A PEGylation-Free Biomimetic Porphyrin Nanoplatform for Personalized Cancer Theranostics

Abstract

PEGylation (PEG) is the most commonly adopted strategy to prolong nanoparticles' vascular circulation by mitigating the reticuloendothelial system uptake. However, there remain many concerns in regards to its immunogenicity, targeting efficiency, etc., which inspires pursuit of alternate, non-PEGylated systems. We introduced here a PEG-free, porphyrin-based ultrasmall nanostructure mimicking nature lipoproteins, termed PLP, that integrates multiple imaging and therapeutic functionalities, including positron emission tomography (PET) imaging, near-infrared (NIR) fluorescence imaging and photodynamic therapy (PDT). With an engineered lipoprotein-mimicking structure, PLP is highly stable in the blood circulation, resulting in favorable pharmacokinetics and biodistribution without the need of PEG. The prompt tumor intracellular trafficking of PLP allows for rapid nanostructure dissociation upon tumor accumulation to release monomeric porphyrins to efficiently generate fluorescence and photodynamic reactivity, which are highly silenced in intact PLP, thus providing an activatable mechanism for low-background NIR fluorescence imaging and tumor-selective PDT. Its intrinsic copper-64 labeling feature allows for noninvasive PET imaging of PLP delivery and quantitative assessment of drug distribution. Using a clinically relevant glioblastoma multiforme model, we demonstrated that PLP enabled accurate delineation of tumor from surrounding healthy brain at size less than 1 mm, exhibiting the potential for intraoperative fluorescence-guided surgery and tumor-selective PDT. Furthermore, we demonstrated the general applicability of PLP for sensitive and accurate detection of primary and metastatic tumors in other clinically relevant animal models. Therefore, PLP offers a biomimetic theranostic nanoplatform for pretreatment stratification using PET and NIR fluorescence imaging and for further customized cancer management via imaging-guided surgery, PDT, or/and potential chemotherapy.

Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma

“…While several other chemotherapeutic agents have been incorporated in HDL nanoparticles for targeted delivery, 29,30,[40][41][42] the approach described here offers several distinct advantages with respect to the ease of clinical translation. Most biomimetic HDL nanoparticles are assembled using the full-length ApoA 1 protein, 15 which is technically difficult and costly to produce, making ApoA 1 -based HDL delivery not commercially feasible.…”

Synthetic high-density lipoproteins for delivery of 10-hydroxycamptothecin

“…Several groups including us have reported accumulation of fluorescent dye-loaded sHDL in subcutaneous tumor xenographs as well as liver, lungs, and spleen. 10,11 The uniqueness of this study is that we have merged the ability to prepare very homogeneous pharmaceutical quality peptide-based synthetic HDL nanoparticles with loading of a hydrophobic drug. Several investigators have successfully loaded hydrophobic drugs, peptides and siRNA, and vaccine antigens in sHDL.…”

“…6,7 Several groups have utilized the ability of HDL to retain hydrophobic anticancer drugs and selectively deliver chemotherapeutics to tumors. 1,[7][8][9][10][11] A long circulation half-life and a very small particle size allow for sHDL to effectively accumulate in a tumor region and to penetrate extracellular matrix. 12 Yet the clinical translation of this concept is lacking due to high cost and technical difficulty in…”

Multimodal Image-Guided Surgical and Photodynamic Interventions in Head and Neck Cancer: From Primary Tumor to Metastatic Drainage

“…Recently, we developed a novel biomimetic, porphyrin lipoprotein-mimicking nanoparticle (PLP), which integrates multiple functionalities, including PET, near-infrared (NIR) fluorescence imaging, and PDT into an ultra-small ($20 nm) nanoscaffold (20). Intrinsic copper-64 labeling allows for preoperative PET imaging of PLP delivery as well as sensitive and accurate detection of various primary and metastatic tumor types in mouse models.…”