Abstract
The synergistic combination of docetaxel (DTX) and cisplatin (CIS) by local drug delivery with a pluronic lecithin organogel (PLO) to facilitate high drug concentrations at tumor sites and less nonspecific distribution to normal organs is thought to be beneficial in chemotherapy. In this study, using Capryol-90 (C90) with the addition of lecithin as the oil phase was developed to carry DTX, which was then incorporated into a PLO-containing CIS to formulate a dual-drug injectable PLO for local delivery. An optimal PLO composite, P13L0.15O1.5, composed of PF127:lecithin:C90 at a 13:0.15:1.5 weight ratio was obtained. The sol–gel transition temperature of P13L0.15O1.5 was found to be 33 °C. Tumor inhibition studies illustrated that DTX/CIS-loaded P13L0.15O1.5 could efficiently suppress tumor growth by both intratumoral and peritumoral injections in SKOV-3 xenograft mouse model. Pharmacokinetic studies showed that subcutaneous administration of P13L0.15O1.5 was able to sustain the release of DTX and CIS leading to their slow absorption into the systemic circulation resulting in lower area under the plasma concentration curve at 0–72 h (AUC0–72) and maximum concentration (Cmax) values but longer half-life (T1/2) and mean residence time (MRT) values. An in vivo biodistribution study showed lower DTX and CIS concentrations in organs compared to other treatment groups after IT administration of the dual drug-loaded P13L0.15O1.5. It was concluded that the local co-delivery of DTX and CIS by PLOs may be a promising and effective platform for local anticancer drug delivery with minimal systemic toxicities.
Highlights
The use of multiple therapeutic agents in combination has become the primary strategy to treat cancer because it suppresses multidrug resistance, reduces individual drug-related toxicity through different mechanisms of action, and generates synergistic anticancer effects (Parhi et al, 2012)
In order to develop a thermosensitive hydrogel for the local drug delivery of a synergistic combination of DTX and CIS for chemotherapy, a thermosensitive Pluronic F127 (PF127) hydrogel was incorporated with C90 with the addition of lecithin as a nonpolar phase to formulate pluronic lecithin organogel (PLO) that were presented in the sol state at 4 and 25 C and transformed to a gel state immediately after the temperature was increased to 37 C
With substitution of traditionally used isopropyl myristate or palmitate in PLOs with C90 to enhance the solubility of hydrophobic cancer drugs, the PLO (P13L0.15O1.5) composed of PF127, lecithin, and C90 at a 13:0.15:1.5 ratio was optimized in this study with characteristics of being a transparent liquid at 4 and 25 C, and it transforms to a gel in
Summary
The use of multiple therapeutic agents in combination has become the primary strategy to treat cancer because it suppresses multidrug resistance, reduces individual drug-related toxicity through different mechanisms of action, and generates synergistic anticancer effects (Parhi et al, 2012). Combination therapy with therapeutic agents that are demonstrated to be effective as mono-therapy in the clinic should provide better therapeutic effects without additional toxicity. Clinical outcomes of combination therapies are not always as good as anticipated; rather they are often associated with higher toxicities, non-overlapping toxicity is a major consideration for selecting drug combination candidates (Lee & Nan, 2012). Controlling and predicting therapeutic mixtures and providing a better understanding of this increasingly important new paradigm of cancer treatment that reaches diseased tissues and cells has become a major clinical challenge. The flourishing strategy to co-deliver drug combinations using a better scheme for precise and controlled delivery has interested an increasing number of researchers since (Hu & Zhang, 2012)
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