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.
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.
The superiore fficacy … …ofaminopolycarboxylic acid conjugated lipid nanoparticles over standard liposomal nanoparticles is described by Juan Chen, Gang Zheng et al. in their Research Article (e202218218). EDTA-lipid based nanoparticles fluidize the cell membrane in a detergent-like manner and improve delivery to the cell by 25-fold. This novel nanoparticle design feature can be deployed across lipid nanoparticles to accelerate cancer nanomedicine drug delivery.
Background: Accumulation of systemically administered nanoparticles (NPs) in lymph nodes has been exploited clinically for diagnostic imaging (e.g., USPIOs for lymph node metastasis) and therapeutic applications (e.g., vaccine delivery). However, the combination of diagnostic and therapeutic functionalities into a single theranostic NP has obliged undesirable trade-offs between either the imaging or drug delivery of the NP and their specific accumulation in lymph nodes. To overcome these trade-offs, we conducted a screen of various lipid-based theranostic NPs focusing on differing NP design and their resulting pharmacokinetic behaviours in healthy and diseased lymph node models. Methods: Lipid-based theranostic NPs with varying physicochemical characteristics (e.g., formulation, size and morphology, surface targeting, etc.) were prepared with positron emitting Cu-64 and administered systemically at equivalent NP doses in healthy and diseased rodent models (i.e., mice and rats). NP types were assessed for time-dependent accumulation in major lymph node basins via non-invasive whole-body PET/MR imaging at two or more timepoints per animal. 72-hours post-injection the animals were sacrificed, and lymph nodes and major organs were excised for gamma counting and pathological evaluation. Pharmacokinetic behaviour of NPs in healthy versus diseased lymph nodes were calculated in individual animals and in naïvely pooled datasets using non-compartmental analysis. Results: Preliminary analysis identified a leading NP candidate with specific lymph node targeting in healthy and diseased rodents: a discoidal, 35-nm peptide-targeted HDL-mimetic. In comparison with a spherical, 100-nm PEGylated NP, the discoidal NP obtained greater absolute (%ID) and relative (%ID/g) amounts of injected dose in anatomically matched lymph nodes than the spherical NP, regardless of lymph node pathology. At greatest measured concentration in healthy lymph nodes, typically 24-hpi, the differences between the discoidal and spherical NPs were on average 3-fold greater (2.893 vs. 0.864, %ID/g). Differences in other pharmacokinetic parameters such as AUC (%ID/g*h) and MRT (h) were equally pronounced. Conclusions: Our preliminary analysis uncovered a discoidal, peptide-targeted HDL-mimetic with remarkable accumulation in lymph nodes of healthy and diseased models. Future investigations will focus on the biochemical and cellular mechanisms underlying their unique lymphatic pharmacokinetics. These preliminary results provide key insights for design of theranostic NPs for non-invasive imaging and staging lymph node pathologies, and for applications in delivery of therapeutics to lymph nodes following systemic administration. Citation Format: Michael S. Valic, Mark Zheng, Lili Ding, Michelle Lai, Chris J. Zhang, Tina Ye, Jenny Ma, Michael Halim, Pamela Schimmer, Wenlei Jiang, Juan Chen, Gang Zheng. Lymph node accumulation of theranostic lipid-based nanoparticles in healthy and diseased models: Preliminary results comparing nanoparticle morphology and targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 307.
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