Biology subjects

Patel, N. L.

Publications and source records attributed to Patel, N. L..

3 recordsLinked to original sources

bioRxiv2025

PEGylation strategies for enhanced nanoparticle delivery to tumor associated immune cells

Barriers to nanoparticle drug delivery to the tumor microenvironment such as ECM deposition and clearance by the mononuclear phagocyte system have necessitated strategies for more effective tumor penetration. Adding polyethylene glycol (PEG) chains to the surface of nanoparticles (PEGylation) has been widely used to both enhance accumulation at the tumor site and increase blood circulation time. Recent work has also shown that immune cells (e.g. macrophages, dendritic cells, neutrophils) play an important role in the ability of NPs to effectively target and spread within a tumor. PEG chain characteristics such as size and branching affects how nanoparticles interact with tissues; however, it is unclear how PEGylation type affects NP uptake and cellular distribution in the tumor microenvironment. In this study, we evaluated the influence of both linear and branched PEGylation on nanoparticle biodistribution and uptake in tumor cells as well as tumor-infiltrating immune cells. As compared to conventional surface coatings with linear PEG, we show that modifying PEG structure to a branched conformation increases nanoparticle accumulation in the spleen of tumor-bearing mice, primarily due to significantly enhanced uptake by leukocytes. As compared to uncoated particles, we also found that nanoparticles densely coated with linear or branched PEG accumulated to a greater extent in tumors showing [≥]8-fold increases in uptake by tumor-associated macrophages and dendritic cells. These studies provide insight into PEG architecture as a design parameter in nanomedicine that can facilitate the design of more effective cancer therapies. Translational ImpactThis work uncovers immune-mediated mechanisms and design strategies to enhance NP delivery to tumors via PEGylation which provide a foundation for clinical development of cancer therapeutics. The PEGylation strategies described could be readily integrated into clinically relevant nanoparticle delivery systems (e.g. lipid nanoparticles) with minimal effort making this a highly appealing approach to address the current limitations of cancer nanomedicine.

bioengineering↗

bioRxiv2025

Granzyme-targeting quenched activity-based probes for assessing tumor response to immunotherapy

Molecular imaging of immune activation holds tremendous potential for the development of novel immunotherapy. In particular, chemical probes capable of detecting immune responses before changes in tumor size occur can guide early therapeutic strategies. Here, we present quenched activity-based probes targeting granzymes as a biomarker of antitumor immunity. Through optimization of peptide recognition element and functional chemical warhead, we have developed an optical imaging probe Cy5-IEPCyaPhP-QSY21, which rapidly reacts with GzmB at substoichiometric concentrations and enables efficient, selective labeling of the active enzyme in a complex proteome. With high specificity and minimal background signal, this probe produces GzmB-induced near-infrared fluorescence signals in the tumors of living mice shortly after injection. Both in vivo and ex vivo fluorescence signals correlate with GzmB expression and activity, and the population of CD8+ cells in tumor tissues. Moreover, it demonstrates the potential to track tumor response to immunotherapy. Thus, this study offers a chemical tool for assessing immune-mediated anticancer activity using noninvasive optical imaging. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/643086v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1bff748org.highwire.dtl.DTLVardef@3c80dorg.highwire.dtl.DTLVardef@4301ceorg.highwire.dtl.DTLVardef@12b7c8a_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Metastatic organotropism in small cell lung cancer

Metastasis is the leading cause of cancer-related deaths, yet its regulatory mechanisms are not fully understood. Small-cell lung cancer (SCLC) is the most metastatic form of lung cancer, with most patients presenting with widespread disease, making it an ideal model for studying metastasis. However, the lack of suitable preclinical models has limited such studies. We utilized rapid autopsy-derived tumors to develop xenograft models that mimic key features of SCLC, including histopathology, rapid and widespread development of metastasis to the liver, brain, adrenal, bone marrow, and kidneys within weeks, and response to chemotherapy. By integrating in vivo lineage selection with comprehensive bulk and single cell multiomic profiling of transcriptomes and chromatin accessibility, we identified critical cellular programs driving metastatic organotropism to the liver and brain, the most common sites of SCLC metastasis. Our findings reveal the key role of nuclear-cytoskeletal interactions in SCLC liver metastasis. Specifically, the loss of the nuclear envelope protein lamin A/C, encoded by the LMNA gene, increased nuclear deformability and significantly increased the incidence of liver metastasis. Human liver metastases exhibited reduced LMNA expression compared to other metastatic sites, correlating with poorer patient outcomes and increased mortality. This study introduces novel preclinical models for SCLC metastasis and highlights pathways critical for organ-specific metastasis, offering new avenues for the development of targeted therapies to prevent or treat metastatic disease.

cancer biology↗