High-Density Lipoprotein Composition Influences Lymphatic Transport after Subcutaneous Administration

Abstract

Interstitial administration (e.g., subcutaneous (SC) administration) of immunotherapies and vaccines within nanoparticles can improve access to lymph-resident immune cells, leading to enhanced efficacy and reduced off-target effects. Recently, endogenous high-density lipoproteins (HDLs) were found to return from peripheral tissue back to the systemic circulation via the lymphatic vessels and nodes. This suggests the potential utility of HDLs as biocompatible lymphatic-targeted therapeutic carriers. However, we have a limited understanding of the mechanisms that drive HDL uptake into peripheral lymphatics from the interstitium. This study investigated the influence of HDL physicochemical properties on lymphatic transport and lymph node (LN) retention of HDL after SC administration. A range of HDL particles was prepared and characterized. Sphere-shaped endogenous HDLs were isolated from biological fluids (rat lymph, rat plasma, and human plasma) and separated into two subclasses based on the density. Discoidal-shaped synthetic (reconstituted) HDLs (rHDLs) of similar sizes were assembled from lipids and apolipoprotein A-I. All HDLs had similar sizes of 10–20 nm and a slightly negative surface charge. All HDLs were radiolabeled with 3H-cholesteryl ester (3H-CE) and/or 14C-free cholesterol (14C FC) and administered SC into the hind leg of thoracic lymph-cannulated rats. The recovery of radiolabels in lymph, plasma, LN, and tissues was determined. From the interstitial injection site, all HDLs were preferentially transported into the lymph and not blood vessels as indicated by high lymph-to-plasma concentration ratios of the radiolabels (up to 100:1 during the absorption phase) and greater radiolabel recovery in LNs draining the injection site compared to the contralateral side. Several HDLs with unique composition demonstrated significantly higher lymphatic transport compared to other HDLs despite possessing similar physical properties, suggesting that HDL lymphatic transport is less influenced by physical properties. The LN retention of HDL was positively correlated to increasing the negative charge of HDL, which was related to surface composition. Overall, this study informs the optimal design of HDL-based nanoparticles to promote lymphatic targeting of immunotherapies and vaccines.

Advanced Generation Therapeutics: Biomimetic Nanodelivery System for Tumor Immunotherapy

“…In addition to the intact cell membranes described above, bioactive substances (e.g., endogenous proteins) are also natural candidates for building BNDS. Among them, high-density lipoproteins (HDLs) and granzyme B protein are representatives of endogenous proteins. As a kind of natural nanocarrier that exists in the human body, HDLs are considered as biomimetic nanomaterials with infinite potential for the characteristics of biocompatibility, nonimmunogenicity, and complete biodegradability.…”

Nanovaccines for Advancing Long-Lasting Immunity against Infectious Diseases

“…For example, albumin programmed the formation of a manganese nanoadjuvant (MnARK; diameter, 9.77 ± 3.26 nm) and, as expected, MnARK and RBD antigen were codelivered to LNs and accumulated in LNs 12 h after injection at approximately twice the level observed using RBD antigen alone (Figure 4e,g); 221 albumin has also been successfully used in other applications. 222,223 Vaccines are generally administrated peripherally, captured by APCs, such as DCs or macrophages at injection sites, and thereby migrate to LNs; 206 however, cell-mediated antigen transport to LNs has limited efficacy. Approaches that promote cell-mediated antigen trafficking lead to much lower antigen levels in the draining LNs than technologies with direct lymphatic targeting of particulate vaccines.…”

Targeting Lymphatics for Nanoparticle Drug Delivery

“…Indeed, the researchers' development of a lymphatic-cannulation technique has allowed them to directly observe the transport of lymph from the small intestine through lymphatic vessels and lymph nodes that converge at the superior mesenteric lymph duct (Trevaskis et al, 2015b). This technique was also applied to examine the fate of subcutaneously administered, high-density lipoprotein nanoparticles (HDLs), finding that HDLs preferentially drained via lymphatic vessels, as opposed to blood vessels, and that LN retention of HDL was positively correlated to increasing the negative charge of HDL (Gracia et al, 2020). For more detailed descriptions of such prodrug formulations, we direct readers to this recent review (Dahan et al, 2014).…”