Periodic Reporting for period 1 - AIDViC (Antibiotic intracellular delivery via virus-like carriers)
Reporting period: 2017-07-01 to 2018-12-31
According to the last report (2018) of the World Health Organization (WHO), infectious diseases are listed as the top-10 diseases causing deaths worldwide. In particular, the respiratory infections are ranked as the 4th with almost 3 millions of deaths per year, diarrhea diseases and tuberculosis (TB) are listed as the 9th and the 10th, respectively, with an average of about 1.3 millions death worldwide each (Fig.1 orange).
This alone establishes the critical interaction is the result of the co-evolution between prokaryotic (the parasite) and eukaryotic cells (the host). One of the most striking examples is the Mycobacterium tuberculosis, the etiological agent of human TB, which has selected one of the harshest intracellular environments where to proliferate, the macrophage (MΦ) lysosomes. Given that MΦ cells are mononuclear phagocytes programmed to destroy ingested prey and promote the development of adaptive immunity, this is one of the ultimate paradoxes in the study of host–pathogen interactions indeed.
In this work, we demonstrate the effective targeting and intracellular delivery of antibiotics to both circulating monocytes and resident macrophages, using pH sensitive nanoscopic polymersomes made of poly(2-(methacryloyloxy)ethyl phosphorylcholine)-co-poly(2-(di-isopropylamino)ethyl methacrylate) (PMPC-PDPA). In vivo biodistribution analyses confirmed that polymersomes selectively target a specific sub-population of circulating monocytes, namely the non-classical monocytes responsible to invade infected tissues to restore the local homeostasis. Also, polymersomes have been proved to intracellularly deliver high payloads of antimycobacterial drugs (isoniazid and rifampicin). We confirmed the effective eradication of M tuberculosis, using both in vitro and in vivo approaches, as well as other intracellular parasites including the Mycobacterium bovis, Mycobacterium marinum and the most common bacteria associated with antibiotic resistance, the Staphylococcus aureus.
This alone establishes the critical interaction is the result of the co-evolution between prokaryotic (the parasite) and eukaryotic cells (the host). One of the most striking examples is the Mycobacterium tuberculosis, the etiological agent of human TB, which has selected one of the harshest intracellular environments where to proliferate, the macrophage (MΦ) lysosomes. Given that MΦ cells are mononuclear phagocytes programmed to destroy ingested prey and promote the development of adaptive immunity, this is one of the ultimate paradoxes in the study of host–pathogen interactions indeed.
In this work, we demonstrate the effective targeting and intracellular delivery of antibiotics to both circulating monocytes and resident macrophages, using pH sensitive nanoscopic polymersomes made of poly(2-(methacryloyloxy)ethyl phosphorylcholine)-co-poly(2-(di-isopropylamino)ethyl methacrylate) (PMPC-PDPA). In vivo biodistribution analyses confirmed that polymersomes selectively target a specific sub-population of circulating monocytes, namely the non-classical monocytes responsible to invade infected tissues to restore the local homeostasis. Also, polymersomes have been proved to intracellularly deliver high payloads of antimycobacterial drugs (isoniazid and rifampicin). We confirmed the effective eradication of M tuberculosis, using both in vitro and in vivo approaches, as well as other intracellular parasites including the Mycobacterium bovis, Mycobacterium marinum and the most common bacteria associated with antibiotic resistance, the Staphylococcus aureus.