skip to main content

Title: Enhanced Tumor Accumulation of Multimodal Magneto‐Plasmonic Nanoparticles via an Implanted Micromagnet‐Assisted Delivery Strategy

One of the major shortcomings of nano carriers‐assisted cancer therapeutic strategies continues to be the inadequate tumor penetration and retention of systemically administered nanoformulations and its off‐target toxicity. Stromal parameters‐related heterogeneity in enhanced permeability and retention effect and physicochemical properties of the nanoformulations immensely contributes to their poor tumor extravasation. Herein, a novel tumor targeting strategy, where an intratumorally implanted micromagnet can significantly enhance accumulation of magneto‐plasmonic nanoparticles (NPs) at the micromagnet‐implanted tumor in bilateral colorectal tumor models while limiting their off‐target accumulation, is demonstrated. To this end, novel multimodal gold/iron oxide NPs comprised of an array of multifunctional moieties with high therapeutic, sensing, and imaging potential are developed. It is also discovered that cancer cell targeted NPs in combination with static magnetic field can selectively induce cancer cell death. A multimodal caspase‐3 nanosensor is also developed for real‐time visualization of selective induction of apoptosis in cancer cells. In addition, the photothermal killing capability of these NPs in vitro is evaluated, and their potential for enhanced photothermal ablation in tissue samples is demonstrated. Building on current uses of implantable devices for therapeutic purposes, this study envisions the proposed micromagnet‐assisted NPs delivery approach may be used to accelerate the clinical translation of various nanoformulations.

more » « less
Author(s) / Creator(s):
 ;  ;  ;  ;  ;  
Publisher / Repository:
Wiley Blackwell (John Wiley & Sons)
Date Published:
Journal Name:
Advanced Healthcare Materials
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Abstract

    In treatment of hypoxic tumors, oxygen‐dependent photodynamic therapy (PDT) is considerably limited. Herein, a new bimetallic and biphasic Rh‐based core–shell nanosystem (Au@Rh‐ICG‐CM) is developed to address tumor hypoxia while achieving high PDT efficacy. Such porous Au@Rh core–shell nanostructures are expected to exhibit catalase‐like activity to efficiently catalyze oxygen generation from endogenous hydrogen peroxide in tumors. Coating Au@Rh nanostructures with tumor cell membrane (CM) enables tumor targeting via homologous binding. As a result of the large pores of Rh shells and the trapping ability of CM, the photosensitizer indocyanine green (ICG) is successfully loaded and retained in the cavity of Au@Rh‐CM. Au@Rh‐ICG‐CM shows good biocompatibility, high tumor accumulation, and superior fluorescence and photoacoustic imaging properties. Both in vitro and in vivo results demonstrate that Au@Rh‐ICG‐CM is able to effectively convert endogenous hydrogen peroxide into oxygen and then elevate the production of tumor‐toxic singlet oxygen to significantly enhance PDT. As noted, the mild photothermal effect of Au@Rh‐ICG‐CM also improves PDT efficacy. By integrating the superiorities of hypoxia regulation function, tumor accumulation capacity, bimodal imaging, and moderate photothermal effect into a single nanosystem, Au@Rh‐ICG‐CM can readily serve as a promising nanoplatform for enhanced cancer PDT.

    more » « less
  2. Transitional cell carcinoma of the bladder is particularly devastating due to its high rate of recurrence and difficulty in retention of treatments within the bladder. Current cystoscopic approaches to detect and stage the tumor are limited by the penetrative depth of the cystoscope light source, and intravesical dyes that highlight tumors for surgical resection are non-specific. To address the needs for improved specificity in tumor detection and follow-up, we report on a novel technology relying on the engineered core of mesoporous silica (MSN) with surface modifications that generate contrast in fluorescence and magnetic resonance imaging (MRI). The particle surface was further functionalized to include a bladder cancer cell specific peptide, Cyc6, identified via phage display. This peptide possesses nanomolar specificity for bladder cancer cells and homology across multiple species including mouse, canine, and human. Our study takes advantage of its target expression in bladder tumor which is not expressed in normal bladder wall. When functionalized to MSN, the Cyc6 improved binding efficiency and specificity for bladder cancer cells in vitro. In an in vivo model, MSN instilled into bladders of tumor-bearing mice enhanced T 1- and T 2-weighted MRI signals, improving the detection of the tumor boundaries. These findings support the notion that our targeted nanomaterial presents new options for early detection and eventual therapeutic intervention. Ultimately, the combination of real-time and repeated MRI evaluation of the tumors enhanced by nanoparticle contrast have the potential for translation into human clinical studies for tumor staging, therapeutic monitoring, and drug delivery. 
    more » « less

    Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of human malignancies. PDAC is characterized by dense fibrous stroma which obstructs drug delivery and plays complex tumor‐promoting roles. Photodynamic therapy (PDT) is a light‐based modality which has been demonstrated to be clinically feasible and effective for tumors of the pancreas. Here, we usein vitroheterocellular 3D co‐culture models in conjunction with imaging, bulk rheology and microrheology to investigate photodegradation of non‐cellular components of PDAC stroma (photodynamic stromal depletion, PSD). By measuring the rheology of extracellular matrix (ECM) before and after PDT we find that softening of ECM is concomitant with increased transport of nanoparticles (NPs). At the same time, as shown by us previously, photodestruction of stromal fibroblasts leads to enhanced tumor response to PDT. Here we specifically evaluate the capability of PSD to enhance RNA nanomedicine delivery, using a NP carrying an inhibitor of miR‐21‐5P, a PDAC oncomiR. We confirm improved delivery of this therapeutic NP after PSD by observation of increased expression of PDCD4, a protein target of miR‐21‐5P. Collectively, these results in 3D tumor models suggest that PSD could be developed to enhance delivery of other cancer therapeutics and improve tumor response to treatment.

    more » « less
  4. Abstract

    Tumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.

    more » « less
  5. Abstract

    Nanoparticle‐based nucleic acid conjugates (NP‐NACs) hold great promise for theragnostic applications. However, several limitations have hindered the realization of their full potential in the clinical treatment of cancer and other diseases. In diagnoses, NP‐NACs suffer from low signal‐to‐noise ratios, while the efficiency of NP‐NACs‐mediated cancer therapies has been limited by the adaptation of alternative prosurvival pathways in cancer cells. The recent emergence of personalized and precision medicine has outlined the importance of having both accurate diagnosis and efficient therapeutics in a single platform. As such, the controlled assembly of hybrid graphene oxide/gold nanoparticle (Au@GO NP)‐based cancer‐specific NACs (Au@GO NP‐NACs) for multimodal imaging and combined therapeutics is reported. The developed Au@GO NP‐NACs show excellent surface‐enhanced Raman scattering (SERS)‐mediated live‐cell cancer detection and multimodal synergistic cancer therapy through the use of photothermal, genetic, and chemotherapeutic strategies. Synergistic and selective killing of cancer cells are then demonstrated using in vitro microfluidic models. Moreover, with the distinctive advantages of the Au@GO NP‐NACs for cancer theragnostics, precision cancer treatment through the detection of cancer cells in vivo using SERS followed by efficient ablation of tumors is shown. Therefore, the Au@GO NP‐NACs can pave a new road for advanced disease theragnostics.

    more » « less