Drug-Loaded Lipid Nanoparticles for Improved Cancer Treatment: Engineering, In-Vitro, and In-Vivo Evaluation Public Deposited

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Last Modified
  • March 22, 2019
Creator
  • Ma, Ping
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics
Abstract
  • The objectives of these studies were to develop lipid-based nanoparticles (NPs) of anthracyclines (idarubicin, IDA and doxorubicin, DOX) and taxanes (paclitaxel, PX) for improved cancer treatment. Two types of lipid-based NPs were developed, one was solid lipid NPs (SLNs) for the delivery of IDA and DOX, and the other one was oil-filled nanocapsules for PX delivery. Both of the NPs were engineered using a warm microemulsion precursor method, and polyoxyl 20-stearyl ether (Brij 78) and D-alpha-tocopheryl polyethylene glycol succinate (TPGS) were utilized in NPs as the surfactants in both NPs. The difference between the NPs was that the emulsifying wax was used as the oil phase in SLNs, while Miglyol 812 was utilized in oil-filled NPs. In the studies of IDA and DOX SLNs, anionic ion-pairing agents of sodium taurodeoxycholate (STDC) and sodium tetradecyl sulfate (STS) were used to neutralize the charges of the cationic anthracyclines and enhance the entrapment of the drugs in the SLNs. The IC50 value of DOX NPs was 9-fold lower than that of free DOX solution in resistant P388/ADR cell line. In contrast, free IDA had comparable IC50 values as IDA NPs in P-gp-overexpressing P388/ADR and HCT-15 cells. The in-vivo results were well correlated with the in-vitro studies, where the DOX NPs resulted significantly prolonged survival time than free DOX and controls in a P388/ADR leukemia mouse model but IDA NPs were as effective as free IDA in P-gp-overexpressing mouse tumor models. The present studies suggest that the SLNs may offer potential to deliver anticancer drugs for the treatment of P-gp-mediated multiple drug resistance; however, selection of target drug may be very important. In the studies of PX oil-filled nanocapsules, a novel 2'-behenoyl-paclitaxel (C22-PX) was synthesized to increase the lipophilicity of PX and facilitate its retention within the core of the oil-filled nanocapsules. The solubility of C22-PX in Miglyol 812 increased 25-fold compared to PX. C22-PX was less active than PX which was confirmed by the in-vitro cytotoxicity and tubulin polymerization studies. The maximum tolerated dose (MTD) of C22-PX nanocapsules increased 6-fold compared to Taxol in a 4T1 mouse model, and at MTD C22-PX nanocapsules exhibited significantly better in-vivo antitumor efficacy than all control groups. In-vivo pharmacokinetic and biodistribution studies, the C22-PX nanocapsules demonstrated dramatically improved pharmacokinetic and tumor uptake profiles than Taxol, where the plasma and tumor AUCs of C22-PX from C22-PX nanocapsules were 186- and 24.4-fold greater than PX from Taxol at MTD, respectively. The present studies suggest that C22-PX nanocapsules may offer the potential to treat metastatic breast cancer. In summary, the lipid-based NPs may serve as an alternative platform for the delivery of hydrophobic drugs for improved cancer treatment as compared to the standard of care therapy.
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  • In Copyright
Advisor
  • Mumper, Russell J.
Degree
  • Doctor of Philosophy
Graduation year
  • 2012
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