Introduction Staphylococcus aureus is one of the first pathogens to colonize and infect the lungs of cystic fibrosis (CF) patients, causing recurrent and relapsing infections, particularly in children and adolescents (1,2). Moreover, recent data have demonstrated an increase in S. aureus infections in the CF population being reported both in USA and Europe, with methicillin resistant S. aureus (MRSA) strains being on the rise (3). Emergence of multidrug-resistant bacteria, such as MRSA, therefore poses a special challenge in the treatment of infections in CF and new therapeutic agents are required to eradicate these pathogens. Some persistent lung infections often have low response rates to conventional chemotherapy, in part due to the lack of selectivity of many of antimicrobial drugs and their low bioavailability, especially when administered by a systemic route. Thus, the design of new formulations, that allow dose-intensification with reduced or no systemic side effects, have emerged to provide higher antimicrobial activity. Prolonging plasma circulation time, lowering renal drug exposure, and increasing lung tissue deposition, Solid Lipid Nanoparticles (SLN) are good candidate to facilitate antimicrobial delivery to microbial infection sites. Aim of the work With the ongoing efforts in the nanomedicine field, here we evaluate the biodistribution and “in vivo” safety of SLN specifically designed to encapsulate a new lead antimicrobial agent, exploring the possibility that nanoparticle-based drug delivery systems could improve treatments of bacterial infections. Methods SLN have been produced by Nanovector s.r.l. and specifically designed to encapsulate antimicrobial agents. Their preparation is based on an original warm microemulsion technique allowing the production of nanocarriers in an aqueous solution with a size ranging from approximately 20 nm to 200 nm. The new lead antimicrobial compound SR155 loaded by SLN has been administered in healthy mice via pulmonary route by means of intratracheal aerosolization. The biodistribution of unloaded SLN was evaluated by means of radiochemical technique and in vivo Fluorescent Microscopy Tomography (FMT 1500, Perkin Elmer). Results and discussion Extensive studies have demonstrated that the use of an appropriate nanocarrier for the delivery of therapeutics together with pulmonary route of administration can help to biodistribute the biologically active agents to the lungs and extend their retention period. This can enhance the efficacy of the treatment, reducing possible side effects. Our preliminary results confirmed that [3H]-SLN developed by Nanovector represent a suitable drug delivery system to improve drug bioavailability within the lungs. Inhaled [3H]-SLN ensure greater localization in the lung and lower retention in the liver with a reduced first pass effect. Moreover using a fluorescence microscopy tomography system we were able to evaluate the biodistribution profile of indocarbocyanine iodide(DiR)-labeled SLN in adult mice after single intratracheal instillation (50 µL, 9-18 mg/mL as total lipids). We have shown that DiR-SLN are retained within the lungs for hours after IT aerosolization, and 24 hours after the administration the 20% of the administered dose is still present within the lungs. Biodistribution studies of the SR155 antimicrobial compound are currently running. SR155 loaded by this new SLN formulation IT administered in 4 mice up to the final dose 0.129 mg/mice did not exert any signs of acute toxicity being preserved respiratory functionalities and behavior. Conclusions Many antimicrobial drugs are difficult to administer because of their low water-solubility, cytotoxicity to healthy tissues, rapid degradation and clearance in the blood stream. Their antimicrobial activities against intracellular microbes are also severely limited by poor membrane transport ability. Extensive studies have demonstrated that nanoparticles such as liposomes and solid lipid nanoparticles (SLN) are able to overcome these issues and to facilitate antimicrobial delivery to microbial infection sites. References 1. Cystic Fibrosis Foundation 2012. Patient registry 2011 annual data report. Cystic Fibrosis Foundation, Bethesda, MD, USA. 2. International Journal of Medical Microbiology, 2010, 300: 514-519 3. Med Princ Pract, 2014, DOI:10.1159/000357646

Dal Magro, R., Sancini, G., Musumeci, R., Beretta, S., Bulbarelli, A., Lonati, E., et al. (2014). Development of solid lipid nanoparticles for antimicrobial drug delivery. Intervento presentato a: CRS Italy Chapter November 6th – 8th, Firenze, Italia.

Development of solid lipid nanoparticles for antimicrobial drug delivery

DAL MAGRO, ROBERTA;SANCINI, GIULIO ALFREDO;MUSUMECI, ROSARIO;BULBARELLI, ALESSANDRA;LONATI, ELENA RITA;COCUZZA, CLEMENTINA ELVEZIA;
2014

Abstract

Introduction Staphylococcus aureus is one of the first pathogens to colonize and infect the lungs of cystic fibrosis (CF) patients, causing recurrent and relapsing infections, particularly in children and adolescents (1,2). Moreover, recent data have demonstrated an increase in S. aureus infections in the CF population being reported both in USA and Europe, with methicillin resistant S. aureus (MRSA) strains being on the rise (3). Emergence of multidrug-resistant bacteria, such as MRSA, therefore poses a special challenge in the treatment of infections in CF and new therapeutic agents are required to eradicate these pathogens. Some persistent lung infections often have low response rates to conventional chemotherapy, in part due to the lack of selectivity of many of antimicrobial drugs and their low bioavailability, especially when administered by a systemic route. Thus, the design of new formulations, that allow dose-intensification with reduced or no systemic side effects, have emerged to provide higher antimicrobial activity. Prolonging plasma circulation time, lowering renal drug exposure, and increasing lung tissue deposition, Solid Lipid Nanoparticles (SLN) are good candidate to facilitate antimicrobial delivery to microbial infection sites. Aim of the work With the ongoing efforts in the nanomedicine field, here we evaluate the biodistribution and “in vivo” safety of SLN specifically designed to encapsulate a new lead antimicrobial agent, exploring the possibility that nanoparticle-based drug delivery systems could improve treatments of bacterial infections. Methods SLN have been produced by Nanovector s.r.l. and specifically designed to encapsulate antimicrobial agents. Their preparation is based on an original warm microemulsion technique allowing the production of nanocarriers in an aqueous solution with a size ranging from approximately 20 nm to 200 nm. The new lead antimicrobial compound SR155 loaded by SLN has been administered in healthy mice via pulmonary route by means of intratracheal aerosolization. The biodistribution of unloaded SLN was evaluated by means of radiochemical technique and in vivo Fluorescent Microscopy Tomography (FMT 1500, Perkin Elmer). Results and discussion Extensive studies have demonstrated that the use of an appropriate nanocarrier for the delivery of therapeutics together with pulmonary route of administration can help to biodistribute the biologically active agents to the lungs and extend their retention period. This can enhance the efficacy of the treatment, reducing possible side effects. Our preliminary results confirmed that [3H]-SLN developed by Nanovector represent a suitable drug delivery system to improve drug bioavailability within the lungs. Inhaled [3H]-SLN ensure greater localization in the lung and lower retention in the liver with a reduced first pass effect. Moreover using a fluorescence microscopy tomography system we were able to evaluate the biodistribution profile of indocarbocyanine iodide(DiR)-labeled SLN in adult mice after single intratracheal instillation (50 µL, 9-18 mg/mL as total lipids). We have shown that DiR-SLN are retained within the lungs for hours after IT aerosolization, and 24 hours after the administration the 20% of the administered dose is still present within the lungs. Biodistribution studies of the SR155 antimicrobial compound are currently running. SR155 loaded by this new SLN formulation IT administered in 4 mice up to the final dose 0.129 mg/mice did not exert any signs of acute toxicity being preserved respiratory functionalities and behavior. Conclusions Many antimicrobial drugs are difficult to administer because of their low water-solubility, cytotoxicity to healthy tissues, rapid degradation and clearance in the blood stream. Their antimicrobial activities against intracellular microbes are also severely limited by poor membrane transport ability. Extensive studies have demonstrated that nanoparticles such as liposomes and solid lipid nanoparticles (SLN) are able to overcome these issues and to facilitate antimicrobial delivery to microbial infection sites. References 1. Cystic Fibrosis Foundation 2012. Patient registry 2011 annual data report. Cystic Fibrosis Foundation, Bethesda, MD, USA. 2. International Journal of Medical Microbiology, 2010, 300: 514-519 3. Med Princ Pract, 2014, DOI:10.1159/000357646
No
abstract + poster
Scientifica
Cystic fibrosis; S. Aureus; antimicrobial compounds; solid lipid nanoparticles
English
CRS Italy Chapter November 6th – 8th
Dal Magro, R., Sancini, G., Musumeci, R., Beretta, S., Bulbarelli, A., Lonati, E., et al. (2014). Development of solid lipid nanoparticles for antimicrobial drug delivery. Intervento presentato a: CRS Italy Chapter November 6th – 8th, Firenze, Italia.
DAL MAGRO, R; Sancini, G; Musumeci, R; Beretta, S; Bulbarelli, A; Lonati, E; Galletti, P; Giacomini, D; Cocuzza, C; Gasco, P
File in questo prodotto:
File Dimensione Formato  
Abstract_R.DalMagro.doc

accesso aperto

Dimensione 36 kB
Formato Microsoft Word
36 kB Microsoft Word Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/91312
Citazioni
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
Social impact