Macrophage depletion increases target specificity of bone‐targeted nanoparticles

Abstract

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.

Impact of Nanoparticle Physicochemical Properties on Protein Corona and Macrophage Polarization

“…Amphiphilic diblock copolymers of poly(styrene-alt-maleic anhydride)-b-poly(styrene) (PSMA-b-PS) were synthesized via reversible addition−fragmentation chain transfer (RAFT) polymerization, as described previously. 6,46,47,78,79 PSMA-b-PS copolymers were then self-assembled into NPs via solvent exchange with a hydrophobic core (PS) and a hydrophilic shell (PSMA). 6,46,47,78,79 DMAEMA NPs, consisting of a pH-responsive core and cationic corona, were self-assembled from poly(dimethylmethacrylate)-bpoly(dimethylaminoethyl methacrylate-co-butyl methacrylate-co-propylacrylic acid) or p(DMAEMA)-b-p(DMAEMA-co-BMA-PAA) also synthesized via RAFT, as described previously.…”

Advanced strategies to evade the mononuclear phagocyte system clearance of nanomaterials

“…demonstrated that pre‐treatment with clodronate liposome led to a 3‐ and 1.8‐fold reduction of bone‐targeted NPs in the spleen and liver, respectively, resulting in a significant enhancement in bone accumulation. [ 127 ]…”

“…Ackun-Farmmer et al demonstrated that pre-treatment with clodronate liposome led to a 3-and 1.8-fold reduction of bonetargeted NPs in the spleen and liver, respectively, resulting in a significant enhancement in bone accumulation. [127] To enhance nanodrug delivery to pulmonary fibrotic tissues, Sun et al developed a clodronate liposomal and fibroblast-derived exosomal hybrid drug nanocarrier, where the clodronate can deplete the KC via passive targeting and the homing properties of homologous exosome favor pulmonary fibrosis-specific accumulation and penetration. [128] The nanocarrier significantly enhanced the delivery of nintedanib, an antifibrotic agent approved for treating pulmonary fibrosis, to pulmonary fibrotic lesions and achieved a remarkable improvement in treating pulmonary fibrosis.…”

Micro/Nanosystems for Magnetic Targeted Delivery of Bioagents

“…Namely, cellular hitchhiking meaning the use of various cells as the particle carriers [190] or the RES blockade (saturation) induced before the MNPs injection [191,192] are exploited to delay the blood clearing and increase targeting capability. Although the suppression of mononuclear phagocyte function is generally achieved by injecting large doses of various nanoparticles [193,194], it can be blocked by the organism's own intact cells as well. In particular, Nikitin et al elegantly demonstrated that the pre-induced macrophage saturation with antibody-sensitized erythrocytes (socalled, cytoblockade of mononuclear phagocyte system) increased the circulation half-life of nanoparticles by up to 32-fold [181].…”