| Summary: | [Prec. Nanomed. 2019 July;2(3):303-317](https://precisionnanomedicine.com/article/9660-pyrazinoic-acid-poly-malic-acid-biodegradable-nanoconjugate-for-efficient-intracellular-delivery):
BASIC RESEARCH
Abstract: Tuberculosis is an infectious disease affecting mostly lungs, that is still considered a health global problem as it causes millions of deaths worldwide. Current treatment is effective but associated with severe adverse effects due to the high doses of each anti-tuberculosis drug daily administrated by oral therapy. For the first time, a pyrazinoic acid (PA) biodegradable nanoconjugate was synthesized and developed for pulmonary administration in an attempt to reduce the administered doses by achieving a high drug payload and controlled release at the target site. The conjugate was synthesized by coupling pyrazinoic acid on carboxylic groups of poly(malic acid), which is a biodegradable and biocompatible polymer, and posteriorly self-assembled into nanoconjugates. Characterization confirmed the formation of nanometric, spherical and negatively charged pyrazinoic acid nanoconjugate (NC-PA). NC-PA was stable for 60 days at 4 and 37°C and able to deliver PA in a sustained release manner over time. On macrophages, they exhibited no cell toxicity for a wide range of concentrations (from 1 to 100 µg/mL), demonstrating the safety of NC-PA. In addition, the nanoconjugate was efficiently taken up by RAW 264.7 cells over 6 hours reaching a maximum value after 3 hours of incubation. In conclusion, innovative nanoconjugates are a promising alternative to deliver drugs directly to the lungs and contributing to improving tuberculosis therapy.
[Prec. Nanomed. 2019 July;2(3):344-369:](https://precisionnanomedicine.com/article/9900-physiologic-constraints-of-using-exosomes-in-vivo-as-systemic-delivery-vehicles)
POTENTIAL CLINICAL SIGNIFICANCE
Abstract: Systemic delivery of exosomes meets hurdles which had not been elucidated using live molecular imaging for their biodistribution. Production and uptake of endogenous exosomes are expected to be nonspecific and specific, respectively, where external stimuli of production of exosomes and their quantitative degree of productions are not understood. Despite this lack of understanding of basic physiology of in vivo behavior of exosomes including their possible paracrine or endocrine actions, many engineering efforts are taken to develop therapeutic vehicles. Especially, the fraction of exosomes’ taking the routes of waste disposal and exerting target actions are not characterized after systemic administration. Here, we reviewed the literature about in vivo distribution and disposal/excretion of exogenous or endogenous exosomes and, from these limited resources of knowledge currently available, summarized the knowledge and the uncertainties of exosomes on physiologic standpoints. An eloquent example of the investigations to understand the roles and confounders of exosomes’ action in the brain was highlighted with emphasis on the recent discovery of brain lymphatics and hypothesis of glymphatic/lymphatic clearance pathways in diseases as well as in physiologic processes. The possibility of delivering therapeutic exosomes through the systemic circulation, across blood-brain barriers and finally to target cells such as microglia, astrocytes and/or neurons is a good testbed in which the investigators can formulate problems to solve for both understanding (science) and application (engineering).
[Prec. Nanomed. 2019 July;2(3):318-343:](https://precisionnanomedicine.com/article/9880-electric-charge-conversable-drug-liposomes-enable-to-enhance-treatment-efficacy-of-breast-cancer)
CLINICAL SIGNIFICANCE
Abstract: Intrinsic drug resistance has been demonstrated in different types of breast cancer cells, leading to the recurrence of disease after treatment. Here, we report a functional drug liposome that enables electric charge conversion in the weak acidic milieu of cancer to enhance the treatment efficacy of different breast cancers. The functional drug liposomes were developed by encapsulating daunorubicin and rofecoxib, and modified with new functional material, D-alpha tocopherol acid succinate-polyethylene glycol-glutarate (TPGS1000-glutarate). The results demonstrated that the liposomes promoted the effects of cellular uptake and lysosomal escape, followed by targeting the mitochondria. Consequently, the electric charge conversable drug liposomes significantly enhanced the treatment efficacy by initiating a cascade of reactions through inducing autophagy and apoptosis in different breast cancer cells. In conclusion, the electric charge conversable drug liposomes enable to enhance treatment efficacy of different breast cancers, and hence the study could offer a broadly applicable strategy to enhance efficacy against heterogeneous and refractory cancer cells.
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