Antiangiogenic drugs encompass many of the different cancer drugs currently under clinical investigation. One of the drawbacks of antiangiogenic therapy, though, is that upon cessation of drug treatment tumors can recur with an accelerated growth rate. In this study we investigate the capacity of using affinity interactions between a polymer made from cyclodextrin and four antiangiogenic drugs, tranilast, SU5416, 2-methoxyestradiol, and silibinin, with the ultimate goal of creating delivery profiles on the order of antiangiogenic processes (needing weeks, rather than hours of delivery). In these systems, release rate is dependent on affinity, so using in silico molecular docking studies followed by surface plasmon resonance we determined that silibinin possesses the highest affinity among the drugs screened. Silibinin also showed a differential binding affinity among various cyclodextrins tested, with a greater affinity toward the larger molecular pocket of γ-cyclodextrin than for β-cyclodextrin. Release studies confirmed this affinity to translate into a slower, more sustained release of silibinin. Similarly we found this trend in the release of tranilast. Then using U87 human glioblastoma cells in a mouse xenograft model, we showed that affinity-based cyclodextrin polymers loaded with silibinin showed substantially longer release rates than nonaffinity control polymers; however, both were capable of inhibiting tumor growth in the time frame studied. From this work we showed three different, but chemically similar, polymers, each with a different release rate. Future work is on evaluating longer term tumor models where this longer release rate from affinity delivery systems might have additional advantages over polymers dependent only on diffusion.

Drug delivery strategies generally use inert materials, such as high molecular weight polymers, to encapsulate and control the release rate of therapeutic drugs. Diffusion governs release and depends on the ease of permeation of the polymer alongside the device thickness. Yet in applications such as osteoarthritis, the physiological constraints and limited intra-articular joint space prevent the use of large, solid drug delivery implants. Other investigators have explored the use of micro- and nanoparticle drug delivery systems. However, the small size of the systems limits the total drug that may be encapsulated and its short diffusion distance causes rapid release. Ordinarily, the extremely low diffusivity of a polymer fluid would make this an unsuitable delivery system. Our technology takes advantage of specific molecular interactions between drug and polymer, which can control the rate of release beyond diffusion. With this "affinity-based drug delivery", we have shown that delivery rates from solid polymer can be prolonged from hours and days, to weeks and months. In this paper, we demonstrate that this affinity-based mechanism also applies to low diffusivity fluid-phase polymers. They show release rates that are substantially slower than chemically similar polymers incapable of forming those inclusion complexes. The similarity of this study's liquid polymers to the viscoelastic fluids used in current clinical practice makes it an ample delivery system for osteoarthritic application. We confirmed the capacity of anti-inflammatory delivery of corticosteroids: hydrocortisone, triamcinolone, and dexamethasone; from both solid implants and polymer fluids. Further, we demonstrated that viscoelastic properties are widely tunable, and within the range of native synovial fluid. Lastly, we determined these polymer fluids have no impact on the differentiation of mesenchymal stem cells to cartilage and are not cytotoxic to a common cell line.

The protein chemokine (C-C motif) ligand 7 (CCL7) is significantly over-expressed in urethral and vaginal tissues immediately following vaginal distention in a rat model of stress urinary incontinence. Further evidence, in this scenario and other clinical scenarios, indicates CCL7 stimulates stem cell homing for regenerative repair. This CCL7 gradient is likely absent or compromised in the natural repair process of women who continue to suffer from SUI into advanced age. We evaluated the feasibility of locally providing this missing CCL7 gradient by means of an affinity-based implantable polymer. To engineer these polymers we screened the affinity of different proteoglycans, to use them as CCL7-binding hosts. We found heparin to be the strongest binding host for CCL7 with a 0.323 nM dissociation constant. Our experimental approach indicates conjugation of heparin to a polymer backbone (using either bovine serum albumin or poly (ethylene glycol) as the base polymer) can be used as a delivery system capable of providing sustained concentrations of CCL7 in a therapeutically useful range up to a month in vitro. With this approach we are able to detect, after polymer implantation, significant increase in CCL7 in the urethral tissue directly surrounding the polymer implants with only trace amounts of human CCL7 present in the blood of the animals. Whole animal serial sectioning shows evidence of retention of locally injected human mesenchymal stem cells (hMSCs) only in animals with sustained CCL7 delivery, 2 weeks after affinity-polymers were implanted.

Minocycline (MNC) is a tetracycline antibiotic capable of associating with cyclodextrin (CD), and it is a frontline drug for many instances of implant infection. Due to its broad-spectrum activity and long half-life, MNC represents an ideal drug for localized delivery; however, classic polymer formulations, particularly hydrogels, result in biphasic release less suitable for sustained anti-microbial action. A polymer delivery system capable of sustained, steady drug delivery rates poses an attractive target to maximize the antimicrobial activity of MNC. Here, we formed insoluble hydrogels of polymerized CD (pCD) with a range of crosslinking densities, and then assessed loading, release, and antimicrobial activity of MNC. MNC loads between 5–12 wt % and releases from pCD hydrogels for >14 days. pCD loaded with MNC shows extended antimicrobial activity against S. aureus for >40 days and E. coli for >70 days. We evaluated a range of water/ethanol blends to test our hypothesis that solvent polarity will impact drug-CD association as a function of hydrogel swelling and crosslinking. Increased polymer crosslinking and decreased solvent polarity both reduced MNC loading, but solvent polarity showed a dramatic reduction independent of hydrogel swelling. Due to its high solubility and excellent delivery profile, MNC represents a unique drug to probe the structure-function relationship between drug, affinity group, and polymer crosslinking ratio.

Small molecule drug activators of gene expression have been used in applications ranging from gene therapy, to tissue engineering and regenerative medicine. One concern is that for sustained gene expression, a long-term, controlled delivery system is needed. Insoluble polymers containing a high proportion of cyclodextrin (CD) affinity groups have been shown to prolong drug delivery far beyond that capable of polymers relying on diffusion alone. In this study we evaluate the capacity of such polymers to deliver the transgene inducer doxycycline. Our results show that initial drug loading is proportional to affinity, with ∼8% loading in high-affinity γ-CD polymers; ∼7% loading in moderate-affinity β-CD polymers; and only ∼4.5% loading in the non-affinity control polymer made from linear dextran. When release aliquots from these polymers were incubated with cells genetically modified for inducible transgene expression we observed activation of transgene expression for up to three weeks from samples released by affinity-based polymers. We showed that drug stability is maintained over the course of the study using a bacterial zone of inhibition assay where again affinity-based polymers show sustained availability of drug, weeks longer than non-affinity controls. Lastly we provide theoretical calculations of strength of binding interactions between cyclodextrins and many additional transgene inducers demonstrating the broad utility of this delivery platform.