Mohan Pauliah

Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth

The design of cancer-targeting particles with precisely-tuned physiocochemical properties may enhance delivery of therapeutics and access to pharmacological targets. However, molecular level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (< 10 nm in diameter) poly(ethylene glycol) (PEG)-coated silica nanoparticles, functionalized with melanoma-targeting peptides, can induce a form of programmed cell death known as ferroptosis in starved cancer cells and cancer-bearing mice. Tumor xenografts in mice intravenously injected with nanoparticles using a high-dose multiple injection scheme exhibit reduced growth or regression, in a manner that is reversed by the pharmacological inhibitor of ferroptosis, liproxstatin-1. These data demonstrate that ferroptosis can be targeted by ultrasmall silica nanoparticles and may have therapeutic potential.

Intraoperative mapping of sentinel lymph node metastases using a clinically translated ultrasmall silica nanoparticle.

The management of regional lymph nodes in patients with melanoma has undergone a significant paradigm shift over the past several decades, transitioning from the use of more aggressive surgical approaches, such as lymph node basin dissection, to the application of minimally invasive sentinel lymph node (SLN) biopsy methods to detect the presence of nodal micrometastases. SLN biopsy has enabled reliable, highly accurate, and low-morbidity staging of regional lymph nodes in early stage melanoma as a means of guiding treatment decisions and improving patient outcomes. The accurate identification and staging of lymph nodes is an important prognostic factor, identifying those patients for whom the expected benefits of nodal resection outweigh attendant surgical risks. However, currently used standard-of-care technologies for SLN detection are associated with significant limitations. This has fueled the development of clinically promising platforms that can serve as intraoperative visualization tools to aid accurate and specific determination of tumor-bearing lymph nodes, map cancer-promoting biological properties at the cellular/molecular levels, and delineate nodes from adjacent critical structures. Among a number of promising cancer-imaging probes that might facilitate achievement of these ends is a first-in-kind ultrasmall tumor-targeting inorganic (silica) nanoparticle, designed to overcome translational challenges. The rationale driving these considerations and the application of this platform as an intraoperative treatment tool for guiding resection of cancerous lymph nodes is discussed and presented within the context of alternative imaging technologies. WIREs Nanomed Nanobiotechnol 2016, 8:535-553. doi: 10.1002/wnan.1380 For further resources related to this article, please visit the WIREs website.

Tumor-associated macrophages, nanomedicine and imaging: the axis of success in the future of cancer immunotherapy

The success of any given cancer immunotherapy relies on several key factors. In particular, success hinges on the ability to stimulate the immune system in a controlled and precise fashion, select the best treatment options and appropriate therapeutic agents, and use highly effective tools to accurately and efficiently assess the outcome of the immunotherapeutic intervention. Furthermore, a deep understanding and effective utilization of tumor-associated macrophages (TAMs), nanomedicine and biomedical imaging must be harmonized to improve treatment efficacy. Additionally, a keen appreciation of the dynamic interplay that occurs between immune cells and the tumor microenvironment (TME) is also essential. New advances toward the modulation of the immune TME have led to many novel translational research approaches focusing on the targeting of TAMs, enhanced drug and nucleic acid delivery, and the development of theranostic probes and nanoparticles for clinical trials. In this review, we discuss the key cogitations that influence TME, TAM modulations and immunotherapy in solid tumors as well as the methods and resources of tracking the tumor response. The vast array of current nanomedicine technologies can be readily modified to modulate immune function, target specific cell types, deliver therapeutic payloads and be monitored using several different imaging modalities. This allows for the development of more effective treatments, which can be specifically designed for particular types of cancer or on an individual basis. Our current capacities have allowed for greater use of theranostic probes and multimodal imaging strategies that have led to better image contrast, real-time imaging capabilities leveraging targeting moieties, tracer kinetics and enabling more detailed response profiles at the cellular and molecular levels. These novel capabilities along with new discoveries in cancer biology should drive innovation for improved biomarkers for efficient and individualized cancer therapy.

Ultrasmall Fluorescent Silica Nanoparticles as Intraoperative Imaging Tools for Cancer Diagnosis and Treatment

The ability to sensitively and specifically map biological events that promote cancer at the cellular and molecular levels utilizing particle-based probes may allow the timely stratification of patients to appropriate treatment arms, potentially improving patient quality of life and survival. Probing critical cancer targets may elucidate important insights into biological processes governing cancer progression, metastatic potential, and invasion. Lymph node metastases are a powerful predictor of outcome for melanoma. The earlier detection of micrometastatic disease within the sentinel lymph node (SLN) and/or other regional nodes utilizing a combination of intraoperative optical visualization tools may offer a distinct advantage over standard-of-care agents, particularly in anatomically complex areas of the body. This chapter will discuss the real-time surgical application of clinically translated ultrasmall tumor-directed core-shell silica nanoparticles, Cornell dots (or C dots), as a dual-modality (optical-PET) platform for mapping metastatic nodal spread using a handheld fluorescence camera system. The opportunity to combine the foregoing technologies with new image-driven metrics and informatics tools may potentially improve patient outcome measures by enabling a more predictive medicine to be implemented in clinical practice.

Chapter 11 – Cancer Therapy

Over the last two decades, iron oxide nanoparticles have demonstrated great progress and potential for use in oncological medicine. Due to their overall utility for a vast number of applications, iron oxides have been extensively investigated. This type of nanoparticle has numerous desirable properties such as facile synthesis, ease of functionalization, favorable magnetic characteristics, and biocompatible and biodegradable and is generally considered safe. Cancer therapy has already benefited in a number areas from the use of iron oxide nanoparticles in such areas as cancer imaging, a variety of therapeutic approaches including immunotherapy, cell tracking and monitoring, improved efficacy, and safety. While several forms of magnetite-based nanoparticle formulations are FDA approved as either magnetic resonance imaging (MRI) contrast agents or iron-deficiency therapeutics, there are still a number of other applications that these nanoparticles can be used for. Iron oxide nanoparticles can come in a number of shapes, sizes, and composition and can have modifiable coatings with targeting molecules such as antibodies, peptides, and small molecules. These surface moieties can improve tumor-targeting capabilities, while the nanoparticle itself can allow for monitoring by MRI and even optical methods depending on the modifications used and intended applications. Other potential cancer applications include improved delivery of cancer therapeutics, magnetic hypothermia, photothermal ablation, personalized medicine approaches, and photodynamic therapy. These approaches can result in multifunctional and/or theranostic nanoparticles suitable for diagnosis, treatment, and treatment monitoring of cancer.

Chapter 9 – Drug Delivery

Iron oxide nanoparticles have been approved for many biomedical applications, because of their ultrafine size, biocompatibility, and superparamagnetic properties. Superparamagnetic iron oxide nanoparticles (SPIONs), in conjunction with external magnetic fields, enable particles to be delivered to the desired target site and keep them at the site during drug release to act locally. Therefore, this combination decreases the medication dosage and minimizes the drugs systemic effect. The potential for SPION applications has grown substantially in recent years. Following new advancements, these nanoparticles have been extensively used as delivery systems for drugs, genes, and radionuclides in clinical medicine. Here, we discuss the role of iron oxide nanoparticles in drug delivery and passive and active drug targeting systems.

Chapter 10 – Tumor-Targeted Therapy

Abstract With the increase in cancer incidences, developments of precise diagnostic and therapeutic methods have gained further significance. Iron oxide nanoparticles have been used as targeted cancer therapy agents and contrast enhancement agents for targeted cancer diagnosis. In this chapter, we discuss the applications of iron oxide nanoparticles for targeted tumor therapy and as multimodal imaging contrast agents.