Self-Assembled Porphyrin Nanodiscs with Structure-Dependent Activation for Phototherapy and Photodiagnostic Applications

Abstract

The abilities to deliver and subsequently activate a therapeutic at the intended site of action are two important challenges in the synthesis of novel nanoparticles. Poor tumor permeability as a result of a dense microenvironment can impede the delivery of nanoparticles to the site of action. The design of a sub-40 nm activatable porphyrin nanodisc, based on protein-induced lipid constriction, is described. The biophotonic nanoparticle, self-assembled from aggregated porphyrin-lipid, is stabilized by an amphipathic alpha helical protein and becomes photoactive when its structure is perturbed. Enzymatic cleavage of the constricting protein leads to conversion of the particle from a disc- to a vesicle-shaped structure and provides further evidence that the apolipoprotein serves a functional role on the nanodisc. Fluorescence measurements of these nanodiscs in a detergent show that fluorescence is over 99% quenched in the intact state with a 12-fold increase in singlet oxygen generation upon disruption. Cellular fluorescence unquenching and dose-dependent phototoxicity demonstrate that these nanodiscs can be internalized and unquenched intracellularly. Finally, nanodiscs were found to display a 5-fold increase in diffusion coefficient when compared with the protein-free control ((3.5±0.1)×10(-7) vs (0.7±0.03)×10(-7) cm2 s(-1)). The ability to incorporate large amounts of photosensitizer drugs into its compact structure allows for phototherapeutic action, fluorescence diagnostic applications, and the potential to effectively deliver photosensitizers deep into poorly permeable tumors.

In situ conversion of porphyrin microbubbles to nanoparticles for multimodality imaging

“…The r.m.s. 2 was then converted to radius R using the equation r.m.s. 2 = 3/5 R 2 , assuming the pNPs are a solid sphere.…”

Advances in the use of nanoscale bilayers to study membrane protein structure and function

“…In this regard, future modifications of the SMA copolymer (size, pendant group stoichiometry and functionalization with molecular tags) will likely be useful in the development of novel experimental applications. In addition to their utility in basic research, these nanoscale bilayers have vast potential for applied technologies, including the development of biocompatible systems for hydrophobic drug delivery and diagnostic applications (Murakami, 2012;Ng, Lovell, Vedadi, Hajian, & Zheng, 2013;Numata et al, 2013), nanoelectronic devices (Goldsmith et al, 2011;Ham et al, 2010), and multiplexed sensor arrays to detect protein interactions (Sloan, Marty, Sligar, & Bailey, 2013). Given the commercial availability of all components required for the synthesis of nanodiscs and SMAPLs/Lipodisqs®, we are sure to see these systems applied to an ever-expanding repertoire of MPs by many independent groups in the coming years.…”

Recent advances in the development of organic photothermal nano-agents

“…2) [55][56][57]. By changing the ways that porphyrin-lipid assembles were formed, ultra small porphyrin nanodiscs and large porphyrin shell microbubbles were fabricated in their later studies, for applications in photodynamic therapy and ultrasound imaging, respectively [58,59]. Furthermore, metal ions can be introduced into these porphysomes owing to the intrinsic metal chelating property of the porphyrin ring.…”