Thermomechanical properties, antibiotic release, and bioactivity of a sterilized cyclodextrin drug delivery system

Zuckerman²,

Korley³

et al. 2017

Acta Biomaterialia

Self Cite

Current post-operative standard of care for surgical procedures, including device implantations, dictates prophylactic antimicrobial therapy, but a percentage of patients still develop infections. Systemic antimicrobial therapy needed to treat such infections can lead to downstream tissue toxicities and generate drug-resistant bacteria. To overcome issues associated with systemic drug administration, a polymer incorporating specific drug affinity has been developed with the potential to be filled or refilled with antimicrobials, post-implantation, even in the presence of bacterial biofilm. This polymer can be used as an implant coating or stand-alone drug delivery device, and can be translated to a variety of applications, such as implanted or indwelling medical devices, and/or surgical site infections. The filling of empty affinity-based drug delivery polymer was analyzed in an in vitro filling/refilling model mimicking post-implantation tissue conditions. Filling in the absence of bacteria was compared to filling in the presence of bacterial biofilms of varying maturity to demonstrate proof-of-concept necessary prior to in vivo experiments. Antibiotic filling into biofilm-coated affinity polymers was comparable to drug filling seen in same affinity polymers without biofilm demonstrating that affinity polymers retain ability to fill with antibiotic even in the presence of biofilm. Additionally, post-implantation filled antibiotics showed sustained bactericidal activity in a zone of inhibition assay demonstrating post-implantation capacity to deliver filled antibiotics in a timeframe necessary to eradicate bacteria in biofilms. This work shows affinity polymers can fill high levels of antibiotics post-implantation independent of biofilm presence potentially enabling device rescue, rather than removal, in case of infection.

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Affinity interactions drive post-implantation drug filling, even in the presence of bacterial biofilm

Zuckerman²,

Korley³

et al. 2017

Acta Biomaterialia

Self Cite

“…CDs are cyclic oligosaccharides with a hydrophilic exterior and a hydrophobic interior that enable the encapsulation of hydrophobic drugs through the formation of a drug-inclusion complex. 18 The use of CD polymers is particularly desirable in device coatings because they have been shown to increase antibiotic loading in devices 10-fold 36 and have shown in vitro stability for nearly eight months 37 and controlled in vivo delivery for 28 days. 11,38 Alternatively, other groups have taken another approach altogether to reduce these detrimental effects yet still obtain antibacterial device coatings.…”

Section: Introductionmentioning

confidence: 99%

Emerging technologies for long-term antimicrobial device coatings: advantages and limitations

Recum

2017

Exp Biol Med (Maywood)

This work provides an overview, with advantages and limitations of the most recently developed antibacterial coating technologies, enabling other researchers in the field to more easily determine which technology is most advantageous for them to further develop and pursue. AbstractOver the past 20 years, the field of antimicrobial medical device coatings has expanded nearly 30-fold with technologies shifting their focus from diffusion-only based (short-term antimicrobial eluting) coatings to long-term antimicrobial eluting and intrinsically antimicrobial functioning materials. A variety of emergent coatings have been developed with the goal of achieving long-term antimicrobial activity in order to mitigate the risk of implanted device failure. Specifically, the coatings can be grouped into two categories: those that use antibiotics in conjunction with a polymer coating and those that rely on the intrinsic properties of the material to kill or repel bacteria that come into contact with the surface. This review covers both long-term drug-eluting and non-eluting coatings and evaluates the inherent advantages and disadvantages of each type while providing an overview of variety applications that the coatings have been utilized in.

“…With these CD polymers, we then show high loading levels and slow, sustained release of many different drugs. [27][28][29][30][31] While unmodified DOX is capable of binding pCD, we hypothesized that by adding additional affinity groups we can substantially reduce the rate of release to almost none, and through the use of a pH-sensitive linkage enabling tumor-dependent cleavage of the extra affinity moiety, bringing the release rate back up to therapeutically relevant rates. In this paper, AD-DOX was synthesized according to previously published work.…”

mentioning

confidence: 99%

Featured Article: Chemotherapeutic delivery using pH-responsive, affinity-based release

Recum

2017

Exp Biol Med (Maywood)

Impact statementDoxorubicin (DOX) is especially cytotoxic to the heart, liver, kidneys, and healthy tissues surrounding the tumor microenvironment. This systemic toxicity can be partially addressed by local, tumor-specific drug delivery systems. While pH-sensitive DOX delivery systems have been developed by several other groups, many lack a prolonged and consistent release profile required to successfully treat heterogeneous tumors. Our system of a chemically modified form of DOX combined with an affinity-based cyclodextrin delivery system is capable of delivering DOX for 87 days while maintaining its the drug cytotoxicity. This finding is particularly relevant to improving cancer treatments because it enables regulated local delivery of DOX specifically to tumor tissue and allows the drug to be continuously delivered over a therapeutically relevant amount of time. AbstractDoxorubicin is a chemotherapeutic drug typically administered systemically which frequently leads to cardiac and hepatic toxicities. Local delivery to a tumor has a chance to mitigate some of these toxicities and can further be mitigated by including a means of tumor-specific drug release. Our laboratory has explored the use of molecular interactions to control the rate of drug release beyond that capable of diffusion alone. To this system, we added an additional affinity group (adamantane) to doxorubicin through a pH-sensitive hydrazone bond. The result was a modified doxorubicin which had an even higher affinity to our drug delivery polymer, and virtually no release in normal conditions, but showed accelerated release of drug in tumor-like low pH. Further, we show that adamantanemodified doxorubicin (adamantane-doxorubicin) and cleaved adamantane-doxorubicin showed equivalent capacity to kill human U-87 glioblastoma cells in vitro as unmodified doxorubicin. Taken together, these data demonstrate our ability to load high levels of modified chemotherapeutic drugs into our affinity-based delivery platform and deliver these drugs almost exclusively in the acidic microenvironments, such as those surrounding the tumor tissue via pH-cleavable bond while minimizing drug delivery in neutral pH tissue, with the ultimate goal of reducing systemic through better local delivery.