Cellular uptake and concentrations of tamoxifen upon administration in poly(ε-caprolactone) nanoparticles

Abstract

INTRODUCTIONPurpose: In an attempt to increase the local concentration of tamoxifen in estrogen receptor positive breast cancer cells, we have prepared and characterized poly(İ-caprolactone) (PCL) nanoparticle formulation. Methods: PCL (mol wt 14,800 daltons) nanoparticles were prepared by the solvent displacement method in acetonewater system in the presence of Pluronic F-68. PCL nanoparticles, labeled with rhodamine123, were incubated with MCF-7 estrogen receptor positive breast cancer cells to determine uptake, intracellular distribution, and localization as a function of time. Intracellular drug concentrations over a specified period of time using different initial doses were examined using tritiated [ 3 H]-tamoxifen. Results: A significant fraction of the administered rhodamine123-loaded PCL nanoparticles was found in the perinuclear region of the MCF-7 cells, where estrogen receptors are also localized, after 1 hour of incubation. Measurements of the intracellular concentrations revealed that most of the administered nanoparticle dose was internalized within the first 30 minutes of incubation, and the uptake followed saturable transport kinetics. Conclusion: Results of this study show that PCL nanoparticles were rapidly internalized in MCF-7 cells and intracellular tamoxifen concentrations followed a saturable process. This approach may provide better therapeutic benefit by delivering the drug locally, near the tumor cells, for a longer period of time.One of the major problems facing cancer chemotherapy is administering the required therapeutic concentration of the drug at the tumor site for the desired period of time without causing undesirable effects on other organs after systemic administration.1-3 The tumor vasculature, formed by hypersecretion of angiogenic factors, is highly disorganized and tortuous and serves as a major barrier to drug transport. Tumors also have a very high interstitial hydrostatic pressure, which prevents drug entry into the core. Furthermore, the lack of a functional lymphatic system in tumors allows the drug oozing out of the mass to be diluted in the surrounding tissues and fluids.4,5 Targeted drug delivery to solid tumors, therefore, is necessary in order to achieve optimum therapeutic outcomes.Oral administration of the nonsteroidal anti-estrogen tamoxifen is the treatment of choice for patients with all stages of estrogen receptor positive breast cancer.6 Tamoxifen belongs to a class of nonsteroidal triphenylethylene derivatives (Figure 1) and is considered the first selective estrogen receptor modulator. 7,8 Tamoxifen exhibits a good bioavailability upon oral administration and is mainly employed as a long-term prophylactic therapy in women with high risk for breast cancer and in postmenopausal women. The drug exhibits anti-estrogenic activity by binding to the intracellular estrogen receptor. 9 The tamoxifen-estrogen receptor complex binds with DNA and can alter or block subsequent mRNA transcription and lead to cellular apoptosis.10 Tamoxifen is also thought to...

Tamoxifen-loaded solid lipid nanoparticles-induced apoptosis in breast cancer cell lines

“…Thus, TAM arrests the cell cycle in the G1 phase, thereby decreasing cell proliferation [27] and promoting apoptosis. [9] The estrogen receptor-mediated antiestrogenic effect of TAM on breast cancers could lead to either cytostatic or cytotoxic effects. This effect of TAM is concentration dependent.…”

“…On the basis of these results, it can be concluded that while TAM governs the morphological changes of the cells and exert in vitro cytostatic activity. Its cytotoxic effect is evident only when the drug is applied in the free form for at least after 48 and 72 h. According to Chawla and Amiji, [9] TAM blocks the cell cycle in the G1 phase, thereby decreasing cell proliferation and increasing apoptosis. This finding is also reflected in this study.…”

“…The basis of this formulation is to obtain the necessary dose of drug at tumour location for a known period of time and reducing adverse effects on normal organs in the body. [9] We have previously reported the effect of TAM-loaded solid lipid nanoparticles (SLNs) on the LA7 cell-induced rat mammary tumour gland. The result showed that TAM-loaded SLNs have similar effect on the tumour as free TAM, which promotes apoptosis in the rat mammary gland tumour.…”

Poly(Ethylene Oxide)-Modified Poly(β-Amino Ester) Nanoparticles as a pH-Sensitive System for Tumor-Targeted Delivery of Hydrophobic Drugs: Part 2. In Vivo Distribution and Tumor Localization Studies

“…Over the years, an array of drug delivery systems has been developed using PCL (14)(15)(16)(17)(18)(19)(20)(21).…”

Conventional Chemotherapeutic Drug Nanoparticles for Cancer Treatment

“…A significant fraction of the administered rhodamine123-loaded poly(e-caprolactone) nanoparticles was found in the perinuclear region of the MCF-7 cells, where estrogen receptors are also localized, after 1 h of incubation. These nanoparticles were rapidly internalized in MCF-7 cells and intracellular tamoxifen concentrations followed a saturable process [93]. In another study, the biodistribution profile of tamoxifen encapsulated in polymeric nanoparticulate formulations after intravenous administration was evaluated, with or without surface-stabilizing agents.…”