Nano-formulating dexamethasone, and administering it via intravenous injection or inhalation, may help to improve anti-COVID-19 treatment efficacy by targeting the potent corticosteroid drug to hyper-activated immune cells, by potentiating its anti-oedema activity and by exploiting its anti-fibrotic effects.
Highlights d We have developed a trained immunity-inducing nanobiologic therapeutic named MTP-HDL d MTP-HDL favorably accumulates in hematopoietic organs of mice and non-human primates d MTP-HDL nanotherapy induces trained immunity through bone marrow progenitors in vivo d MTP-HDL nanotherapy inhibits tumor growth and potentiates immune checkpoint inhibition
Although the first
nanomedicine was clinically approved more than
two decades ago, nanoparticles’ (NP)
in vivo
behavior is complex and the immune system’s role in their
application remains elusive. At present, only passive-targeting nanoformulations
have been clinically approved, while more complicated active-targeting
strategies typically fail to advance from the early clinical phase
stage. This absence of clinical translation is, among others, due
to the very limited understanding for
in vivo
targeting
mechanisms. Dynamic
in vivo
phenomena such as NPs’
real-time targeting kinetics and phagocytes’ contribution to
active NP targeting remain largely unexplored. To better understand
in vivo
targeting, monitoring NP accumulation and distribution
at complementary levels of spatial and temporal resolution is imperative.
Here, we integrate
in vivo
positron emission tomography/computed
tomography imaging with intravital microscopy and flow cytometric
analyses to study α
v
β
3
-integrin-targeted
cyclic arginine-glycine-aspartate decorated liposomes and oil-in-water
nanoemulsions in tumor mouse models. We observed that ligand-mediated
accumulation in cancerous lesions is multifaceted and identified “NP
hitchhiking” with phagocytes to contribute considerably to
this intricate process. We anticipate that this understanding can
facilitate rational improvement of nanomedicine applications and that
immune cell–NP interactions can be harnessed to develop clinically
viable nanomedicine-based immunotherapies.
Core-crosslinked polymeric micelles (CCPM) based on PEG-b-pHPMA-lactate are clinically evaluated for the treatment of cancer. We macroscopically and microscopically investigated the biodistribution and target site accumulation of CCPM. To this end, fluorophore-labeled CCPM were intravenously injected in mice bearing 4T1 triple-negative breast cancer (TNBC) tumors, and their localization at the whole-body, tissue and cellular level was analyzed using multimodal and multiscale optical imaging. At the organism level, we performed non-invasive 3D micro computed tomography-fluorescence tomography (μCT-FLT) and 2D fluorescence reflectance imaging (FRI). At the tissue and cellular level, we performed extensive immunohistochemistry, focusing primarily on cancer, endothelial and phagocytic immune cells. The CCPM achieved highly efficient tumor targeting in the 4T1 TNBC mouse model (18.6 % ID/g), with values twice as high as those in liver and spleen (9.1 and 8.9 % ID/g, respectively). Microscopic analysis of tissue slices revealed that at 48 h post injection, 67% of intratumoral CCPM were localized extracellularly. Phenotypic analyses on the remaining 33% of intracellularly accumulated CCPM showed that predominantly F4/80 + phagocytes had taken up the nanocarrier formulation. Similar uptake patterns were observed for liver and spleen. The propensity of CCPM to primarily accumulate in the extracellular space in tumors suggests that the anticancer efficacy of the #
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