Sustained and Long-Term Release of Doxorubicin from PLGA Nanoparticles for Eliciting Anti-Tumor Immune Responses

Abstract

Immunogenic cell death (ICD) is a powerful trigger eliciting strong immune responses against tumors. However, traditional chemoimmunotherapy (CIT) does not last long enough to induce sufficient ICD, and also does not guarantee the safety of chemotherapeutics. To overcome the disadvantages of the conventional approach, we used doxorubicin (DOX) as an ICD inducer, and poly(lactic-co-glycolic acid) (PLGA)-based nanomedicine platform for controlled release of DOX. The diameter of 138.7 nm of DOX-loaded PLGA nanoparticles (DP-NPs) were stable for 14 days in phosphate-buffered saline (PBS, pH 7.4) at 37 °C. Furthermore, DOX was continuously released for 14 days, successfully inducing ICD and reducing cell viability in vitro. Directly injected DP-NPs enabled the remaining of DOX in the tumor site for 14 days. In addition, repeated local treatment of DP-NPs actually lasted long enough to maintain the enhanced antitumor immunity, leading to increased tumor growth inhibition with minimal toxicities. Notably, DP-NPs treated tumor tissues showed significantly increased maturated dendritic cells (DCs) and cytotoxic T lymphocytes (CTLs) population, showing enhanced antitumor immune responses. Finally, the therapeutic efficacy of DP-NPs was maximized in combination with an anti-programmed death-ligand 1 (PD-L1) antibody (Ab). Therefore, we expect therapeutic efficacies of cancer CIT can be maximized by the combination of DP-NPs with immune checkpoint blockade (ICB) by achieving proper therapeutic window and continuously inducing ICD, with minimal toxicities.

Size-Controlled Preparation of Docetaxel- and Curcumin-Loaded Nanoemulsions for Potential Pulmonary Delivery

“…Moreover, concentrated drug targeting possibly prolongs drug occupancy in pulmonary receptors, thus increasing the effective drug dosage and minimizing adverse side effects [ 21 , 24 , 25 ]. Nowadays, nanocarriers have attracted attention as delivery vectors to protect the drug from early discharge, aid cellular uptake, and boost maximum drug absorption with negligible toxicity [ 26 , 27 , 28 ]. Moreover, the lipid excipient accessibilities within safety standards and capabilities of nanocarriers to enhance hydrophobic drug solubility, long-term stability, ease of production, and deep-lung deposition capacity have revolutionized lipid-based systems, specifically nanoemulsions, as promising drug carrier systems for pulmonary delivery applications.…”

Membrane-Wrapped Nanoparticles for Enhanced Chemotherapy of Acute Myeloid Leukemia

“…Future directions for this work could tune and slow the release rate of DOX from the NPs by increasing the polymer concentration during synthesis and then examine how release kinetics impact therapeutic efficacy. Papers have shown that by using PLGA at a concentration of 25 mg/mL, instead of the 2 mg/mL used in this work, the release of DOX from the NP can be extended over 14 days . Our NPs exhibit rapid DOX release within the first 4 h of exposure to physiological conditions (Figure ).…”

“…Papers have shown that by using PLGA at a concentration of 25 mg/mL, instead of the 2 mg/mL used in this work, the release of DOX from the NP can be extended over 14 days. 55 Our NPs exhibit rapid DOX release within the first 4 h of exposure to physiological conditions (Figure 3). This is due to the phenomenon of burst release, a common concern when using loaded PLGA.…”

DA-LSTM-VAE: Dual-Stage Attention-Based LSTM-VAE for KPI Anomaly Detection

“…In contrast, encodings in this paper use the same encoder. Besides, both [16] and [18] do use only one encoder for recoding in the inference stage, but not perform the same consistency constraint as we do in the training stage. Distributionally-shifted image transformation.…”