Abstract
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.
Highlights
Approximately 650,000 cancer patients receive neoadjuvant, standard or adjuvant chemotherapy[1]
Local drug delivery systems, such as in situ forming implants (ISFIs), can deliver high concentrations of the drug directly to the tumor site, avoiding systemic toxicities seen in clinical Pgp inhibitors[47]
Current clinical trials using Pgp inhibitors suffer due to systemic toxicity
Summary
Approximately 650,000 cancer patients receive neoadjuvant, standard or adjuvant chemotherapy[1]. Site-specific inhibitors, such as Valspodar (Val), competitively bind with the drug binding domain in Pgp and directly inhibit the conformation change required to eject the drug[16,17,18] Val has made it to Phase III clinical trials for patients with acute myeloid leukemia but was terminated early due to excessive mortality[19] and interactions with cytochrome P450 3A4, a liver enzyme, causing poor drug metabolism leading to toxic drug plasma concentrations[20,21,22]. Lack of clinical success are attributed to MDR which occurs in 90% of patients with metastatic CRC32–34 This approach can concurrently address the systemic toxicity issues and improve local drug retention within the tumor over time. We have evaluated the ability of both Pgp inhibitors to improve the Dox penetration and retention intratumorally and enhance the therapeutic efficacy
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