Improving the drug delivery to solid tumor and rheumatoid arthritis through peptide targeting and EV modulation

Abstract

Both cancer and rheumatoid arthritis (RA) are intricate diseases that pose significant threats to human health. Targeted therapy is a treatment approach that delivers drugs specifically to the disease site, leading to maximum efficacy and minimized toxicity and adverse effects. Peptides are a promising targeting molecule for scientific exploration, among the numerous available treatment methods for these two diseases. Chapter 2 describes the design of a thermosensitive hydrogel formulation to deliver peptide-functionalized drugs subcutaneously for a more patient-friendly method and controlled drug release. Dexamethasone (DEX) is commonly used to decrease inflammation and relieve pain, but it often causes adverse effects due to nonspecific biodistribution. A solution to this problem is the conjugation of DEX with an inflammation-targeting peptide, CRV, which increases DEX accumulation in inflamed joints while decreasing it in healthy organs. Chapter 2 of this work described the design of a thermosensitive hydrogel formulation that delivered peptide-functionalized drug subcutaneously, allowing for controlled drug release and a more patient-friendly treatment method. The HP hydrogel forms a sol state at room temperature and transfers to a gel state at 31 °C, exhibiting shear-thinning behavior and robust solid-like properties. Gel erosion induces drug predominant release and presents good correlation under zero-order kinetics. Subcutaneous injection of CRV loaded-HP hydrogel in mice shows the systemic circulation time of CRV is prolonged to 48 hours attributed to the sustained release behavior of HP hydrogel. Although the biodistribution of CRV-DEX decreases DEX concentration in non-targeted organs, compared to DEX alone, there is currently no evidence indicating its efficacy in targeting joints. Further investigation is needed to explore how CRV peptide can target to joints via subcutaneous injection with hydrogel. In Chapter 3, recent studies showed that a significant portion of NPs are transferred inside extracellular vesicles (EVs), and inhibition of EV biogenesis significantly reduces tumor accumulation and vascular penetration of NPs in vivo. A manual chemical screen identified LDN-214117, an activin receptor-like kinase-2 (ALK-2) inhibitor, as an agonist of NP intercellular exchange that increases EV biogenesis via the BMP (bone morphogenetic protein)-MAPK (mitogen-activated protein kinase) signaling pathway. LDN-214117 treatment in vivo enhances the tumor accumulation and vascular penetration of various NPs, improving their antitumor efficacy. This study showcases the identification of a novel chemical compound with intercellular exchange assays to modulate EV biogenesis and EV-mediated transport, thus boosting the delivery and therapeutic efficacy of nanomaterial. Overall, this work shows improved drug delivery to treat RA and solid tumor by CRV peptide targeting and EV modulation.