New therapies that challenge existing paradigms are needed for the treatment of cancer. We report a nanoparticle-enabled therapeutic approach to B-cell lymphoma using synthetic high density lipoprotein nanoparticles (HDL-NPs). HDL-NPs are synthesized using a gold nanoparticle template to control conjugate size and ensure a spherical shape. Like natural HDLs, biomimetic HDL-NPs target scavenger receptor type B-1, a high-affinity HDL receptor expressed by lymphoma cells. Functionally, compared with natural HDL, the gold NP template enables differential manipulation of cellular cholesterol flux in lymphoma cells, promoting cellular cholesterol efflux and limiting cholesterol delivery. This combination of scavenger receptor type B-1 binding and relative cholesterol starvation selectively induces apoptosis. HDL-NP treatment of mice bearing B-cell lymphoma xenografts selectively inhibits B-cell lymphoma growth. As such, HDL-NPs are biofunctional therapeutic agents, whose mechanism of action is enabled by the presence of a synthetic nanotemplate. HDL-NPs are active in B-cell lymphomas and potentially, other malignancies or diseases of pathologic cholesterol accumulation.nanotechnology | therapy | biologic

Lipoproteins are a set of natural nanoparticles whose main role is the transport of fats within the body. While much work has been done to develop synthetic nanocarriers to deliver drugs or contrast media, natural nanoparticles such as lipoproteins represent appealing alternatives. Lipoproteins are biocompatible, biodegradable, non-immunogenic and are naturally targeted to some disease sites. Lipoproteins can be modified to act as contrast agents in many ways, such as by insertion of gold cores to provide contrast for computed tomography. They can be loaded with drugs, nucleic acids, photosensitizers or boron to act as therapeutics. Attachment of ligands can re-route lipoproteins to new targets. These attributes render lipoproteins attractive and versatile delivery vehicles. In this review we will provide background on lipoproteins, then survey their roles as contrast agents, in drug and nucleic acid delivery, as well as in photodynamic therapy and boron neutron capture therapy.

Cancer cells have altered metabolism and, in some cases, an increased demand for cholesterol. It is important to identify novel, rational treatments based on biology, and cellular cholesterol metabolism as a potential target for cancer is an innovative approach. Toward this end, we focused on diffuse large B-cell lymphoma (DLBCL) as a model because there is differential cholesterol biosynthesis driven by B-cell receptor (BCR) signaling in germinal center (GC) versus activated B-cell (ABC) DLBCL. To specifically target cellular cholesterol homeostasis, we employed high-density lipoprotein-like nanoparticles (HDL NP) that can generally reduce cellular cholesterol by targeting and blocking cholesterol uptake through the high-affinity HDL receptor, scavenger receptor type B-1 (SCARB1). As we previously reported, GC DLBCL are exquisitely sensitive to HDL NP as monotherapy while ABC DLBCL are less sensitive. Herein, we report that enhanced BCR signaling and resultant de novo cholesterol synthesis in ABC DLBCL drastically reduces the ability of HDL NPs to reduce cellular cholesterol and induce cell death. Therefore, we combined HDL NP with the BCR signaling inhibitor ibrutinib and the SYK inhibitor R406. By targeting both cellular cholesterol uptake and BCR-associated de novo cholesterol synthesis, we achieved cellular cholesterol reduction and induced apoptosis in otherwise resistant ABC DLBCL cell lines. These results in lymphoma demonstrate that reduction of cellular cholesterol is a powerful mechanism to induce apoptosis. Cells rich in cholesterol require HDL NP therapy to reduce uptake and molecularly targeted agents that inhibit upstream pathways that stimulate de novo cholesterol synthesis, thus, providing a new paradigm for rationally targeting cholesterol metabolism as therapy for cancer.

Purpose of review The purpose of this review is to summarize the most recent pre-clinical and clinical advancements in therapeutic nano-oncology. Recent findings First generation nanotherapies are well-tolerated in humans and evidence shows that they are efficacious while at the same time reducing the burden of side effects. Most of these therapies are not specifically targeted but take advantage of enhanced passive accumulation within tumors to preferentially deliver chemotherapies that are toxic when systemically administered. Actively targeted nanotherapies are entering the clinical arena and preliminary data are encouraging. Finally, a number of exciting pre-clinical developments in nanotechnology provide clear evidence that nanotherapies will continue to find their way into the clinic and will have a significant impact in oncology. Summary A number of intriguing nanoparticle therapies are being tested in pre-clinical and clinical trials. Nanoparticles with increasing molecular sophistication, specific targeting properties, and unique mechanisms-of-action will find their way to the clinic. Certainly, nanoparticle-based therapies will be increasingly represented in drug development pipelines, and will continue to provide efficacious and safe drug options for patients with cancer.

We report the development of potential theranostic agents for cardiovascular disease that are based on high-density lipoprotein-like magnetic nanostructures (HDL-MNS). The HDL-MNS offer prospects for diagnosis via noninvasive magnetic resonance imaging for anatomic detection and also serve as effective cholesterol efflux agents to address atherosclerotic vascular lesions. The HDL-MNS are synthesized by adding phospholipids and the HDL-defining apolipoprotein A1 to the surface of magnetic nanostructures (MNS) to mimic some aspects of natural HDL particles. From a diagnostic perspective, HDL-MNS show a 5 times higher contrast (r 2 relaxivity up to 383 mM–1 s–1) in magnetic resonance imaging (MRI) than commercially available T2 MRI contrast agents (e.g., Ferumoxytol). Internalization of HDL-MNS by macrophage cells was confirmed by transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDX), inductive-coupled plasma mass spectrometry (ICP-MS), and successfully imaged via MRI. Also, the HDL-MNS particles show capacity to induce cholesterol efflux (∼4.8%) from macrophage cells comparable to natural HDL (∼4.7%), providing a pathway to prevent and treat cardiovascular disease via reverse cholesterol transport. The ability to image macrophage cells that have internalized HDL-MNS along with the cholesterol efflux capacity demonstrates the potential of the HDL-MNS particles as theranostic agents.