Developing a Dissociative Nanocontainer for Peptide Drug Delivery

Abstract

The potency, selectivity, and decreased side effects of bioactive peptides have propelled these agents to the forefront of pharmacological research. Peptides are especially promising for the treatment of neurological disorders and pain. However, delivery of peptide therapeutics often requires invasive techniques, which is a major obstacle to their widespread application. We have developed a tailored peptide drug delivery system in which the viral capsid of P22 bacteriophage is modified to serve as a tunable nanocontainer for the packaging and controlled release of bioactive peptides. Recent efforts have demonstrated that P22 nanocontainers can effectively encapsulate analgesic peptides and translocate them across blood-brain-barrier (BBB) models. However, release of encapsulated peptides at their target site remains a challenge. Here a Ring Opening Metathesis Polymerization (ROMP) reaction is applied to trigger P22 nanocontainer disassembly under physiological conditions. Specifically, the ROMP substrate norbornene (5-Norbornene-2-carboxylic acid) is conjugated to the exterior of a loaded P22 nanocontainer and Grubbs II Catalyst is used to trigger the polymerization reaction leading to nanocontainer disassembly. Our results demonstrate initial attempts to characterize the ROMP-triggered release of cargo peptides from P22 nanocontainers. This work provides proof-of-concept for the construction of a triggerable peptide drug delivery system using viral nanocontainers.

Virus‐like particles: Next‐generation nanoparticles for targeted therapeutic delivery

“…VLPs are an emerging class of targeted delivery vehicles with the potential to overcome the limitations of other NPs . In recent years, several groups have shown that VLPs can pack and deliver therapeutic cargo such as chemotherapeutic drugs, siRNA, RNA aptamers, proteins, and peptides . However, there are still challenges when using VLPs.…”

Design and Applications of Protein‐Cage‐Based Nanomaterials

“…Kelly et al developed ap eptide drug-delivery system using P22 bacteriophage,w hich was modified to serve as at unable nanocontainer fort he packaging and applied ring-opening metathesis polymerization (ROMP) reactiont ot rigger disassembly of the capsida nd release of bioactive peptides under physiological conditions. [60] Gd 3 + -based MR contrast agents have drawn strongi nterest in recent years. Site-selective initiation of atom-transfer radical Figure 6.…”

From Mollusks to Medicine: A Venomics Approach for the Discovery and Characterization of Therapeutics from Terebridae Peptide Toxins

“…By modifying the scaffold protein that templates the self-assembly of the P22 procapsid, an arbitrary gene product can be incorporated within the procapsid shell [ 197 , 198 ]. Among the proteins that have been successfully packaged within the procapsid are the fluorescent proteins EGFP, mCherry, and ziconotide [ 186 , 197 , 199 ].…”

“…This was the first demonstration of delivery of ziconotide across a BBB model using a nanoparticle delivery system, providing an alternative route to intrathecal injection, which has thus far been the only delivery method. The results of this proof-of-concept experiment are promising towards the development of a tunable VLP nanocontainer for the delivery of peptide therapeutics across the BBB [ 186 , 199 ].…”