Polymeric microneedles enable simultaneous delivery of cancer immunomodulatory drugs and detection of skin biomarkers

Abstract

Background: Immune-modulating therapies impart positive outcomes in a subpopulation of cancer patients. Improved delivery strategies and non-invasive monitoring of anti-tumor effects can help enhance those outcomes and understand the mechanisms associated with the generation of anti-tumor immune responses following immunotherapy. Methods: We report on the design of a microneedle (MN) platform capable of simultaneous delivery of immune activators and collection of interstitial skin fluid (ISF) to monitor therapeutic responses. While either approach has shown promise, the integration of the therapy and diagnostic arms into one MN platform has hardly been explored before. MNs were synthesized out of crosslinked hyaluronic acid (HA) and loaded with a model immunomodulatory nanoparticle-containing drug, CpG oligodinucleotides (TLR9 agonist), for cancer therapy in melanoma and colon cancer models. The therapeutic response was monitored by longitudinal analysis of entrapped immune cells in the MNs following patch retrieval and digestion. Results: Transdermal delivery of CpG-containing NPs with MNs induced anti-tumor immune responses in multiple syngeneic mouse cancer models. CpG-loaded MNs stimulated innate immune cells and reduced tumor growth. Intravital microscopy showed deposition and spatiotemporal co-localization of CpG-NPs within the tumor microenvironment when delivered with MNs. Analysis of MN-sampled ISF revealed similar immune signatures to those seen in the bulk tumor homogenate, such as increased populations of macrophages and effector T cells following treatment. Conclusions: Our hydrogel-based MNs enable effective transdermal drug delivery into immune cells in the tumor microenvironment, and upon retrieval, enable studying the immune response to the therapy over time. This platform has the theranostic potential to deliver a range of combination therapies while detecting biomarkers.

Poly(β-amino ester)s-Based Delivery Systems for Targeted Transdermal Vaccination

“…While strictly theoretical, these results support the potential of polyelectrolyte films for solvent-free gene vaccination, especially when integrated with non-invasive devices such as MNs. We, and others, have confirmed the therapeutic merit of PBAE-derived systems for transdermal drug delivery in the context of gene vaccination [24,25] but also for the delivery of other nucleic acid immunomodulators such as TLR agonist [30]. When integrated with microneedles, either as PEMS or as polyplexes, PBAE-derived systems induced potent responses for immunization and immunomodulation.…”

“…Polyelectrolyte films (PEMs) can virtually cover any substrate, allowing surface-mediated transfection through the skin when deposited onto transdermal delivery devices [24][25][26]. Here, we also studied the transfection potential of OM-and MM-PBAEs when deposited as PEMs onto microneedles (MNs) as they offer self-administered, needle-free, and painless means for transdermal vaccination when integrated with PBAE-based systems [27][28][29][30][31]. We report that active targeting with mannose, if helpful, does not dictate transfection efficacy as it is the inclusion of oligopeptides that ultimately rendered cell-specific targeting in APCs.…”

Molecular imaging research in atherosclerosis: A 23-year scientometric and visual analysis

“…Interestingly, Weissleder R from Harvard University was a unique writer with high centrality (0.14), and he was the person who first proposed the concept of “Molecular Imaging” and was named by Thomson Reuters as one of the “The World’s Most Influential Scientific Minds”. Furthermore, his research group developed novel molecular technologies for non-invasive imaging of cellular function so as to create next-generation diagnostics and therapeutics in AS ( Cremer et al, 2020 ; Nahrendorf et al, 2020 ) and cancers ( Dosta et al, 2023 ). Significantly, all the most productive and co-cited authors mentioned above were from the United States.…”

Monitoring Melanoma Responses to STING Agonism and Focused Ultrasound Thermal Ablation Using Microneedles and Ultrasensitive Single Molecule Arrays

“…[33,34] We and others have proposed using hydrogel-based microneedles (MNs) for skin ISF sampling. [35][36][37][38][39][40] MNs are comprised of an array of submillimetric needles that are engineered to allow efficient tissue penetration and high swelling capacity. Hyaluronic acid-based microneedles (HA MNs) are especially attractive as these hydrogels are biocompatible and were shown to achieve high swelling characteristics postapplication, allowing for efficient collection of cells [39] and other biomarkers present in the ISF, such as proteins.…”

“…Hyaluronic acid-based microneedles (HA MNs) are especially attractive as these hydrogels are biocompatible and were shown to achieve high swelling characteristics postapplication, allowing for efficient collection of cells [39] and other biomarkers present in the ISF, such as proteins. [36,40] Analyzing cytokines and chemokines in the ISF could provide valuable insights, as these biomolecules are key mediators of immune cell communication in the TME. [41] However, the ISF volume collected by MNs is low (<3 μL), and gets further diluted while isolating proteins from it.…”