Compartmentalized Polymeric Nanoparticles Deliver Vancomycin in a pH-Responsive Manner

Abstract

Vancomycin (VCM) is a last resort antibiotic in the treatment of severe Gram-positive infections. However, its administration is limited by several drawbacks such as: strong pH-dependent charge, tendency to aggregate, low bioavailability, and poor cellular uptake. These drawbacks were circumvented by engineering pH-responsive nanoparticles (NPs) capable to incorporate high VCM payload and deliver it specifically at slightly acidic pH corresponding to infection sites. Taking advantage of peculiar physicochemical properties of VCM, here we show how to incorporate VCM efficiently in biodegradable NPs made of poly(lactic-co-glycolic acid) and polylactic acid (co)polymers. The NPs were prepared by a simple and reproducible method, establishing strong electrostatic interactions between VCM and the (co)polymers’ end groups. VCM payloads reached up to 25 wt%. The drug loading mechanism was investigated by solid state nuclear magnetic resonance spectroscopy. The engineered NPs were characterized by a set of advanced physicochemical methods, which allowed examining their morphology, internal structures, and chemical composition on an individual NP basis. The compartmentalized structure of NPs was evidenced by cryogenic transmission electronic microscopy, whereas the chemical composition of the NPs’ top layers and core was obtained by electron microscopies associated with energy-dispersive X-ray spectroscopy. Noteworthy, atomic force microscopy coupled to infrared spectroscopy allowed mapping the drug location and gave semiquantitative information about the loadings of individual NPs. In addition, the NPs were stable upon storage and did not release the incorporated drug at neutral pH. Interestingly, a slight acidification of the medium induced a rapid VCM release. The compartmentalized NPs could find potential applications for controlled VCM release at an infected site with local acidic pH.

Quantification of drug loading in polymeric nanoparticles using AFM-IR technique: a novel method to map and evaluate drug distribution in drug nanocarriers

“…This phenomenon, previously reported for PLA NPs, was attributed to a phase shift during the contact between the tip and the NPs in tapping AFM. 19,21…”

“…This phenomenon, previously reported for PLA NPs, was attributed to a phase shift during the contact between the tip and the NPs in tapping AFM. 19,21 Analyst Accepted Manuscript The areas, where a phase shift is observed, are excluded for the DL calculation. Furthermore, it is possible to estimate the percentage of the Np volume, where this phase shift artifact appears: it is around 10 to 20% of the Np volume.…”

“…AFM-IR appears a priori as a versatile technique to be used on almost any organic material under ambient conditions with a high resolution that is promising to quantify the composition of individual drug-loaded NPs. Pioneering studies in our groups demonstrated that AFM-IR is a reliable, non-destructive and direct method able to precisely locate and chemically characterize polymeric NPs 19,21 as well as study from another group on liposomal nanocarriers 22 . In another study, PLA NPs of about 150 nm in diameter were characterized inside the cells without the need for labelling.…”

“…Pioneering studies in our groups demonstrated that AFM-IR is a reliable, non-destructive and direct method able to precisely locate and chemically characterize polymeric NPs 19,21 as well as investigation from another group on liposomal nanocarriers. 22 In another study, PLA NPs of about 150 nm in diameter were characterized inside the cells without the need for labelling.…”

Polymeric nanomaterial strategies to encapsulate and deliver biological drugs: points to consider between methods

“…176 As can be seen from the articles reviewed in this paper, the size of the BDs may impact the efficiency of the encapsulation. For example, in Markwalter et al, 87,107 vancomycin is typically only 1.45 kDa in size, and thus can easily escape from the packaging envelope during the encapsulation process. 177 So far, there are only a few studies encapsulating small molecular weight BDs with polymeric materials.…”