Ultrasound Triggered Drug Release from Affinity-Based ß-Cyclodextrin Polymers for Infection Control.

This work demonstrates a slow, sustained drug delivery system that provides on-demand delivery bursts through the application of pulsed therapeutic ultrasound (TUS). Insoluble ß-cyclodextrin-polymer (pCD) disks were loaded with a saturated antibiotic solution of rifampicin (RIF) and used for drug delivery studies. To obtain on-demand release from the implants, TUS was applied at an intensity of 1.8 W/cm2. The therapeutic efficacy of the combination treatment was assessed in bacterial culture via an in vitro Staphylococcus aureus bioluminescence assay. The results demonstrated that the application of pulsed TUS at 3 MHz and 1.8 W/cm2 to pCD implants leads to a significantly higher short-term burst in the drug release rate compared to samples not treated with TUS. The addition of TUS increased the drug release by 100% within 4 days. The pCD disk + RIF stimulated with TUS showed a comparatively higher bacterial eradication with CFU/mL of 4.277E+09, and 8.00E+08 at 1 and 24 h compared with control treated bacteria at 1.48E+10. Overall, these results suggest that the addition of pulsed TUS could be an effective technology to noninvasively expedite antibiotic release on demand at desired intervals.

In situ forming implants exposed to ultrasound enhance therapeutic efficacy in subcutaneous murine tumors.

In situ forming implants (ISFIs) allow for a high initial intratumoral concentration and sustained release of the chemotherapeutic. However, clinical translation is impeded primarily due to limited drug penetration from the tumor/boundary interface and poor intratumoral drug retention. Therapeutic ultrasound (TUS) has become a popular approach for improving drug penetration of transdermal devices and increasing cellular uptake of nanoparticles. These effects are driven by the mechanical and thermal bioeffects associated with TUS. In this study, we characterize the released drug penetration, retention, and overall therapeutic response when exposing ISFI to the combination of the mechanical and thermal effects of TUS (C-TUS). ISFIs were intratumorally injected into subcutaneous murine tumors then exposed to C-TUS (exposure: 5 min, duty factor: 0.33, frequency: 3 MHz, intensity: 2.2 W/cm2, pulse duration: 2 ms, pulse repetition frequency: 165 Hz, effective radiating area: 5 cm2, energy delivered: 896 J, time average intensity: 0.88 W/cm2). Tumors treated with the combination of ISFI + C-TUS demonstrated a 2.5-fold increase in maximum drug penetration and a 3-fold increase in drug retention at 5- and 8-days post-injection, respectively, compared to ISFIs without TUS exposure. These improvements in drug penetration and retention translated into an enhanced therapeutic response. Mice treated with ISFI + C-TUS showed a 62.6% reduction in tumor progression, a 50.0% increase in median survival time, and a 26.6% increase in necrotic percentage compared to ISFIs without TUS exposure. Combining intratumoral ISFIs with TUS may be beneficial for addressing some long-standing challenges with local drug delivery in cancer treatment and may serve as a viable noninvasive method to improve the poor clinical success of local drug delivery systems.

Improving Treatment Efficacy of In Situ Forming Implants via Concurrent Delivery of Chemotherapeutic and Chemosensitizer.

P-glycoprotein (Pgp), a member of the ATP-binding cassette family, is one of the major causes of multidrug resistance in tumors. Current clinical treatments to overcome MDR involve the co-delivery of a Pgp inhibitor and a chemotherapeutic. A concern for this treatment that has led to varied clinical trial success is the associated systemic toxicities involving endogenous Pgp. Local drug delivery systems, such as in situ forming implants (ISFIs), alleviate this problem by delivering a high concentration of the drug directly to the target site without the associated systemic toxicities. ISFIs are polymeric drug solutions that undergo a phase transition upon injection into an aqueous environment to form a solid drug eluting depot allowing for a high initial intratumoral drug concentration. In this study, we have developed an ISFI capable of overcoming the Pgp resistance by co-delivering a chemotherapeutic, Doxorubicin (Dox), with a Pgp inhibitor, either Pluronic P85 or Valspodar (Val). Studies investigated in vitro cytotoxicity of Dox when combined with either Pgp inhibitor, effect of the inhibitors on release of Dox from implants in PBS, in vivo Dox distribution and retention in a subcutaneous flank colorectal murine tumor, and therapeutic response characterized by tumor growth curves and histopathology. Dox + Val showed a 4-fold reduction in the 50% lethal dose (LD50) after 48 hours. Concurrent delivery of Dox and Val showed the greatest difference at 16 days post injection for both Dox penetration and retention. This treatment group had a 5-fold maximum Dox penetration compared to Dox alone ISFIs (0.53 ± 0.22 cm vs 0.11 ± 0.11 cm, respectively, from the center of the ISFI). Additionally, there was a 3-fold increase in normalized total intratumoral Dox intensity with the Dox + Val ISFIs compared to Dox alone ISFIs (0.54 ± 0.11 vs 0.18 ± 0.09, respectively). Dox + Val ISFIs showed a 2-fold reduction in tumor growth and a 27.69% increase in necrosis 20 days post-injection compared to Dox alone ISFIs. These findings demonstrate that co-delivery of Dox and Val via ISFI can avoid systemic toxicity issues seen with clinical Pgp inhibitors.

Tunable Polymer Embolic Implant for Vascular Occlusion.

In this study, we have developed a tunable polymer vascular embolic implant (TPVEI) with adjustable precipitation rates allowing for personalized, controlled vascular occlusion depths. We hypothesized that reducing the water miscibility of the solvent would result in slower TPVEI precipitation, leading to distal vascular occlusion. To investigate homogeneous vascular distribution and occlusion control, the TPVEI was directly injected into the portal vein of a rat and imaged with microCT. Changing the solvent ratio of NMP/BB from 100/0 to 50/50 showed a significant (p < 0.05) decrease in vessel size occluded from 675 ± 20 to 170 ± 25 µm, respectively. The 60/40 (NMP/BB) formulation was able to occlude several branches throughout the whole liver, displaying a homogeneous vasculature distribution. Broadband Doppler ultrasound validated that there was complete portal vein occlusion after embolization with all materials. These findings suggest that adjusting the solvent polarity allows embolization control and with appropriate optimization, phase-inverting embolics could be used better to control depth of occlusion for endovascular therapies.