Despite several decades of progress, bone-specific drug delivery is still a major challenge. Current bone-acting drugs require high-dose systemic administration which decreases therapeutic efficacy and increases off-target tissue effects. Here, a bone-targeted nanoparticle (NP) delivery system for a β-catenin agonist, 3-amino-6-(4-((4-methylpiperazin-1-yl)-sulfonyl)phenyl)-N-(pyridin-3-yl)pyrazine-2-carboxamide, a glycogen synthase kinase 3 beta (GSK-3β) inhibitor, was developed to enhance fracture healing. The GSK-3β inhibitor loading capacity was found to be 15 wt % within highly stable poly(styrene-alt-maleic anhydride)-b-poly(styrene) NPs, resulting in ~50 nm particles with ~ −30 mV surface charge. A peptide with high affinity for tartrate-resistant acid phosphatase (TRAP), a protein deposited by osteoclasts on bone resorptive surfaces, was introduced to the NP corona to achieve preferential delivery to fractured bone. Targeted NPs showed improved pharmacokinetic profiles with greater accumulation at fractured bone, accompanied by significant uptake in regenerative cell types (mesenchymal stem cells (MSCs) and osteoblasts). MSCs treated with drug-loaded NPs in vitro exhibited 2-fold greater β-catenin signaling than free drug that was sustained for 5 days. To verify similar activity in vivo, TOPGAL reporter mice bearing fractures were treated with targeted GSK-3β inhibitor-loaded NPs. Robust β-galactosidase activity was observed in fracture callus and periosteum treated with targeted carriers versus controls, indicating potent β-catenin activation during the healing process. Enhanced bone formation and microarchitecture were observed in mice treated with GSK-3β inhibitor delivered via TRAP-binding peptide-targeted NPs. Specifically, increased bone bridging, ~4-fold greater torsional rigidity, and greater volumes of newly deposited bone were observed 28 days after treatment, indicating expedited fracture healing.
Leukemias are challenging diseases to treat due, in part, to interactions between leukemia cells and the bone marrow microenvironment (BMME) that contribute significantly to disease progression. Studies have shown that leukemic cells secrete C-chemokine (C-C motif) ligand 3 (CCL3), to disrupt the BMME resulting in loss of hematopoiesis and support of leukemic cell survival and proliferation. In this study, a murine model of blast crisis chronic myelogenous leukemia (bcCML) that expresses the translocation products BCR/ABL and Nup98/HoxA9 was used to determine the role of CCL3 in BMME regulation. Leukemic cells derived from CCL3 −/− mice were shown to minimally engraft in a normal BMME, thereby demonstrating that CCL3 signaling was necessary to recapitulate bcCML disease. Further analysis showed disruption in hematopoiesis within the BMME in the bcCML model. To rescue the altered BMME, therapeutic inhibition of CCL3 signaling was investigated using bone-targeted nanoparticles (NP) to deliver Maraviroc, an inhibitor of 2 of 14 | ACKUN-FARMMER Et Al.
Despite efforts to achieve tissue selectivity, the majority of systemically administered drug delivery systems (DDSs) are cleared by the mononuclear phagocyte system (MPS) before reaching target tissues regardless of disease or injury pathology. Previously, we showed that while tartrate‐resistant acid phosphatase (TRAP) binding peptide (TBP)‐targeted polymeric nanoparticles (TBP‐NP) delivering a bone regenerative Wnt agonist improved NP fracture accumulation and expedited healing compared with controls, there was also significant MPS accumulation. Here we show that TBP‐NPs are taken up by liver, spleen, lung, and bone marrow macrophages (Mϕ), with 76 ± 4%, 49 ± 11%, 27 ± 9%, and 92 ± 5% of tissue‐specific Mϕ positive for NP, respectively. Clodronate liposomes (CLO) significantly depleted liver and spleen Mϕ, resulting in 1.8‐fold and 3‐fold lower liver and spleen and 1.3‐fold and 1.6‐fold greater fracture and naïve femur accumulation of TBP‐NP. Interestingly, depletion and saturation of MPS using 10‐fold greater TBP‐NP doses also resulted in significantly higher TBP‐NP accumulation at lungs and kidneys, potentially through compensatory clearance mechanisms. The higher NP dose resulted in greater TBP‐NP accumulation at naïve bone tissue; however, other MPS tissues (i.e., heart and lungs) exhibited greater TBP‐NP accumulation, suggesting uptake by other cell types. Most importantly, neither Mϕ depletion nor saturation strategies improved fracture site selectivity of TBP‐NPs, possibly due to a reduction of Mϕ‐derived osteoclasts, which deposit the TRAP epitope. Altogether, these data support that MPS‐mediated clearance is a key obstacle in robust and selective fracture accumulation for systemically administered bone‐targeted DDS and motivates the development of more sophisticated approaches to further improve fracture selectivity of DDS.
No abstract
2.2. Poly(styrene-alt-maleic anhydride)-b-poly(styrene) Nanoparticles as a Platform to Study cCBP-Mediated Targeting of MV411 Cells Scheme 1. Synthesis of poly(styrene-alt-maleic anhydride)-b-poly(styrene) (PSMA-b-PS) based diblock copolymers via one-step RAFT polymerization.
Micheliolide (MCL) is a naturally occurring sesquiterpene lactone that selectively targets leukemic stem cells (LSCs), which persist after conventional chemotherapy for myeloid leukemias, leading to disease relapse. To overcome modest MCL cytotoxicity, analogs with ≈two-threefold greater cytotoxicity against LSCs are synthesized via late-stage chemoenzymatic C─H functionalization. To enhance bone marrow delivery, MCL analogs are entrapped within bone-targeted polymeric nanoparticles (NPs). Robust drug loading capacities of up to 20% (mg drug mg −1 NP) are obtained, with release dominated by analog hydrophobicity. NPs loaded with a hydrolytically stable analog are tested in a leukemic mouse model. Median survival improved by 13% and bone marrow LSCs are decreased 34-fold following NP MCL treatments versus controls. Additionally, selective leukemic cell and LSC cytotoxicity of the treatment versus normal hematopoietic cells is observed. Overall, these studies demonstrate that MCL-based antileukemic agents combined with bone-targeted NPs offer a promising strategy for eradicating LSCs.
Antigen-specific tolerance is a key goal of experimental immunotherapies for autoimmune disease and allograft rejection. This outcome could selectively inhibit detrimental inflammatory immune responses without compromising functional protective immunity. A major challenge facing antigen-specific immunotherapies is ineffective control over immune signal targeting and integration, limiting efficacy and causing systemic non-specific suppression. Here we use intra-lymph node injection of diffusion-limited degradable microparticles that encapsulate self-antigens with the immunomodulatory small molecule, rapamycin. We show this strategy potently inhibits disease during pre-clinical type 1 diabetes and allogenic islet transplantation. Antigen and rapamycin are required for maximal efficacy, and tolerance is accompanied by expansion of antigen-specific regulatory T cells in treated and untreated lymph nodes. The antigen-specific tolerance in type 1 diabetes is systemic but avoids non-specific immune suppression. Further, microparticle treatment results in the development of tolerogenic structural microdomains in lymph nodes. Finally, these local structural and functional changes in lymph nodes promote memory markers among antigen-specific regulatory T cells, and tolerance that is durable. This work supports intra-lymph node injection of tolerogenic microparticles as a powerful platform to promote antigen-dependent efficacy in type 1 diabetes and allogenic islet transplantation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.