Polyester Nanoparticles with Controlled Topography for Peroral Drug Delivery Using Insulin as a Model Protein
Ingrid Marie Heyns
;
Meenakshi Arora
;
Raghu Ganugula
, et al.
ACS Nano,2024,18(18):11863-11875.
DOI:
10.1021/acsnano.4c01027
PubMed ID:
38622996
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Abstract: Receptor-mediated polyester drug delivery systems have tremendous potential for improving the clinical performance of existing pharmaceutical drugs. Despite significant progress made in this area, it remains unclear how and to what extent the polyester nanoparticle surface topography would affect the in vitro, ex vivo and in vivo performance of a drug, and if there exists a correlation between in vitro and in vivo, as well as healthy versus pathophysiological states. Herein, we report a systematic investigation of the interactions between ligands and receptors as a function of the linker length, two-carbon (2C) versus four-carbon (4C). The in vitro, ex vivo and in vivo in healthy models validate the hypothesis that 4C has better reach and binding to the receptors. The results indicate that 4C offered better performance over 2C in vivo in improving the oral bioavailability of insulin (INS) by 1.1-fold (3.5-fold compared to unfunctionalized nanoparticles) in a healthy rat model. Similar observations were made in pathophysiological models; however, the effects were less prominent compared to those in healthy models. Throughout, ligand decorated nanoparticles outperformed unfunctionalized nanoparticles. Finally, a semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was developed using the experimental data sets to quantitatively evaluate the effect of P2Ns-GA on oral bioavailability and efficacy of insulin. The study presents a sophisticated oral delivery system for INS or hydrophilic therapeutic cargo, highlighting the significant impact on bioavailability that minor adjustments to the surface chemistry can have.
Keywords:
nanobiointerface ;
nanotopography ;
oral insulin delivery ;
polyester nanoparticles ;
receptor-mediated transcytosis
Purchased from AmBeed:
2754-41-8
Lymph node targeting of cyclosporine ameliorates ocular manifestations in a mouse model of systemic lupus erythematosus (SLE) via PD-L1
Raghu Ganugula
;
Kabirat T. Babalola
;
Ingrid M. Heyns
, et al.
Nano Today,2024,57,102359.
DOI:
10.1016/j.nantod.2024.102359
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Abstract: One-third of systemic lupus erythematosus (SLE) patients experience various degrees of ocular manifestations, with immunosuppressants recommended as a treatment option. Targeted immune suppression via oral administration is challenging due to the harsh gastrointestinal tract environment combined with complex physiological barriers. Here, we report the efficacy of orally administered cyclosporine (CsA)-laden polymer nanoparticles decorated with the ligand – Gambogic Acid (P2Ns-GA-CsA) in sustained lymph node delivery. This is the first report demonstrating the CD71 specificity of P2Ns-GA-CsA in the CD71 knockout mouse model and the influence of spacer length in achieving target tissue bioavailability in a lupus mouse model. P2Ns-GA-CsA effectively regulates T-cell chemotaxis by PD-L1 at a 50 % lower dose compared to conventional CsA in a mouse model exhibiting lupus-associated corneal inflammation. Collectively, these results suggest the possibility for further development of P2Ns-GA to target a diverse range of lymphatic disorders
Keywords:
Systemic Lupus Erythematosus ;
Cornea ;
Programmed Cell Death- Ligand 1 ;
Lymph Node Targeting
Purchased from AmBeed:
2754-41-8
 via PD-L1.png)
Engineered urolithin A-laden functional polymer-lipid hybrid nanoparticles prevent cisplatin-induced proximal tubular injury in vitro
W. Pula
;
R. Ganugula
;
E. Esposito
, et al.
Eur. J. Pharm. Biopharm.,2024,200,114334.
DOI:
10.1016/j.ejpb.2024.114334
PubMed ID:
38768764
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Abstract: Functional polymer-lipid hybrid nanoparticles (H-NPs) are a promising class of nanocarriers that combine the benefits of polymer and lipid nanoparticles, offering biocompatibility, structural stability, high loading capacity, and, most importantly, superior surface functionalization. Here, we report the synthesis and design of highly functional H-NPs with specificity toward the transferrin receptor (TfR), using a small molecule ligand, gambogic acid (GA). A fluorescence study revealed the molecular orientation of H-NPs, where the lipid-dense core is surrounded by a polymer exterior, functionalized with GA. Urolithin A, an immunomodulator and anti-inflammatory agent, served as a model drug-like compound to prepare H-NPs via traditional emulsion-based techniques, where H-NPs led to smaller particles (132 nm) and superior entrapment efficiencies (70 % at 10 % drug loading) compared to GA-conjugated polymeric nanoparticles (P-NPs) (157 nm and 52 % entrapment efficiency) and solid lipid nanoparticles (L-NPs) (186 nm and 29 % entrapment efficiency). H-NPs showed superior intracellular accumulation compared to individual NPs using human small intestinal epithelial (FHs 74) cells. The in vitro efficacy was demonstrated by flow cytometry analysis, in which UA-laden H-NPs showed excellent anti-inflammatory properties in cisplatin-induced injury in healthy human proximal tubular cell (HK2) model by decreasing the TLR4, NF-κβ, and IL-β expression. This preliminary work highlights the potential of H-NPs as a novel functional polymer-lipid drug delivery system, establishing the foundation for future research on its therapeutic potential in addressing chemotherapy-induced acute kidney injury in cancer patients.
Keywords:
Anti-inflammatory ;
Polymer-lipid hybrid nanoparticles ;
Tubular injury ;
Urolithin A
Purchased from AmBeed:
2754-41-8
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