Poly Ethylene Oxide Modified Polys Caprolactone Nanoparticles

Poly(s-caprolactone) (PCL) is another biodegradable polymer that has been used to encapsulate hydrophobic drugs. Using this polymer, nanoparticles were prepared by solvent displacement in an acetone-water system in the presence of Pluronic®. The solvent displacement technique used for the preparation of PCL nanoparticles facilitates instant adsorption of PPO-PEO groups when the organic solution of the polymer is introduced into aqueous solution containing the stabilizer.51 In addition, it also favors the encapsulation of hydrophobic drugs such as tamoxifen that could be dissolved along with the polymer in the organic phase, resulting in a high entrapment efficiency of greater than 90% at loading levels of 20% of the weight of the drug. The intracellular uptake of these nanoparticles in MCF-7 estrogen receptor-positive breast cancer cells and MDA-MB231 human breast adenocarcinoma cells was monitored at different time points using tritiated [3H]-tamoxifen. The results showed that the cell uptake followed saturable kinetics with most of the nanoparticles being internalized within the first 30 min of incubation.52

The in vivo disposition of these PEO-modified PCL nanoparticles was completed in mice bearing MDA-MB231 xenograft breast cancer tumors as it is a well-characterized and simpler model compared to MCF-7 that requires estrogen priming for growth. This study was used to compare the biodistribution profiles of the nanoparticles modified by the Pluronic® F-68 containing 30 residues of propylene oxide (PO) and 76 residues of ethylene oxide (EO) with those of Pluronic® F-108 that has 56 PO residues and 122 EO residues. The nanoparticulate formulations encapsulated with radiolabled tamoxifen were used. As expected, upon intravenous administration, the Pluronic®-modified nanoparticles had higher tumor concentrations in comparision to the tamoxifen solution and drug-loaded, unmodified nanoparticles. At early time points (one hour), the nanoparticles modified with Pluronic® F-108 had greater concentration in the tumor with no significant difference in the concentration of the Pluronic®-modified formulations at six hours post-injection. A similar trend has been observed in plasma concentration-time profiles with PEO-PCL formulations circulating for a longer time than the controls.40

In a parallel study, the PEO-modified PCL nanoparticles were radiolabeled by a similar procedure specific to PEO-PBAE nanoparticles. The nanoparticles, encapsulated with [3H] tritium-labeled paclitaxel, were used to understand the change in concentration and localization of the drug in ovarian tumors (SKOV3). From the biodistribution studies, it was shown that the modification of PCL nanoparticles with PEO had extended the mean residence time to up to 25 h. Hydrophobic drugs such as paclitaxel were found to have high plasma concentrations as a result of their protein binding capacity; however, they were cleared from the blood within 24 h. The circulation time of such drugs has been enhanced by encapsulating them in PEO-PCL nanoparticles that, in turn, has resulted in higher concentrations of the drug in the tumors. The PEO-PCL nanoparticles have resulted in an 8.7-fold increase in drug concentration at five-hour time points when compared to the solution form of the drug.40

In another study, PEO-modified PCL nanoparticles were used for combination therapy of ceramide with paclitaxel in order to overcome MDR, particularly in cases of breast and ovarian cancers. Several MDR specimens of cancer were found to exhibit elevated levels of the enzyme glucosylceramide synthease (GCS) (also called ceramide glucosyl transferase) that is responsible for the inactivation of ceramide, a messenger in apoptotic signaling to its non-functional moiety glucosylceramide.53-55 These findings suggest the importance of the role of ceramide in the mediation of a cytotoxic response and its function as an apoptotic messenger in the signaling pathway.

To potentially overcome MDR in ovarian cancer cell lines, C6-ceramide has been encapsulated along with paclitaxel into PEO-modified PCL nanoparticles. Upon treatment of the cells with paclitaxel, the MDR cell line SKOV3/TR exhibited 65.65+2.16% viability at 1 mM dose; the sensitive cell line SKOV3 showed 16.37 + 0.41% viability at 100 nM dose. Co-treatment of these cells along with 20 mM C6-ceramide in addition to paclitaxel (1 mM in the case of a resistant cell line and 100 nM in a sensitive cell line) resulted in a cell viability of 2.69 + 0.51% with the resistant cells and 7.38 + 1.25% with the sensitive cell lines, indicating a significant increase in cell death when compared to the paclitaxel treatment alone. Furthermore, the co-encapsulation of these drugs within PEO-PCL nanoparticles resulted in enhanced cell kill compared to the drugs alone. A 10 nM dose of paclitaxel, delivered in combination with ceramide in PEO-PCL nanoparticles, resulted in 63.98 +4.9% viability, and the free drugs in solution at these doses did not provoke any cell kill in the resistant cell line. The use of these drug-loaded nanoparticles resulted in a 100-fold increase in chemosensitivity of the MDR cells. These results demonstrate the clinical use of PEO-PCL nanoparticles in overcoming MDR by combination therapy.

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