{"doi":"10.1093/lifemedi/lnae039","title":"Targeted delivery of a cationic dendrimer with a plaque-homing peptide for the treatment of atherosclerosis","abstract":"Dear Editor, Cardiovascular diseases (CVDs) lead to mortality across the globe, and atherosclerosis represents a major force in driving CVD-associated deaths. Atherosclerosis develops as fatty streaks accumulate along arterial walls, a process initiated by elevated levels of circulating cholesterol, particularly apolipoprotein B-containing lipoproteins. This excess cholesterol leads to the recruitment of macrophages, which engulf lipids, transform into foam cells, and deposit in the inner arterial lining [1]. Currently, lipid-lowering agents like statins and PCSK9 inhibitors are the primary drugs used to reduce the risk of atherosclerosis progression. However, atherosclerosis is increasingly appreciated as a chronic immune disorder ridden with plaque and systemic inflammation. Consequently, there is a growing interest in exploring anti-inflammatory or immunomodulating therapies, although these treatments pose the risk of systemic immunosuppression [1, 2]. Nanomedicine is emerging as an effective means of drug delivery and therapeutic intervention, thanks to the biocompatibility and physiochemical diversity of nanomaterials [2]. For example, polycation-based nanomaterials like polyamidoamine (PAMAM) dendrimers are known for their anti-inflammatory properties via their ability to neutralize negatively charged pathogens [3]. We have previously shown that P-G3, a third-generation PAMAM dendrimer with 32 surface amine groups, can preferentially deposit in the extracellular matrix (ECM) of white adipose tissue (WAT) when delivered intraperitoneally [4]. This accumulation is particularly noted in obesity, where the expansion of WAT and an increased amount of ECM results in an abundance of negatively charged biomacromolecules [5]. P-G3 effectively reduces inflammation and inhibits WAT expansion in such conditions [6]. These observations led us to explore the targeted delivery of P-G3 into atherosclerotic plaques, aiming for a noninvasive strategy to decrease the inflammatory burden within the plaque microenvironment. We first hypothesized that P-G3, if administered intravenously, could accumulate in atherosclerotic plaques, either via macrophage uptake or through the leaky vasculature to adhere to the plaque matrix (Fig. 1A) [7]. P-G3 was efficiently taken up by cultured bone-marrow-derived macrophages (Fig. 1B), as well as by foam cells loaded with oxidized LDL (Fig. 1C). In vivo experiments involved administering Cy5-labeled P-G3 intravenously to Ldlr−/− mice on a western diet with established atherosclerosis. Subsequent biodistribution analysis showed that while P-G3 was deposited primarily in the liver and kidneys, it was not present in the plaque-rich aorta at least when observed under low-resolution optical imaging (Fig. 1D). Targeted delivery of P-G3 Lyp1 in atherosclerotic plaques.(A) Schematic of our hypothesis illustrating PAMAM dendrimer delivery to ECM-rich atherosclerotic plaques via macrophage uptake or through leaky vasculature. (B) Bone-marrow-derived macrophages (BMDMs) were treated with 10 μg/mL Cy5-labeled P-G3 under basal conditions and (C) under oxidized LDL (oxLDL) loading to form foam cells. Filipin was used to detect intracellular free cholesterol. Cells were imaged at 40×, scale bar = 100 μm. (D) Tissue distribution of Cy5-labeled P-G3 dendrimers post-intraperitoneal (IP) or intravenous (IV) injection, visualized using IVIS optical imaging at 24 hours. (E) Structure of P-G3 Lyp1 compounds generated by conjugating a Lyp1 TFA plaque-homing peptide to P-G3 dendrimers. (F) Optical imaging of heart and aorta collected from mice 24-hour post-IV injection with 10 μg/g Cy5-labeled P-G3 or P-G3 Lyp1. (G) Quantification of radiance in the aortic root area circled in (F), calculated as average radiant efficiency, n = 3–6. (H) Confocal images of aortic root sections from mice injected with 10 μg/g Cy5-labeled P-G3 or P-G3 Lyp1, stained for CD68 and SMA and captured at 20×, scale bar = 100 µm. (I) Quantification of Cy5 flu","journal":"Life Medicine","year":2024,"id":506579,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":352702,"name":"Tianyu Li","orcid":"0000-0002-3719-1459","position":1,"is_corresponding":false},{"id":643983,"name":"Divya Bhansali","orcid":"0000-0001-8777-3089","position":2,"is_corresponding":false},{"id":323931,"name":"Qianfen Wan","orcid":"0000-0003-2483-0087","position":3,"is_corresponding":false},{"id":235103,"name":"Kam W. Leong","orcid":"0000-0002-8133-4955","position":4,"is_corresponding":false},{"id":1357752,"name":"Qiang Li","orcid":"0000-0002-9724-5439","position":5,"is_corresponding":false},{"id":567590,"name":"Tarik Zahr","orcid":"0000-0002-2754-6092","position":0,"is_corresponding":true}],"reference_count":8,"raw_metadata":null,"created_at":"2026-07-19T02:10:54.646711Z","pmid":"39872152","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}