Novel Nanoparticles for the Selective Delivery of Targeted Immunotherapy System
Authors: Rachid Ousama , Haik Yousef , Abdi Reza 
Published: April 2020

Purpose

Conventional interventions of type 1 diabetes (T1D) are based on insulin delivery to control blood glucose, but all suffer from inability to regulate insulin without patient intervention. Among the numerous approaches to treat T1D, immune therapies have shown promising results and long lasting effect, and could prevent the action of effector cells involved in beta cell damage to prevent or delay the induction of diabetogenic cells. Targeted drug carriers using polymeric nanoparticles (NPs) have emerged as highly innovative materials to targeted delivery and hold particular promise to enhance the delivery of immunoregulatory agents to treat T1D. During insulitis, inflammatory signals and endothelial cell activation have been reported to render islet endothelial morphology and characteristics to high endothelial venules (HEVs). The aim of this study was to evaluate the feasibility of selective delivery of targeted NPs to the pancreatic lymph nodes and pancreata for potential use in targeted delivery and on site controlled release.

Methods

Polylactide‐drug conjugated NP were developed via drug‐initiated polymerization of lactide followed by nanoprecipitation. Non‐targeted and MECA79‐targeted poly(lactic‐coglycolic acid) (PLGA) NPs were engineered using a self‐assembly single step nanoprecipitation method. MECA79 antibody was covalently conjugated to the surface of NPs using polyethylene glycol (PEG) chains as linkers. The ability to shorten the T1 longitudinal relaxation time of protons of water were measured by imaging test tubes containing Gd‐NP, empty NP, or PBS. The MECA79‐NPs were injected intravenously into an anesthetized 12‐week NOD mice, followed by high‐resolution T1‐weighted image collection on a 7 T Signal MRI scanner and evaluation of the trafficking processes on HEVs.

Results

In T1 weighted images, samples containing Gd‐NPs showed higher signal intensity and their calculated T1 relaxation times were significantly lower in comparison to samples containing empty NPs or no NPs in PBS. As shown in Figure
1, the MRI signal intensity in the inguinal LN was increased after intravenous injection of MECA79‐NP. The extent by which ectopic HEV are formed within the pancreata is an important question which determines the efficacy of drug delivery. Our serial sectioning of pancreas shows up to 70% of islets are accompanied with numerous ectopic HEV (12 week NOD mice), which indicates that the target is abundantly available for the MECA79‐NP to attach in the pancreata. Figure
2 shows numerous HEV within the environment of islets and the presence of embedded HEV within the CD3 and B220 cells.

Conclusion

Data presented here confirm for the first time that selective delivery of targeted NPs to the pancreatic lymph nodes and pancreata is feasible in diabetic mice. These experiments serve the basis for developing more of multifunctional NP. Our primary intention is to increase translatability, by utilizing biocompatible NP materials, targeted delivery, and drugs with extensive preliminary data in mice and humans.

Support or Funding Information

This work was made possible by the National Priorities Research Program award [NPRP9‐350‐3‐074] from the Qatar National Research Fund (a member of The Qatar Foundation). The contents herein are solely the responsibility of the author.

In vitro (A) and in vivo imaging of LN prior (B) and postNP‐Gd‐MECA79 injection (C).

Figure 1

Numerous HEV are found within the islets complex (left and middle figures).Ectopic HEVs are embedded amongst CD3 and B220 B cells in NOD pancreas.

Figure 2