped, and displayed across a large surgical field at 60 frames per second. Pathological validation studies indicate that these SNR values correspond to statistical confidence levels similar (but not identical) to those of normal distributions. When the tumor fluorescence has an SNR of 3, pathological data show a confidence level of approximately 95% in identifying the true tumor lesions. For clinical relevance, we have also carried out first-in-human clinical studies for both oral and esophageal tumors, achieving tumor margin precisions of 1–2 mm with 87.5% histological accuracy and no false positives.

Read the full paper:

Signal-to-Noise Ratio Imaging and Real-Time Sharpening of Tumor Boundaries for Image-Guided Cancer Surgery

pubs.acs.org/doi/full/10....

(6/7)

This method offers potential for precise, real-time, quantitative guidance during cancer resection to help surgeons ensure complete tumor removal while preserving healthy tissue. (5/7)

The approach was validated first in xenograft models and then successfully translated to clinical samples through our collaboration with China Medical University, achieving millimeter scale diagnosis with 87.5% accuracy with no false negatives. (4/7)

By stratifying fluorescence signal by standard deviations above background, we demonstrated that SNR thresholds correlate strongly with cancer probability. (3/7)

Our work reveals a strong correlation between tumor and surrounding tissue fluorescence variance, enabling stable tumor boundary identification for up to 24 hours post-injection - a key finding that could help to standardize the window for guided resections. (2/7)

Comparison of tumor visibility under - no guidance - fluorescence guidance - and fluorescence + SNR guidance. SNR Strata correspond directly with presence of cancer in histological evaluation, allowing risk informed determination of the tumor boundary in real time.

Today, I'm excited to congratulate my student Ziyang Wang who lead our team's latest paper on statistical image processing for cancer margin detection during surgery which has just been accepted in Analytical Chemistry.
#medsky #academicsky
#fgs #icg #fluorescence-guided #surgery

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