Liposomes, nanoscale spherical structures composed of amphiphilic lipids, hold great promise for various pharmaceutical applications, especially as nanocarriers in targeted drug delivery, due to their biocompatibility, biodegradability, and low immunogenicity. Understanding the factors influencing their physicochemical properties is crucial for designing and optimizing liposomes. In this study, we have presented the kernel-weighted local polynomial regression (KwLPR) nano-quantitative structure-property relationships (nano-QSPR) model to predict the zeta potential (ZP) based on the structure of 12 liposome formulations, including 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol (DC-Chol), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and L-α-phosphatidylcholine (EPC). The developed model is well-fitted (__-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__R2 = 0.96, __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__RMSEC = 5.76), flexible (__-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__QCVloo2 = 0.83, __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__RMSECVloo = 10.77), and reliable (__-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__QExt2= 0.89 __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__RMSEExt = 5.17). Furthermore, we have established the formula for computing molecular nanodescriptors for liposomes, based on constituent lipids' molar fractions. Through the correlation matrix and principal component analysis (PCA), we have identified two key structural features affecting liposomes' zeta potential: hydrophilic-lipophilic balance (HLB) and enthalpy of formation. Lower HLB values, indicating a more lipophilic nature, are associated with a higher zeta potential, and thus stability. Higher enthalpy of formation reflects reduced zeta potential and decreased stability of liposomes. We have demonstrated that the nano-QSPR approach allows for a better understanding of how the composition and molecular structure of liposomes affect their zeta potential, filling a gap in ZP nano-QSPR modeling methodologies for nanomaterials (NMs). The proposed proof-of-concept study is the first step in developing a comprehensive and computationally based system for predicting the physicochemical properties of liposomes as one of the most important drug nano-vehicles.

01 Apr 2024·International Journal of Pharmaceutics

Polymer-lipid hybrid nanomedicines to deliver siRNA in and against glioblastoma cells

Article

Author: Dumas, Florence ; Roy, Charlotte ; Imbriano, Carol ; Ruozi, Barbara ; Boury, Frank ; Tosi, Giovanni ; Duskey, Jason Thomas ; Ottonelli, Ilaria ; Vandelli, Maria Angela ; Belluti, Silvia ; Rinaldi, Arianna ; Garcion, Emmanuel

Small interfering RNA (siRNA) holds great potential to treat many difficult-to-treat diseases, but its delivery remains the central challenge. This study aimed at investigating the suitability of polymer-lipid hybrid nanomedicines (HNMeds) as novel siRNA delivery platforms for locoregional therapy of glioblastoma. Two HNMed formulations were developed from poly(lactic-co-glycolic acid) polymer and a cationic lipid: 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) or 3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol (DC-Chol). After characterization of the HNMeds, a model siRNA was complexed onto their surface to form HNMed/siRNA complexes. The physicochemical properties and siRNA binding ability of complexes were assessed over a range of nitrogen-to-phosphate (N/P) ratios to optimize the formulations. At the optimal N/P ratio of 10, complexes effectively bound siRNA and improved its protection from enzymatic degradation. Using the NIH3T3 mouse fibroblast cell line, DOTAP-based HNMeds were shown to possess higher cytocompatibility in vitro over the DC-Chol-based ones. As proof-of-concept, uptake and bioefficacy of formulations were also assessed in vitro on U87MG human glioblastoma cell line expressing luciferase gene. Complexes were able to deliver anti-luciferase siRNA and induce a remarkable suppression of gene expression. Noteworthy, the effect of DOTAP-based formulation was not only about three-times higher than DC-Chol-based one, but also comparable to lipofectamine model transfection reagent. These findings set the basis to exploit this nanosystem for silencing relevant GB-related genes in further in vitro and in vivo studies.

01 Nov 2023·Journal for ImmunoTherapy of Cancer

Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade

Article

Author: Knutson, Keith L ; Jones, Katherine A ; Shreeder, Barath ; Block, Matthew S ; Luo, Yan ; Shi, Huashan ; Bahr, Deborah A ; Necela, Brian M ; Lamichhane, Purushottam ; Zhou, Kexun ; Daum, Joshua I ; Dutta, Navnita ; Kurian, Sophia ; Cannon, Martin J ; Jenkins, James W

BackgroundOvarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing.MethodsID8 tumor cells were injected intraperitoneally into mice. Mice were treated with Th17-DC or conventional DC (cDC) vaccine alone or with immune checkpoint blockade (ICB). Systemic immunity, tumor associated immunity, tumor size and survival were examined using a variety of experimental strategies.ResultsTh17-DC vaccines increased Th17 T cells in the tumor microenvironment, reshaped the myeloid microenvironment, and improved mouse survival compared with cDC vaccines. ICB had limited efficacy in OC, but Th17-inducing DC vaccination sensitized it to anti-PD-1 ICB, resulting in durable progression-free survival by overcoming IL-10-mediated resistance. Th17-DC vaccine efficacy, alone or with ICB, was mediated by CD4 T cells, but not CD8 T cells.ConclusionsThese findings emphasize using biologically relevant immune modifiers, like Th17-DC vaccines, in OC treatment to reshape the tumor microenvironment and enhance clinical responses to ICB therapy.

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Indication	Highest Phase	Country/Location	Organization	Date
Myeloid Leukemia	Discovery	US	RGene Therapeutics, Inc.	-

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