Chemical conjugation mitigates immunotoxicity of chemotherapy of Lipid Nanoparticles
While chemotherapy can stimulate antitumor immunity, it may also impair immune cell function and induce lymphodepletion, reducing effectiveness of subsequent immunotherapy. Thus, nanoparticle-based drug delivery systems have been developed for its improved drug biodistribution and reduced toxicity, striking a delicate balance between efficacy and safety. However, the interaction between nanoparticles and immune system, particularly the formation of protein corona on nanoparticle surfaces, remains unclear.
ApoA-1, a natural ligand of scavenger receptor class B type 1 (SR-B1), is commonly enriched in protein corona of lipid nanoparticles and plays crucial roles in modulating nanoparticle-cell interactions. High-density lipoprotein (HDL) is a natural nanoparticle containing ApoA-1, and via binding with SR-B1, HDL mainly transports hydrophobic cargo directly into the cytosol in an endocytosis-independent pathway, while ApoA-1 remains in circulation and finally undergoes degradation in the kidney. Recently, synthetic HDLs (sHDLs) composed of ApoA-1 mimic peptides have been explored, resembling natural HDL in biocompatibility and SR-B1-based cell specificity. Though of different origins, both natural HDLs and sHDLs show capability of regulating innate immune responses.
In a study published in Science Advances on June 5, a research team led by ZHANG Pengcheng from ShanghaiTech University, LI Yaping from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences, along with WANG Hao from China State Institute of Pharmaceutical Industry and other collaborators, revealed that ApoA-1 can transport drugs encapsulated within lipid nanoparticles to myeloid cells, leading to myelopenia and consequently lymphopenia. They demonstrated that these side effects can largely be avoided simply by conjugating drugs to the nanoparticles, without reducing antitumor activity of drugs.
To investigate the influence of ApoA-1 on the immune response, researchers created two variants of maytansine (DM1)-loaded synthetic high-density lipoproteins (D-sHDL) with DM1 either physically entrapped (ED-sHDL) or chemically conjugated to ApoA-1 (CD-sHDL). By comparing their cell uptake mechanism, biodistribution, in vivo efficacy and safety, researchers found that CD-sHDL showed less accumulation in the tumor-draining lymph nodes (DLNs) and femur. This resulted in lower toxicity against myeloid cells than ED-sHDL via avoiding SR-B1-mediated DM1 transportation into granulocyte-monocyte progenitors and dendritic cells.
Therefore, higher densities of lymphocytes in tumors, DLNs, and blood were recorded in mice receiving CD-sHDL, leading to better efficacy and immune memory against colon cancer. Furthermore, liposomes with conjugated DM1 (CD-Lipo) showed lower immunotoxicity than those with entrapped drugs (ED-Lipo) through the same mechanism after the opsonization of ApoA-1 in protein corona, indicating the broad universality of these findings.
Given high translational potential of the two investigated lipid nanoparticles (sHDL and liposome) and prevalence of ApoA-1 as a main component of the protein corona, these findings shed light on designing nanoparticle-based chemotherapy strategies by elucidating the role of ApoA-1 in modulating immune responses.
This study also deepens our understanding of immune interaction of nanoparticles. Figuring out the complex interplay between nanoparticles and immune system will pave the way for development of more effective and less toxic cancer therapies in the future, and will impact on the clinical translation of nanoparticles for immune manipulation.
DOI: 10.1126/sciadv.adk9996
Link: https://doi.org/10.1126/sciadv.adk9996
![](./W020240611351071847867.jpg)
Schematic illustration of sHDL preparation and different impact on toxicity and efficacy of drug loading patterns in sHDL. (Image by ZHENG Chao)
Contact:
JIANG Qingling
Shanghai Institute of Materia Medica, Chinese Academy of Sciences
E-mail: qljiang@stimes.cn