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Enhanced drug transport through alginate biofilms using magnetic nanoparticles


Shayna McGill, an INCBN IGERT Trainee at the University of New Mexico, is investigating whether magnetic nanoparticles, under the influence of a static magnetic field, may be used to penetrate through an in vitro model of P. aeruginosa biofilms. To determine this capability, transport efficiencies of fluorescent-labeled magnetic nanoparticles on the macro-scale using bulk diffusion experiments are being compared to the nano-scale results using single particle tracking methods in the presence and absence of a magnetic field. Qualitatively, transport of the magnetic nanoparticles was significantly influenced by the application of a magnetic field in the alginate model (Fig. 1). The photo-montage shown in Fig. 1 was obtained using a digital camera over 120 sec. A small permanent magnet was placed below the dish (black bar), to which the magnetic nanoparticles were drawn (grey mass). Fig. 1 demonstrates that magnetic nanoparticles have increased bulk transport through alginate when exposed to a magnetic field.

Though witnessed qualitatively, bulk transport of magnetic nanoparticles was further quantified within the alginate solution using a side-by-side diffusion apparatus. To quantify magnetic nanoparticle flux across the alginate biofilm into the receptor compartment, iron content of the samples was quantified with a FerroZine assay method. Cumulative mass of iron was calculated by from the concentration of iron found within the receptor side (Fig. 2). Calculated permeation rate during magnetically enhanced transport and control is shown in Fig. 3. The permeability of the magnetic nanoparticles through the model alginate biofilm was enhanced 13.6 fold using an external magnetic field relative to the control (no magnetic field).

A concomitant velocity change at the single particle level was also observed using particles with different surface chemistry but identical core composition. Fluorescent magnetic nanoparticles possessing different surface functional groups were individually evaluated for transport behavior in the alginate biofilm model. Transport was evaluated using single particle tracking and quantified with a Matlab algorithm producing a velocity for each of the magnetic nanoparticle types, with or without a magnetic field, plotted against both size and functional groups (Fig. 4). Increased transport was seen for particles irrespective of size or functional group when the particles were exposed to a magnetic field.

Biofilms represent formidable barriers to both the body’s own defenses and anti-microbial therapeutic agents. These polymeric exopolysaccharides are used by bacterial colonies as a defense mechanism, leading to a chronic infection. The function of the biofilm for the inhabiting bacteria is multifaceted but includes the ability to reduce opsonization and subsequent phagocytosis by the patient’s immune system, and the ability to limit diffusion of solutes and macromolecules (such as therapeutic agents). As a consequence of these highly evolved defense mechanisms, invading bacteria can become permanent within the patient and eventually require severe clinical interventions (e.g. removal of an implant) or may cause a premature death of the patient (e.g. in cystic fibrosis patient). There have been a variety of attempts to modify therapeutic agents or their delivery systems to overcome biofilm barriers. However, to our knowledge this is the first study that has looked at the potential for magnetic nanoparticle to penetrate biofilms as carriers for drugs.

Significant increases in transport rates of iron oxide nanoparticles through alginate biofilm were observed in the presence of a magnetic field. On a bulk-scale, particles had enhanced permeabilities on the order of 13.6 fold relative to no magnetic fields. On the nanoscale, enhancement of transport was greater than 40 fold. These magnitudes of transport increases in the presence of an external magnetic field represent significant opportunities to increase drug transport into previously unreachable areas of infection. By drug loading these magnetic nanoparticles and causing triggered drug release from the nanoparticle surface, antibiotic penetration of P. aeurginosa biofilm can be achieved. Thicker biofilms will decrease the diffusion of antibiotics, in turn exposing the antibiotics to depleted oxygen or enzymes that destroy or limit their effectiveness. We were able to achieve increased permeation through the biofilm, resulting in 3.3 ug/mL concentration of accumulated iron particles 60 minutes following treatment.

Ms. McGill’s research demonstrates that magnetic nanoparticles can be pulled through a biofilm and could potentially deliver therapeutics to the site of the bacterial cells. Additionally, considerable transport enhancement ratios for these particles has been demonstrated on the nanoscale. These data strongly support the need for further investigation of the potential of magnetic nanoparticles to promote directed drug delivery through biofilms.

Address Goals

These proof-of-concept studies demonstrate the potential of magnetic nanoparticles to enhance the drug delivery in a directed motion through biofilms and would be limited if it were not for this NSF fellowship. The collaborative nature of the INCBN IGERT fellowship allowed this research to span over various fields, not just in pharmaceutics but also physics and engineering. This new development is to help in overcoming a drug delivery barrier that is present not just in in P. aeurginosa bacteria but has been observed in many other virulent types of bacteria. Being able to learn how to apply magnetic nanoparticles to a biologically created system to form a new method of using these nanoparticles for a pharmaceutical problem would not have been possible without the interdisciplinary goals of the Integrating Nanotechnology with Cell Biology and Neuroscience (INCBN) IGERT.