Targeted chemotherapy via HER2-based chimeric antigen receptor(CAR)engineered T-cell membrane coated polymeric nanoparticles

Cell membrane-derived nanoparticles(NPs)have recently gained popularity due to their desirable features in drug delivery such as mimicking properties of native cells,impeding systemic clearance,and altering foreign body responses.Besides NP technology,adoptive immunotherapy has emerged due to its promise in cancer specificity and therapeutic efficacy.In this research,we developed a biomimetic drug carrier based on chimeric antigen receptor(CAR)transduced T-cell membranes.For that purpose,anti-HER2 CAR-T cells were engineered via lentiviral transduction of anti-HER2 CAR coding lentiviral plasmids.Anti-HER2 CAR-T cells were characterized by their specific activities against the HER2 antigen and used for cell membrane extraction.Anti-cancer drug Cisplatin-loaded poly(D,L-lactide-co-glycolic acid)(PLGA)NPs were coated with anti-human epidermal growth factor receptor 2(HER2)-specific CAR engineered T-cell membranes.Anti-HER2 CAR-T-cell membrane-coated PLGA NPs(CAR-T-MNPs)were characterized and confirmed via fluorescent microscopy and flow cytometry.Membrane-coated NPs showed a sustained drug release over the course of 21 days in physiological conditions.Cisplatin-loaded CAR-T-MNPs also inhibited the growth of multiple HER2+cancer cells in vitro.In addition,in vitro uptake studies revealed that CAR-T-MNPs showed an increased uptake by A549 cells.These results were also confirmed via in vivo biodistribution and therapeutic studies using a subcutaneous lung cancer model in nude mice.CAR-T-MNPs localized preferentially at tumor areas compared to those of other studied groups and consisted of a significant reduction in tumor growth in tumor-bearing mice.In Conclusion,the new CAR modified cell membrane-coated NP drug-delivery platform has demonstrated its efficacy both in vitro and in vivo.Therefore,CAR engineered membrane-coated NP system could be a promising cell-mimicking drug carrier that could improve therapeutic outcomes of lung cancer treatments.

Spatial distribution and network morphology of epicardial,endocardial,interstitial,and Purkinje cell-associated elastin fibers in porcine left ventricle

Cardiac extracellular matrices(ECM)play crucial functional roles in cardiac biomechanics.Previous studies have mainly focused on collagen,the major structural ECM in heart wall.The role of elastin in cardiac mechanics,however,is poorly understood.In this study,we investigated the spatial distribution and microstructural morphologies of cardiac elastin in porcine left ventricles.We demonstrated that the epicardial elastin network had location-and depth-dependency,and the overall epicardial elastin fiber mapping showed certain correlation with the helical heart muscle fiber architecture.When compared to the epicardial layer,the endocardial layer was thicker and has a higher elastin-collagen ratio and a denser elastin fiber network;moreover,the endocardial elastin fibers were finer and more wavy than the epicardial elastin fibers,all suggesting various interface mechanics.The myocardial interstitial elastin fibers co-exist with the perimysial collagen to bind the cardiomyocyte bundles;some of the interstitial elastin fibers showed a locally aligned,hinge-like structure to connect the adjacent cardiomyocyte bundles.This collagen-elastin combination reflects an optimal design in which the collagen provides mechanical strength and elastin fibers facilitate recoiling during systole.Moreover,cardiac elastin fibers,along with collagen network,closely associated with the Purkinje cells,indicating that this ECM association could be essential in organizing cardiac Purkinje cells into“fibrous”and“branching”morphologies and serving as a protective feature when Purkinje fibers experience large deformations in vivo.In short,our observations provide a structural basis for future in-depth biomechanical investigations and biomimicking of this long-overlooked cardiac ECM component.

Temperature-sensitive polymeric nanogels encapsulating withβ-cyclodextrin and ICG complex for high-resolution deep-tissue ultrasound-switchable fluorescence imaging

One of the thorny problems currently impeding the applications of the fluorescence imaging technique is the poor spatial resolution in deep tissue.Ultrasound-switchable fluorescence(USF)imaging is a novel imaging tool that has recently been explored to possibly surmount the above-mentioned bottleneck.Herein,αβ-cyclodextrin/indocyanine green(ICG)complex-encapsulated poly(N-isopropylacrylamide)(PNIPAM)nanogel was synthesized and studied for ex vivo/in vivo deep tissue/high-resolution near infrared USF(NIR-USF)imaging.To be specific,our results revealed that the average diameter of the as-prepared nanogels was significantly decreased to-32 nm from-335 nm compared to the reported ICG-PNIPAM nanoparticles.Additionally,the excitation/emission characteristics of the ICG itself in present nanogels were almost completely retained,and the resultant nanogel exhibited high physiological stability and positive biocompatibility.In particular,the signal-to-noise ratio of the USF image for the PNIPAM/P-cyclodextrin/ICG nanogel(33.01±2.42 dB)was prominently higher than that of the ICG-PNIPAM nanoparticles(18.73±0.33 dB)in 1.5-cm-thick chicken breast tissues.The NIR-USF imaging in 3.5-cm-thick chicken breast tissues was achieved using this new probe.The e x v iv o NIR-USF imaging of the mouse liver was also successfully obtained.Animal experiments showed that the present nanogels were able to be effectively accumulated into U87 tumor-bearing mice via enhanced permeability and retention effects,and the high-resolution NIR-USF imaging of in v ivo tumor was efficiently acquired.The metabolism and in vivo biodistribution of the nanogels were evaluated.Overall,the results suggest that the current nanogel is a highly promising NIR-USF probe for deep tissue and high-resolution USF imaging.

Cell-mediated and cell membrane-coated nanoparticles for drug delivery and cancer therapy

Nanotechnology-based drug delivery platforms have been developed over the last two decades because of their favorable features in terms of improved drug bioavailability and stability.Despite recent advancement in nanotechnology platforms,this approach still falls short to meet the complexity of biological systems and diseases,such as avoiding systemic side effects,manipulating biological interactions and overcoming drug resistance,which hinders the therapeutic outcomes of the NP-based drug delivery systems.To address these issues,various strategies have been developed including the use of engineered cells and/or cell membrane-coated nanocarriers.Cell membrane receptor profiles and characteristics are vital in performing therapeutic functions,targeting,and homing of either engineered cells or cell membrane-coated nanocarriers to the sites of interest.In this context,we comprehensively discuss various cell-and cell membrane-based drug delivery approaches towards cancer therapy,the therapeutic potential of these strategies,and the limitations associated with engineered cells as drug carriers and cell membrane-associated drug nanocarriers.Finally,we review various cell types and cell membrane receptors for their potential in targeting,immunomodulation and overcoming drug resistance in cancer.