STAR-121: A Phase III Randomized Study of Domvanalimab and Zimberelimab in Combination With Chemotherapy Versus Pembrolizumab With Chemotherapy in Untreated Metastatic Non-Small Cell Lung Cancer With No Actionable Gene Alterations.

INTRODUCTION: Dual inhibition with a T-cell immunoreceptor with immunoglobulin and ITIM domains plus programmed death (ligand)-1 (PD[L]-1) inhibitors, with or without chemotherapy, is an emerging therapeutic strategy in metastatic non-small cell lung cancer (mNSCLC). The STAR-121 (NCT05502237) phase III, global, randomized, open-label study will investigate first-line domvanalimab (anti-TIGIT) and zimberelimab (anti-PD-1) plus chemotherapy versus pembrolizumab plus chemotherapy in mNSCLC with no actionable gene alterations. PARTICIPANTS AND METHODS: Approximately 720 participants (≥18 years old) with untreated mNSCLC and no EGFR and ALK mutations will be randomized into 3 groups (A, B, or C) in a 4:4:1 ratio and stratified by baseline PD-L1 expression (tumor cells <50% vs. ≥50%), histology (squamous vs. nonsquamous), and geographic region (East Asia vs. non-East Asia). Group A will receive domvanalimab 1200 mg plus zimberelimab 360 mg plus platinum-doublet chemotherapy (PT), group B will receive pembrolizumab 200 mg plus PT, and group C will receive zimberelimab 360 mg plus PT, every 3 weeks. Treatment will be administered until disease progression or intolerable toxicity. Dual primary endpoints are progression-free survival (by blinded independent central review [BICR]) and overall survival for group A versus B. Key secondary endpoints comprise overall response rate (by BICR), safety, and quality of life. Exploratory endpoints include efficacy and safety between groups A and C, pharmacokinetics, patient-reported outcomes, and biomarkers. CONCLUSION: Enrollment in the STAR-121 study commenced on October 12, 2022, and is currently ongoing with completion planned by September 2024. The study completion is expected by December 2027.

NaCl Nanoparticles as a Cancer Therapeutic.

Many inorganic nanoparticles are prepared and their behaviors in living systems are investigated. Yet, common electrolytes such as NaCl are left out of this campaign. The underlying assumption is that electrolyte nanoparticles will quickly dissolve in water and behave similarly as their constituent salts. Herein, this preconception is challenged. The study shows that NaCl nanoparticles (SCNPs) but not salts are highly toxic to cancer cells. This is because SCNPs enter cells through endocytosis, bypassing cell regulations on ion transport. When dissolved inside cancer cells, SCNPs cause a surge of osmolarity and rapid cell lysis. Interestingly, normal cells are much more resistant to the treatment due to their relatively low sodium levels. Unlike conventional chemotherapeutics, SCNPs cause immunogenic cell death or ICD. In vivo studies show that SCNPs not only kill cancer cells, but also boost an anticancer immunity. The discovery opens up a new perspective on nanoparticle-based therapeutics.

Protein-Adsorbed Magnetic-Nanoparticle-Mediated Assay for Rapid Detection of Bacterial Antibiotic Resistance.

Antibiotic susceptibility tests have been used for years as a crucial diagnostic tool against antibiotic-resistant bacteria. However, due to a lack of biomarkers specific to resistant types, these approaches are often time-consuming, inaccurate, and inflexible in drug selections. Here, we present a novel susceptibility test method named protein-adsorbed nanoparticle-mediated matrix-assisted laser desorption-ionization mass spectrometry, or PANMS. Briefly, we adsorb five different proteins (ß-casein, α-lactalbumin, human serum albumin, fibrinogen, and avidin) onto the surface of Fe3O4. Upon interaction with bacteria surface, proteins were displaced from the nanoparticle surface, the amounts of which were quantified by matrix-assisted laser desorption ionization mass spectrometry. We find that the protein displacement profile was different distinctive among different bacteria strains and, in particular, between wild-type and drug-resistant strains. More excitingly, we observe bacteria resistant to drugs of the same mechanisms share similar displacement profiles on a linear discriminant analysis (LDA) map. This suggests the possibility of using PANMS to identify the type of mechanism behind antibiotic resistance, which was confirmed in a blind test. Given that PANMS is free of drug incubation and the whole procedure takes less than 50 min, it holds great potential as a high-throughput, low-cost, and accurate drug susceptibility test in the clinic.

Red Blood Cell-Facilitated Photodynamic Therapy for Cancer Treatment.

Photodynamic therapy (PDT) is a promising treatment modality for cancer management. So far, most PDT studies have focused on delivery of photosensitizers to tumors. O2, another essential component of PDT, is not artificially delivered but taken from the biological milieu. However, cancer cells demand a large amount of O2 to sustain their growth and that often leads to low O2 levels in tumors. The PDT process may further potentiate the oxygen deficiency, and in turn, adversely affect the PDT efficiency. In the present study, a new technology called red blood cell (RBC)-facilitated PDT, or RBC-PDT, is introduced that can potentially solve the issue. As the name tells, RBC-PDT harnesses erythrocytes, an O2 transporter, as a carrier for photosensitizers. Because photosensitizers are adjacent to a carry-on O2 source, RBC-PDT can efficiently produce 1O2 even under low oxygen conditions. The treatment also benefits from the long circulation of RBCs, which ensures a high intraluminal concentration of photosensitizers during PDT and hence maximizes damage to tumor blood vessels. When tested in U87MG subcutaneous tumor models, RBC-PDT shows impressive tumor suppression (76.7%) that is attributable to the codelivery of O2 and photosensitizers. Overall, RBC-PDT is expected to find wide applications in modern oncology.

Casein-Coated Fe5C2 Nanoparticles with Superior r2 Relaxivity for Liver-Specific Magnetic Resonance Imaging.

Iron oxide nanoparticles have been extensively used as T2 contrast agents for liver-specific magnetic resonance imaging (MRI). The applications, however, have been limited by their mediocre magnetism and r2 relaxivity. Recent studies show that Fe5C2 nanoparticles can be prepared by high temperature thermal decomposition. The resulting nanoparticles possess strong and air stable magnetism, suggesting their potential as a novel type of T2 contrast agent. To this end, we improve the synthetic and surface modification methods of Fe5C2 nanoparticles, and investigated the impact of size and coating on their performances for liver MRI. Specifically, we prepared 5, 14, and 22 nm Fe5C2 nanoparticles and engineered their surface by: 1) ligand addition with phospholipids, 2) ligand exchange with zwitterion-dopamine-sulfonate (ZDS), and 3) protein adsorption with casein. It was found that the size and surface coating have varied levels of impact on the particles' hydrodynamic size, viability, uptake by macrophages, and r2 relaxivity. Interestingly, while phospholipid- and ZDS-coated Fe5C2 nanoparticles showed comparable r2, the casein coating led to an r2 enhancement by more than 2 fold. In particular, casein coated 22 nm Fe5C2 nanoparticle show a striking r2 of 973 mM(-1)s(-1), which is one of the highest among all of the T2 contrast agents reported to date. Small animal studies confirmed the advantage of Fe5C2 nanoparticles over iron oxide nanoparticles in inducing hypointensities on T2-weighted MR images, and the particles caused little toxicity to the host. The improvements are important for transforming Fe5C2 nanoparticles into a new class of MRI contrast agents. The observations also shed light on protein-based surface modification as a means to modulate contrast ability of magnetic nanoparticles.

Gd-encapsulated carbonaceous dots with efficient renal clearance for magnetic resonance imaging.

Nanoprobes for MRI and optical imaging are demonstrated. Gd@C-dots possess strong fluorescence and can effectively enhance signals on T1 -weighted MR images. The nanoprobes have low toxicity, and, despite a relatively large size, can be efficiently excreted by renal clearance from the host after systemic injection.

Ferritins as nanoplatforms for imaging and drug delivery.

INTRODUCTION: Due to unique architecture and surface properties, ferritin has emerged as an important class of biomaterial. Many studies suggest that ferritin and its derivatives hold great potential in a wide range of bio-applications. AREAS COVERED: In this review, we summarize recent progress on employing ferritins as a platform to construct functional nanoparticles for applications in MRI, optical imaging, cell tracking, and drug delivery. EXPERT OPINION: As a natural polymer, ferritins afford advantages such as high biocompatibility, good biodegradability, and a relatively long plasma half-life. These attributes put ferritins ahead of conventional materials in clinical translation for imaging and drug delivery purposes.

Tumor vasculature targeted photodynamic therapy for enhanced delivery of nanoparticles.

Delivery of nanoparticle drugs to tumors relies heavily on the enhanced permeability and retention (EPR) effect. While many consider the effect to be equally effective on all tumors, it varies drastically among the tumors' origins, stages, and organs, owing much to differences in vessel leakiness. Suboptimal EPR effect represents a major problem in the translation of nanomedicine to the clinic. In the present study, we introduce a photodynamic therapy (PDT)-based EPR enhancement technology. The method uses RGD-modified ferritin (RFRT) as "smart" carriers that site-specifically deliver (1)O2 to the tumor endothelium. The photodynamic stimulus can cause permeabilized tumor vessels that facilitate extravasation of nanoparticles at the sites. The method has proven to be safe, selective, and effective. Increased tumor uptake was observed with a wide range of nanoparticles by as much as 20.08-fold. It is expected that the methodology can find wide applications in the area of nanomedicine.

Iron oxide nanoparticle encapsulated diatoms for magnetic delivery of small molecules to tumors.

Small molecules can be co-loaded with iron oxide nanoparticles onto diatoms. With an external magnetic field, the diatoms, after systemic administration, can be attracted to tumors. This study suggests a great potential of diatoms as a novel and powerful therapeutic vehicle.

Fe5C2 nanoparticles with high MRI contrast enhancement for tumor imaging.

An ancient material for magnetic resonance (MR) imaging: For the first time, Fe5C2 is prepared as colloidal stable nanoparticles with good aqueous stability. The nanoparticles boast strong magnetization, excellent chemical inertness, low toxicity, and one of the highest r2 relaxivities reported to date. These nanoparticles hold great potential in MR imaging as well as in other biomedical areas.

Label-free luminescent mesoporous silica nanoparticles for imaging and drug delivery.

We report herein a straightforward and label-free approach to prepare luminescent mesoporous silica nanoparticles. We found that calcination at 400 °C can grant mesoporous organosilica nanoparticles with strong fluorescence of great photo- and chemical stability. The luminescence is found to originate from the carbon dots generated from the calcination, rather than the defects in the silica matrix as was believed previously. The calcination does not impact the particles' abilities to load drugs and conjugate to biomolecules. In a proof-of-concept study, we demonstrated that doxorubicin (Dox) can be efficiently encapsulated into these fluorescent mesoporous silica nanoparticles. After coupled to c(RGDyK), the nanoconjugates can efficiently home to tumors through interactions with integrin αvß3 overexpressed on the tumor vasculature. This calcination-induced luminescence is expected to find wide applications in silica-based drug delivery, nanoparticle coating, and immunofluorescence imaging.

Nanoparticles for Improving Cancer Diagnosis.

Despite the progress in developing new therapeutic modalities, cancer remains one of the leading diseases causing human mortality. This is mainly attributed to the inability to diagnose tumors in their early stage. By the time the tumor is confirmed, the cancer may have already metastasized, thereby making therapies challenging or even impossible. It is therefore crucial to develop new or to improve existing diagnostic tools to enable diagnosis of cancer in its early or even pre-syndrome stage. The emergence of nanotechnology has provided such a possibility. Unique physical and physiochemical properties allow nanoparticles to be utilized as tags with excellent sensitivity. When coupled with the appropriate targeting molecules, nanoparticle-based probes can interact with a biological system and sense biological changes on the molecular level with unprecedented accuracy. In the past several years, much progress has been made in applying nanotechnology to clinical imaging and diagnostics, and interdisciplinary efforts have made an impact on clinical cancer management. This article aims to review the progress in this exciting area with emphases on the preparation and engineering techniques that have been developed to assemble "smart" nanoprobes.

RGD-modified apoferritin nanoparticles for efficient drug delivery to tumors.

Ferritin (FRT) is a major iron storage protein found in humans and most living organisms. Each ferritin is composed of 24 subunits, which self-assemble to form a cage-like nanostructure. FRT nanocages can be genetically modified to present a peptide sequence on the surface. Recently, we demonstrated that Cys-Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys (RGD4C)-modified ferritin can efficiently home to tumors through RGD-integrin αvß3 interaction. Though promising, studies on evaluating surface modified ferritin nanocages as drug delivery vehicles have seldom been reported. Herein, we showed that after being precomplexed with Cu(II), doxorubicin can be loaded onto RGD modified apoferritin nanocages with high efficiency (up to 73.49 wt %). When studied on U87MG subcutaneous tumor models, these doxorubicin-loaded ferritin nanocages showed a longer circulation half-life, higher tumor uptake, better tumor growth inhibition, and less cardiotoxicity than free doxorubicin. Such a technology might be extended to load a broad range of therapeutics and holds great potential in clinical translation.