Language
English
Publication Date
11-1-2023
Journal
Bioengineering & Translational Medicine
DOI
10.1002/btm2.10594
PMID
38023719
PMCID
PMC10658527
PubMedCentral® Posted Date
9-15-2023
PubMedCentral® Full Text Version
Post-print
Abstract
Immune checkpoint inhibitors (ICI), pembrolizumab and atezolizumab, were recently approved for treatment-refractory triple-negative breast cancer (TNBC), where those with Programmed death-ligand 1 (PD-L1) positive early-stage disease had improved responses. ICIs are administered systemically in the clinic, however, reaching effective therapeutic dosing is challenging due to severe off-tumor toxicities. As such, intratumoral (IT) injection is increasingly investigated as an alternative delivery approach. However, repeated administration, which sometimes is invasive, is required due to rapid drug clearance from the tumor caused by increased interstitial fluid pressure. To minimize off-target drug biodistribution, we developed the nanofluidic drug-eluting seed (NDES) platform for sustained intratumoral release of therapeutic via molecular diffusion. Here we compared drug biodistribution between the NDES, intraperitoneal (IP) and intratumoral (IT) injection using fluorescently labeled PD-L1 monoclonal antibody (αPD-L1). We used two syngeneic TNBC murine models, EMT6 and 4T1, that differ in PD-L1 expression, immunogenicity, and transport phenotype. We investigated on-target (tumor) and off-target distribution using different treatment approaches. As radiotherapy is increasingly used in combination with immunotherapy, we sought to investigate its effect on αPD-L1 tumor accumulation and systemic distribution. The NDES-treated cohort displayed sustained levels of αPD-L1 in the tumor over the study period of 14 days with significantly lower off-target organ distribution, compared to the IP or IT injection. However, we observed differences in the biodistribution of αPD-L1 across tumor models and with radiation pretreatment. Thus, we sought to extensively characterize the tumor properties via histological analysis, diffusion evaluation and nanoparticles contrast-enhanced CT. Overall, we demonstrate that ICI delivery via NDES is an effective method for sustained on-target tumor delivery across tumor models and combination treatments.
Keywords
anti PD‐L1, biodistribution, CT, drug delivery, radiotherapy, TNBC, tumor microenvironment
Published Open-Access
yes
Recommended Citation
Liu, Hsuan-Chen; Capuani, Simone; Badachhape, Andrew A; et al., "Intratumoral Nanofluidic System Enhanced Tumor Biodistribution of Pd-L1 Antibody in Triple-Negative Breast Cancer" (2023). Faculty, Staff and Students Publications. 6429.
https://digitalcommons.library.tmc.edu/baylor_docs/6429