Lipoprotein mimetic nanostructures, which consist of an amphiphilic lipid shell, a hydrophobic core, and an apolipoprotein mimetic peptide, serve as a versatile platform for the design of drug delivery vehicles as well as the investigation of supramolecular assemblies. Porphyrin incorporation into biomimetic lipoproteins allows one to take advantage of the inherent multimodal photophysical properties of porphyrins, yielding various fluorescence, photoacoustic, and photodynamic agents. To facilitate their incorporation into a lipoprotein structure, porphyrins have been conjugated through a variety of strategies. However, the effects of the conjugate structure on the associated nanoparticle’s phototherapeutic properties warrants further investigation. Herein, we systematically investigated the effects of two widely utilized porphyrin conjugates, oleylamide and lipid, on biophotonic properties of their resultant porphyrin-lipoprotein nanoparticles in vitro and in vivo. Specifically, we demonstrated that incorporation of the porphyrin moiety as an oleylamide conjugate leads to a highly stable J-aggregate with strong photoacoustic contrast, while incorporation as an ampiphilic lipid moiety into the lipid shell yields an effective fluorescent and photodynamic agent. The current study proposes a rational design strategy for next-generation lipoprotein-based phototheranostic agents, for which nanoassembly-driven biophotonic and therapeutic properties can be tailored through the specific selection of porphyrin conjugate structures.
Nanoparticles' uptake by cancer cells upon reaching the tumor microenvironment is often the ratelimiting step in cancer nanomedicine. Herein, we report that the inclusion of aminopolycarboxylic acid conjugated lipids, such as EDTA-or DTPA-hexadecylamide lipids in liposome-like porphyrin nanoparticles (PS) enhanced their intracellular uptake by 25-fold, which was attributed to these lipids' ability to fluidize the cell membrane in a detergent-like manner rather than by metal chelation of EDTA or DTPA. EDTA-lipidincorporated-PS (ePS) take advantage of its unique active uptake mechanism to achieve > 95 % photodynamic therapy (PDT) cell killing compared to < 5 % cell killing by PS. In multiple tumor models, ePS demonstrated fast fluorescence-enabled tumor delineation within minutes post-injection and increased PDT potency (100 % survival rate) compared to PS (60 %). This study offers a new nanoparticle cellular uptake strategy to overcome challenges associated with conventional drug delivery.
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