MRI Detection of Lymph Node Metastasis through Molecular Targeting of C-C Chemokine Receptor Type 2 and Monocyte Hitchhiking.

Biopsy is the clinical standard for diagnosing lymph node (LN) metastasis, but it is invasive and poses significant risk to patient health. Magnetic resonance imaging (MRI) has been utilized as a noninvasive alternative but is limited by low sensitivity, with only ∼35% of LN metastases detected, as clinical contrast agents cannot discriminate between healthy and metastatic LNs due to nonspecific accumulation. Nanoparticles targeted to the C-C chemokine receptor 2 (CCR2), a biomarker highly expressed in metastatic LNs, have the potential to guide the delivery of contrast agents, improving the sensitivity of MRI.

Spotlight on Genetic Kidney Diseases: A Call for Drug Delivery and Nanomedicine Solutions.

Nanoparticles as drug delivery carriers have benefited diseases, including cancer, since the 1990s, and more recently, their promise to quickly and efficiently be mobilized to fight against global diseases such as in the COVID-19 pandemic have been proven. Despite these success stories, there are limited nanomedicine efforts for chronic kidney diseases (CKDs), which affect 844 million people worldwide and can be linked to a variety of genetic kidney diseases. In this Perspective, we provide a brief overview of the clinical status of genetic kidney diseases, background on kidney physiology and a summary of nanoparticle design that enable kidney access and targeting, and emerging technological strategies that can be applied for genetic kidney diseases, including rare and congenital kidney diseases.

CD70-Targeted Micelles Enhance HIF2α siRNA Delivery and Inhibit Oncogenic Functions in Patient-Derived Clear Cell Renal Carcinoma Cells.

The majority of clear cell renal cell carcinomas (ccRCCs) are characterized by mutations in the Von Hippel−Lindau (VHL) tumor suppressor gene, which leads to the stabilization and accumulation of the HIF2α transcription factor that upregulates key oncogenic pathways that promote glucose metabolism, cell cycle progression, angiogenesis, and cell migration. Although FDA-approved HIF2α inhibitors for treating VHL disease-related ccRCC are available, these therapies are associated with significant toxicities such as anemia and hypoxia. To improve ccRCC-specific drug delivery, peptide amphiphile micelles (PAMs) were synthesized incorporating peptides targeted to the CD70 marker expressed by ccRCs and anti-HIF2α siRNA, and the ability of HIF2α-CD27 PAMs to modulate HIF2α and its downstream targets was evaluated in human ccRCC patient-derived cells.

Immunization using ApoB-100 peptide-linked nanoparticles reduces atherosclerosis.

Active immunization with the apolipoprotein B-100 (ApoB-100) peptide P210 reduces experimental atherosclerosis. To advance this immunization strategy to future clinical testing, we explored the possibility of delivering P210 as an antigen using nanoparticles, given this approach has been used clinically. We first characterized the responses of T cells to P210 using PBMCs from patients with atherosclerotic cardiovascular disease (ASCVD).

Overcoming physiological barriers by nanoparticles for intravenous drug delivery to the lymph nodes.

The lymph nodes are major sites of cancer metastasis and immune activity, and thus represent important clinical targets. Although not as well-studied compared to subcutaneous administration, intravenous drug delivery is advantageous for lymph node delivery as it is commonly practiced in the clinic and has the potential to deliver therapeutics systemically to all lymph nodes. However, rapid clearance by the mononuclear phagocyte system, tight junctions of the blood vascular endothelium, and the collagenous matrix of the interstitium can limit the efficiency of lymph node drug delivery, which has prompted research into the design of nanoparticle-based drug delivery systems.

CCR2-targeted micelles for anti-cancer peptide delivery and immune stimulation.

Signaling between the CC chemokine receptor 2 (CCR2) with its ligand, monocyte chemoattractant protein-1 (MCP-1) promotes cancer progression by directly stimulating tumor cell proliferation and downregulating the expression of apoptotic proteins. Additionally, the MCP-1/CCR2 signaling axis drives the migration of circulating monocytes into the tumor microenvironment, where they mature into tumor-associated macrophages (TAMs) that promote disease progression through induction of angiogenesis, tissue remodeling, and suppression of the cytotoxic T lymphocyte (CTL) response. In order to simultaneously disrupt MCP-1/CCR2 signaling and target CCR2-expressing cancer cells for drug delivery, KLAK-MCP-1 micelles consisting of a CCR2-targeting peptide sequence (MCP-1 peptide) and the apoptotic KLAKLAK peptide were synthesized.

Collagenase-Cleavable Peptide Amphiphile Micelles as a Novel Theranostic Strategy in Atherosclerosis.

Atherosclerosis is an inflammatory disease characterized by plaques that can cause sudden myocardial infarction upon rupture. Such rupture-prone plaques have thin fibrous caps due to collagenase degradation, and a noninvasive diagnostic tool and targeted therapy that can identify and treat vulnerable plaques and may inhibit the onset of acute cardiac events. Toward this goal, monocyte-binding, collagenase-inhibiting, and gadolinium-modified peptide amphiphile micelles (MCG PAMs) are developed.

Peptide-based targeting of immunosuppressive cells in cancer.

Cancer progression is marked by the infiltration of immunosuppressive cells, such as tumor-associated macrophages (TAMs), regulatory T lymphocytes (Tregs), and myeloid-derived suppressor cells (MDSCs). These cells play a key role in abrogating the cytotoxic T lymphocyte-mediated (CTL) immune response, allowing tumor growth to proceed unabated. Furthermore, targeting these immunosuppressive cells through the use of peptides and peptide-based nanomedicine has shown promising results.