Bilirubin Nanoparticle-Assisted Delivery of a Small Molecule-Drug Conjugate for Targeted Cancer Therapy

Abstract

Despite growing interest in targeted cancer therapy with small molecule drug conjugates (SMDCs), the short half-life of these conjugates in blood associated with their small size has limited their efficacy in cancer therapy. In this report, we propose a new approach for improving the antitumor efficacy of SMDCs based on nanoparticle-assisted delivery. Ideally, a nanoparticle-based delivery vehicle would prolong the half-life of an SMDC in blood and then release it in response to stimuli in the tumor microenvironment (TME). In this study, PEGylated bilirubin-based nanoparticles (BRNPs) were chosen as an appropriate delivery carrier because of their ability to release drugs in response to TME-associated reactive oxygen species (ROS) through rapid particle disruption. As a model SMDC, ACUPA-SN38 was synthesized by linking the prostate-specific membrane antigen (PSMA)targeting ligand, ACUPA, to the chemotherapeutic agent, SN38. ACUPA-SN38 was loaded into BRNPs using a film-formation and rehydration method. The resulting ACUPA-SN38@BRNPs exhibited ROS-mediated particle disruption and rapid release of the SMDC, resulting in greater cytotoxicity toward PSMA-overexpressing prostate cancer cells (LNCaP) than toward ROS-

Hyaluronic acid–bilirubin nanomedicine for targeted modulation of dysregulated intestinal barrier, microbiome and immune responses in colitis

“…In summary, we have developed HABN with unique anti-inflammatory properties and demonstrated its therapeutic efficacy after oral administration in a murine model of acute colitis (Figure 1a). While recent reports have explored systemic administration of polymermodified BR for disease treatments [39][40][41] , our work reported here demonstrate the promise of modulating intestinal barrier, microbiome, and immune responses with orally administered HABN. We show that HABN accumulated in DSS-damaged colonic epithelium and proinflammatory macrophages (Figures 1e-g) and upregulated the expression levels of tight junction-associated proteins and anti-microbial peptides in colon, while restoring intestinal barrier functions and protecting the epithelial layer against apoptosis (Figure 3a-e).…”

Heme-Derived Metabolic Signals Dictate Immune Responses

“…The use of enhancers or nano/micro particulate carriers also represents a promising approach for peptide-targeted delivery (194,195). Interestingly, a recent report showed that bilirubin-based nanoparticles may represent a valid carrier option for many small peptides whose therapeutic efficacy is limited by their short circulation halflife (196) and this method could therefore be used for a more efficient delivery of BLVR-based peptides in vivo. Furthermore, BR-based nanoparticles have been tested in several diseases and conditions for their efficacy in tumor targeting and drug release (197)(198)(199)(200)(201)(202).…”

Recent Progress in the Diagnosis and Precise Nanocarrier-Mediated Therapy of Inflammatory Bowel Disease

“…Due to the intrinsic properties of rosmarinic acid (RA) with poor water solubility and low bioavailability, Chung et al developed PEGylated RA-derived nanoparticles (RANPs) with a diameter of 63.5 ± 4.0 nm. 67 The PEGylated bioactive compound-derived nanoparticles not only achieved 100% RA loading capacity 68,69 but also achieved safer and longer RA circulation in the blood after intravenous injection. Therefore, RANPs can prolong the biological activity and have a higher probability of accumulating in the inflamed tissues where the vascular permeability is increased.…”