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 (LD 50) 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. Annually, approximately 650,000 cancer patients receive neoadjuvant, standard or adjuvant chemotherapy 1. Systemic chemotherapy is severely hampered by its dose-limiting toxicity, inefficient transport, and limited retention in tumors leading to sub-lethal doses 2. These sub-lethal concentrations of the drug can cause mutations in cancer cells leading to multidrug-resistant (MDR) tumors. MDR is described as the ability of cancer cells to be resistant to a multitude of drugs that are structurally and functionally different 3. Numerous mechanisms are involved in the development of MDR 4. One of the most studied mechanisms of MDR is the upregulation of transmembrane ATP-binding cassette (ABC) transporters, such as P-glycoprotein (Pgp). They function through ATP hydrolysis at the intracellular domain causing a mechanical conformation of the Pgp thus ejecting the drug into the extracellul...

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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.