an-orthotopic-endometrial-cancer-model-with-retroperitoneal

An Orthotopic Endometrial Cancer Model with Retroperitoneal Lymphadenopathy Made From In Vivo Propagated and Cultured VX2 Cells

Endometrial cancer is the most common gynecologic malignancy in North America and the incidence is rising worldwide. Treatment consists of surgery with or ...

Research in the development of nanoscale drug carriers primarily focuses on maximizing drug delivery efficiency to tumor tissues. However, less attention has been given to minimizing drug toxicity to non-targeted cells to enhance therapeutic selectivity.

Attenuation of nontargeted cell-kill using a high-density lipoprotein-mimicking peptide--phospholipid nanoscaffold.

The main challenge for RNAi therapeutics lies in systemic delivery of siRNA to the correct tissues and transporting them into the cytoplasm of targeted cells, at safe, therapeutic levels. Recently, we developed a high-density lipoprotein-mimicking peptide-phospholipid scaffold (HPPS) and demonstrated its direct cytosolic delivery of siRNA in vitro, thereby bypassing endosomal trapping.

Efficient systemic delivery of siRNA by using high-density lipoprotein-mimicking peptide lipid nanoparticles.

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.

A PEGylation-Free Biomimetic Porphyrin Nanoplatform for Personalized Cancer Theranostics.

Porphysome nanoparticles for enhanced photothermal therapy in a patient-derived orthotopic pancreas xenograft cancer model: a pilot study.

We have developed ultrasmall porphyrin-high-density lipoprotein (HDL) nanoparticles (<20 nm), called "porphyrinHDL," that have a high density of porphyrin molecules and dissociate rapidly upon tumor cell accumulation to become fluorescent and photoactive. This is introduced as a novel activatable photosensitizer for image-guided photodynamic therapy (PDT). Here, we report the studies of these nanoparticles targeted to scavenger receptor class B type I (SR-BI) expressed on lung cancer cells as a first step toward development of a minimally invasive treatment for peripheral lung cancer and metastatic lymph nodes of advanced lung cancer.

Porphyrin-High-Density Lipoprotein: A Novel Photosensitizing Nanoparticle for Lung Cancer Therapy.

We describe a simple and effective bioconjugation strategy to extend the plasma circulation of a low molecular weight targeted phototheranostic agent, which achieves high tumor accumulation (9.74 ± 2.26%ID/g) and high tumor-to-background ratio (10:1). Long-circulating pyropheophorbide (LC-Pyro) was synthesized with three functional building blocks: (1) a porphyrin photosensitizer for positron-emission tomography (PET)/fluorescence imaging and photodynamic therapy (PDT), (2) a urea-based prostate-specific membrane antigen (PSMA) targeting ligand, and (3) a peptide linker to prolong the plasma circulation time. With porphyrin's copper-64 chelating and optical properties, LC-Pyro demonstrated its dual-modality (fluorescence/PET) imaging potential for selective and quantitative tumor detection in subcutaneous, orthotopic, and metastatic murine models. The peptide linker in LC-Pyro prolonged its plasma circulation time about 8.5 times compared to its truncated analog. High tumor accumulation of LC-Pyro enabled potent PDT, which resulted in significantly delayed tumor growth in a subcutaneous xenograft model. This approach can be applied to improve the pharmacokinetics of existing and future targeted PDT agents for enhanced tumor accumulation and treatment efficacy.

Tuning Pharmacokinetics to Improve Tumor Accumulation of a Prostate-Specific Membrane Antigen-Targeted Phototheranostic Agent.

Nonsurgical and minimally invasive approaches for early-stage peripheral lung cancer are needed to avoid the known morbidity of surgical resection, particularly in high-risk patients. We previously demonstrated the utility of multifunctional porphyrin-phospholipid nanoparticles (porphysomes) for fluorescence imaging and phototherapy after preferential accumulation into tumors. The objective of this study was to demonstrate the feasibility of porphysome-mediated imaging and photothermal therapy using a newly developed fiberscope and thoracoscope.

Article	Year
Attenuation of nontargeted cell-kill using a high-density lipoprotein-mimicking peptide--phospholipid nanoscaffold. Nanomedicine (London, England)\| PubMed ID: 21718175	2011
Efficient systemic delivery of siRNA by using high-density lipoprotein-mimicking peptide lipid nanoparticles. Nanomedicine (London, England)\| PubMed ID: 22830501	2012
A PEGylation-Free Biomimetic Porphyrin Nanoplatform for Personalized Cancer Theranostics. ACS nano\| PubMed ID: 25830219	2015
Porphysome nanoparticles for enhanced photothermal therapy in a patient-derived orthotopic pancreas xenograft cancer model: a pilot study. Journal of biomedical optics\| PubMed ID: 27552306	2016
Porphyrin-High-Density Lipoprotein: A Novel Photosensitizing Nanoparticle for Lung Cancer Therapy. The Annals of thoracic surgery\| PubMed ID: 30316853	2019
Tuning Pharmacokinetics to Improve Tumor Accumulation of a Prostate-Specific Membrane Antigen-Targeted Phototheranostic Agent. Bioconjugate chemistry\| PubMed ID: 30350576	2018
Evaluation of Novel Imaging Devices for Nanoparticle-Mediated Fluorescence-Guided Lung Tumor Therapy. The Annals of thoracic surgery\| PubMed ID: 30742818	2019

Lili Ding

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