Elsevier

Biomaterials

Volume 33, Issue 20, July 2012, Pages 5144-5155
Biomaterials

Development and in-vivo characterization of supramolecular hydrogels for intrarenal drug delivery

https://doi.org/10.1016/j.biomaterials.2012.03.052Get rights and content

Abstract

Intrarenal drug delivery from a hydrogel carrier implanted under the kidney capsule is an innovative way to induce kidney tissue regeneration and/or prevent kidney inflammation or fibrosis. We report here on the development of supramolecular hydrogels for this application. We have synthesized two types of supramolecular hydrogelators by connecting the hydrogen bonding moieties to poly(ethylene glycols) in two different ways in order to obtain hydrogels with different physico-chemical properties. Chain-extended hydrogelators containing hydrogen bonding units in the main chain, and bifunctional hydrogelators end-functionalized with hydrogen bonding moieties, were made. The influence of these hydrogels on the renal cortex when implanted under the kidney capsule was studied. The overall tissue response to these hydrogels was found to be mild, and minimal damage to the cortex was observed, using the infiltration of macrophages, formation of myofibroblasts, and the deposition of collagen III as relevant read-out parameters. Differences in tissue response to these hydrogels could be related to the different physico-chemical properties of the three hydrogels. The strong, flexible and slow eroding chain-extended hydrogels are proposed to be suitable for long-term intrarenal delivery of organic drugs, while the weaker, soft and fast eroding bifunctional hydrogel is eminently suitable for short-term, fast delivery of protein drugs to the kidney cortex. The favourable biological behaviour of the supramolecular hydrogels makes them exquisite candidates for subcapsular drug delivery, and paves the way to various opportunities for intrarenal therapy.

Introduction

The worldwide increasing incidence of end-stage renal disease raises the need for innovative therapeutic approaches that promote functional kidney regeneration, thereby preventing chronic renal failure. Current therapies include the systemic, i.e. intravenous or intraperitoneal, administration of anti-inflammatory, immune-suppressive and anti-fibrotic drugs. However, these strategies are accompanied by unwanted side effects due to lack of control over drug localization. Major progress has been made in the research of targeted drug delivery to for example proximal tubular epithelial cells [1]. In this work we show a new approach consisting of the implantation of a drug delivery system under the kidney capsule. As carrier systems we use hydrogels that due to their physical properties are proposed to be able to adjust to the subcapsular space.

Many hydrogels have been used for regenerative medicine and drug delivery purposes [2], [3], frequently by implantation or injection at various sites in the body. Detailed studies on the tissue response to different hydrogels mainly focus on subcutaneous implantation [4], [5], [6] while studies on subcapsular implantation remain limited. The kidney capsule as implantation site is primarily investigated for pancreatic cell or islets transplantation in diabetic animal models [7]. These cells have for example been encapsulated in microcapsules and their survival and function have been studied under the kidney capsule [8], [9]. However, studies on the tissue response to subcapsularly implanted hydrogel systems, that are designed for intrarenal drug delivery, are to our knowledge not present.

In this study we designed and synthesized three supramolecular hydrogels for use as intrarenal drug delivery systems and investigated the renal tissue response after subcapsular implantation. We use supramolecular hydrogels, i.e. hydrogels in which the network is formed by directed non-covalent interactions, so-called transient supramolecular networks. These supramolecular systems are proposed to have physical properties which allow for easy implantation between and adjustment to the renal capsule and the soft cortical kidney tissue. Recently, we have shown that supramolecular building blocks based on ureido-pyrimidinone (UPy) units [10] are excellent elastomeric biomaterials [11], [12], [13]. Also, bioactive supramolecular materials could be made by simple mixing of UPy-modified prepolymers and UPy-functionalized peptides [14], [15]. In the past, the tissue response to these UPy-modified biomaterials have been studied subcutaneously [11], [14], [16], [17]. Here, we apply this supramolecular and modular principle to design hydrogels by introduction of UPy-moieties on poly(ethylene glycol) (PEG) prepolymers. Recently we have published an extensive study on the properties of different telechelic UPy-modified PEGs [18]. Here, we show the difference between two types of PEG hydrogelators, containing UPy-moieties in the main chain 1 and 2, or at the chain ends 3 (i.e. telechelic UPy-PEGs) (Fig. 1A). After discussing the synthesis, formulation procedure and rheological behaviour of these hydrogels, we report on their intrarenal behaviour and tissue response, and propose possible therapeutic applications in relation to their physical properties.

Section snippets

Syntheses of UPy-modified hydrogelators

All syntheses were performed as described in the supplementary information.

Preparation of hydrogels

UPy-polymer 1 was dissolved in THF (Biosolve) and a 0.9% NaCl (B. Braun Melsungen) aqueous solution was added in a ratio 1:1 to obtain a 5 w/w% hydrogel. The clear solution was subsequently put in vacuo to slowly remove the THF, resulting in a very elastic hydrogel. The same procedure was applied to UPy-polymer 2, resulting in an elastic, rigid and shape-persistent 5 w/w% hydrogel. After preparation, gel 1 and 2 were

Synthesis

The three hydrogelators 13 were synthesized as described in the supplementary information (Scheme 1A and Supp. Info). In short, telechelic hydroxy-terminated prepolymers PEG3000 a, PEG6000 b, PCL1250 c, and PEG20000 d were activated with 1,1-carbonyldiimidazole (CDI). The resulting CDI-activated prepolymers were reacted with 1,6-hexyldiamine for 4a–c, or with 1,12-dodecyldiamine in the case of 4d, yielding diamine-terminated polymers 5a–d. Reaction of diamine-terminated 5a and 5b in 1:1 w/w%

Discussion

Irrespective of the nature of the damage, kidney injury is invariably associated with inflammation. Improper resolution or chronic persistence of inflammation sets the stage for fibrosis, which has been identified as the common pathway to kidney failure. Inflammation and fibrosis of the tubulointerstitial space cannot be effectively addressed by systemic drug administration. Moreover, systemic drug administration is associated with the loss of the therapeutic compounds to irrelevant sites in

Conclusions

We have successfully synthesized three different supramolecular hydrogelators based on PEG chains and UPy-moieties. Two chain-extended hydrogelators possessing UPy-units in the main chain, and one bifunctional hydrogelator with UPy-groups at the chain end, were produced. A mixture of water and organic solvent was needed to dissolve the chain-extended hydrogelators. Gelation took place after removal of the organic solvent. In contrast, the bifunctional hydrogelator could be dissolved in only

Acknowledgements

We acknowledge Jan van der Wijk and Frank Smedts for supplying the kidney tissues, Jasper Koerts for cutting the tissue slices, Heleen Rienstra and the clinical chemistry laboratory for performing the creatinine measurements, and Martine Broekema, Marco Harmsen, Jasper Boomker and Travis Baughman for useful discussions. This work is supported by SupraPolix, and the Council for Chemical Sciences of the Netherlands Organization for Scientific Research (CW-NWO).

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