Biodegradable Microneedles for Nanoparticle Drug Delivery Technology

Nanomedicine, in particular nanoparticles, has been explored for application as drug delivery systems for the past two decades. The ability of nanoparticles to protect and deliver their cargo to the target site whilst evading detection by the body, due to their small size, makes them ideal as drug vesicles. However, the translation of nanomedicine from research to clinical applications has been slower than desired. Nanoparticles tend to undergo aggregation and agglomeration - which are undesired phenomena when primary particles assemble and exhibit a collective behaviour in solution, causing them to lose their unique size-dependent properties which make them ideal for drug delivery. Therefore, the formulation of nanoparticles into a usable form is now an important topic of research.

Recent studies have shown that nanoparticles can be stabilised by encapsulation into hydrogels or by using cryoprotectants. This concept of formulating nanoparticles into gels led to the hypothesis that incorporating nanoparticles into a biodegradable polymer would not only prevent aggregation/agglomeration but can also be used to sustainably release them into the epidermis of skin. This is where the potential of microneedle technology for transdermal drug delivery has been realised. Although microneedles have been researched since the 1980s, this field of study is relatively novel and translation to the clinic for medical purposes is yet to be achieved. Microneedles are described as cannulas which are either solid or hollow with the ability to penetrate skin up to the dermis, depending on the desired application. They have been approved for clinical use in many cosmetic procedures, but there is yet to be an approval for a medical application.

Several types of microneedles and biodegradable/dissolvable microneedles were of interest in this work. These microneedles will degrade or dissolve in skin, releasing their cargo, due to their matrix being formulated from biodegradable polymers. Therefore, it was hypothesised that encapsulating nanoparticles into the matrix would lead to nanoparticle stabilisation and enhanced drug delivery due to overcoming the stratum corneum barrier of the skin. In this work, a nanoparticle-microneedle-technology was successfully synthesised and characterised, demonstrating the applicability of this technology for drug delivery, in particular for melanoma treatment.

The first stage of developing this technology was to prepare silica nanoparticles infused with various model drugs (known anti-cancer agents) and drug surrogate (fluorescein isothiocyanate dye) and optimise a characterisation protocol. Two synthetic methods were investigated and microemulsion was preferred as it produced nanoparticles with properties closer to those desired for drug delivery - uniform sizes of 100 nm; a more negative surface charge; and a spherical shape. Dynamic light scattering, transmission electron microscopy and spectrofluorometry were techniques utilised for characterisation. The fabricated silica nanoparticles have the ability to target a desired site and were therefore functionalised with antibodies.

Once the silica nanoparticles had been prepared, the challenge to overcome was their aggregation/agglomeration in solution. Therefore, in the second stage of research, the nanoparticles were formulated into biodegradable microneedles. The materials used for the matrix consisted of a mixture of carboxymethyl cellulose (a polymer) and one of three sugars - trehalose, sucrose, or maltose. The characterisation techniques used to confirm the microneedles contained non-aggregated nanoparticles included confocal microscopy, scanning electron microscopy and optical coherence tomography. Scanning electron microscopy showed uniformly dispersed gold nanoparticles within the conical shaped microneedles. Each array consisted of 324 microneedles of length 750 µm, base diameter 200 µm, and centre-to-centre spacing of 600 µm. Darkfield and confocal microscopy confirmed the microneedles were of conical shape and had formed full needle tips. Optical coherence tomography was also used to display the ability of the microneedles to penetrate skin. However the full needle length had not penetrated the skin as expected due to the uneven surface of the skin. Their dissolution was also studied in situ using optical coherence tomography, demonstrating their potential for applications of topical delivery, in particular melanoma treatment.