Nanotechnology Applications in Breast Cancer Immunotherapy.

Next-generation cancer treatments are expected not only to target cancer cells but also to simultaneously train immune cells to combat cancer while modulating the immune-suppressive environment of tumors and hosts to ensure a robust and lasting response. Achieving this requires carriers that can codeliver multiple therapeutics to the right cancer and/or immune cells while ensuring patient safety. Nanotechnology holds great potential for addressing these challenges.

Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment.

Immune checkpoint inhibitors (ICIs) targeting PD-L1 and PD-1 have improved survival in a subset of patients with advanced non-small cell lung cancer (NSCLC). However, only a minority of NSCLC patients respond to ICIs, highlighting the need for superior immunotherapy. Herein, we report on a nanoparticle-based immunotherapy termed ARAC (Antigen Release Agent and Checkpoint Inhibitor) designed to enhance the efficacy of PD-L1 inhibitor.

Targeted Nanoparticle for Co-delivery of HER2 siRNA and a Taxane to Mirror the Standard Treatment of HER2+ Breast Cancer: Efficacy in Breast Tumor and Brain Metastasis.

The first-line treatment of advanced and metastatic human epidermal growth factor receptor type 2 (HER2+) breast cancer requires two HER2-targeting antibodies (trastuzumab and pertuzumab) and a taxane (docetaxel or paclitaxel). The three-drug regimen costs over $320,000 per treatment course, requires a 4 h infusion time, and has many adverse side effects, while achieving only 18 months of progression-free survival. To replace this regimen, reduce infusion time, and enhance efficacy, a single therapeutic is developed based on trastuzumab-conjugated nanoparticles for co-delivering docetaxel and siRNA against HER2 (siHER2).

In Situ Tumor Vaccination with Nanoparticle Co-Delivering CpG and STAT3 siRNA to Effectively Induce Whole-Body Antitumor Immune Response.

The success of immunotherapy with immune checkpoint inhibitors (ICIs) in a subset of individuals has been very exciting. However, in many cancers, responses to current ICIs are modest and are seen only in a small subsets of patients. Herein, a widely applicable approach that increases the benefit of ICIs is reported.

Augmenting the therapeutic window of radiotherapy: A perspective on molecularly targeted therapies and nanomaterials.

Radiation therapy is a cornerstone of modern cancer therapy alongside surgery, chemotherapy, and immunotherapy, with over half of all cancer patients receiving radiation therapy as part of their treatment regimen. Development of novel radiation sensitizers that can improve the therapeutic window of radiation therapy are sought after, particularly for tumors at an elevated risk of local and regional recurrence such as locally-advanced lung, head and neck, and gastrointestinal tumors. This review discusses clinical strategies to enhance radiotherapy efficacy and decrease toxicity, hence, increasing the overall therapeutic window.

PLK1 and EGFR targeted nanoparticle as a radiation sensitizer for non-small cell lung cancer.

Radiation sensitizers that can selectively act on cancer cells hold great promise to patients who receive radiation therapy. We developed a novel targeted therapy and radiation sensitizer for non-small cell lung cancer (NSCLC) based on cetuximab conjugated nanoparticle that targets epidermal growth factor receptor (EGFR) and delivers small interfering RNA (siRNA) against polo-like kinase 1 (PLK1). EGFR is overexpressed in 50% of lung cancer patients and a mediator of DNA repair, while PLK1 is a key mitotic regulator whose inhibition enhances radiation sensitivity.

Lanthanide-Loaded Nanoparticles as Potential Fluorescent and Mass Probes for High-Content Protein Analysis.

Multiparametric and high-content protein analysis of single cells or tissues cannot be accomplished with the currently available flow cytometry or imaging techniques utilizing fluorophore-labelled antibodies, because the number of spectrally resolvable fluorochromes is limited. In contrast, mass cytometry can resolve more signals by exploiting lanthanide-tagged antibodies; however, only about 100 metal reporters can be attached to an antibody molecule. This makes the sensitivity of lanthanide-tagged antibodies substantially lower than fluorescent reporters.

Removal of a gadolinium based contrast agent by a novel sorbent hemoperfusion in a chronic kidney disease (CKD) rodent model.

Gadolinium based contrast agents (GBCAs) have been linked to toxicity in patients, regardless of having impaired or normal renal function. Currently, no therapy is considered highly effective for removing gadolinium (Gd) from the body. We propose a new strategy to reduce blood Gd content that facilitates whole body removal of Gd using a hemoperfusion system consisting of a cartridge of porous silica beads (Davisil®) functionalized with 1,2-hydroxypyridinone (1,2-HOPO).

Lyophilization and stability of antibody-conjugated mesoporous silica nanoparticle with cationic polymer and PEG for siRNA delivery.

Introduction: Long-term stability of therapeutic candidates is necessary toward their clinical applications. For most nanoparticle systems formulated in aqueous solutions, lyophilization or freeze-drying is a common method to ensure long-term stability. While lyophilization of lipid, polymeric, or inorganic nanoparticles have been studied, little has been reported on lyophilization and stability of hybrid nanoparticle systems, consisting of polymers, inorganic particles, and antibody.

Lack of acquired resistance in HER2-positive breast cancer cells after long-term HER2 siRNA nanoparticle treatment.

Intrinsic and acquired resistance to current HER2 targeted therapies remains a challenge in clinics. We have developed a therapeutic HER2 siRNA delivered using mesoporous silica nanoparticles modified with polymers and conjugated with HER2 targeting antibodies. Our previous studies have shown that our HER2 siRNA nanoparticles could overcome intrinsic and acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancers.

Targeted Treatment of Metastatic Breast Cancer by PLK1 siRNA Delivered by an Antioxidant Nanoparticle Platform.

Metastatic breast cancer is developed in about 20% to 30% of newly diagnosed patients with early-stage breast cancer despite treatments. Herein, we report a novel nanoparticle platform with intrinsic antimetastatic properties for the targeted delivery of Polo-like kinase 1 siRNA (siPLK1). We first evaluated it in a triple-negative breast cancer (TNBC) model, which shows high metastatic potential.

Current development of targeted oligonucleotide-based cancer therapies: Perspective on HER2-positive breast cancer treatment.

This Review discusses the various types of non-coding oligonucleotides, which have garnered extensive interest as new alternatives for targeted cancer therapies over small molecule inhibitors and monoclonal antibodies. These oligonucleotides can target any hallmark of cancer, no longer limited to so-called "druggable" targets. Thus, any identified gene that plays a key role in cancer progression or drug resistance can be exploited with oligonucleotides.

Therapeutic siRNA for drug-resistant HER2-positive breast cancer.

HER2 is overexpressed in about 20% of breast cancers and contributes to poor prognosis. Unfortunately, a large fraction of patients have primary or acquired resistance to the HER2-targeted therapy trastuzumab, thus a multi-drug combination is utilized in the clinic, putting significant burden on patients. We systematically identified an optimal HER2 siRNA from 76 potential sequences and demonstrated its utility in overcoming intrinsic and acquired resistance to trastuzumab and lapatinib in 18 HER2-positive cancer cell lines.

Cationic Polymer Modified Mesoporous Silica Nanoparticles for Targeted SiRNA Delivery to HER2+ Breast Cancer.

delivery of siRNAs designed to inhibit genes important in cancer and other diseases continues to be an important biomedical goal. We now describe a new nanoparticle construct that has been engineered for efficient delivery of siRNA to tumors. The construct is comprised of a 47-nm mesoporous silica nanoparticle (MSNP) core coated with a cross-linked PEI-PEG copolymer, carrying siRNA against the HER2 oncogene, and coupled to the anti-HER2 monoclonal antibody (trastuzumab).