Dataset Information

Effective drug delivery, in vitro and in vivo, by carbon-based nanovectors noncovalently loaded with unmodified Paclitaxel.

ABSTRACT: Many new drugs have low aqueous solubility and high therapeutic efficacy. Paclitaxel (PTX) is a classic example of this type of compound. Here we show that extremely small (<40 nm) hydrophilic carbon clusters (HCCs) that are PEGylated (PEG-HCCs) are effective drug delivery vehicles when simply mixed with paclitaxel. This formulation of PTX sequestered in PEG-HCCs (PTX/PEG-HCCs) is stable for at least 20 weeks. The PTX/PEG-HCCs formulation was as effective as PTX in a clinical formulation in reducing tumor volumes in an orthotopic murine model of oral squamous cell carcinoma. Preliminary toxicity and biodistribution studies suggest that the PEG-HCCs are not acutely toxic and, like many other nanomaterials, are primarily accumulated in the liver and spleen. This work demonstrates that carbon nanomaterials are effective drug delivery vehicles in vivo when noncovalently loaded with an unmodified drug.

SUBMITTER: Berlin JM

PROVIDER: S-EPMC2935702 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effective drug delivery, in vitro and in vivo, by carbon-based nanovectors noncovalently loaded with unmodified Paclitaxel.

Berlin Jacob M JM Leonard Ashley D AD Pham Tam T TT Sano Daisuke D Marcano Daniela C DC Yan Shayou S Fiorentino Stefania S Milas Zvonimir L ZL Kosynkin Dmitry V DV Price B Katherine BK Lucente-Schultz Rebecca M RM Wen Xiaoxia X Raso M Gabriela MG Craig Suzanne L SL Tran Hai T HT Myers Jeffrey N JN Tour James M JM

ACS nano 20100801 8

Many new drugs have low aqueous solubility and high therapeutic efficacy. Paclitaxel (PTX) is a classic example of this type of compound. Here we show that extremely small (<40 nm) hydrophilic carbon clusters (HCCs) that are PEGylated (PEG-HCCs) are effective drug delivery vehicles when simply mixed with paclitaxel. This formulation of PTX sequestered in PEG-HCCs (PTX/PEG-HCCs) is stable for at least 20 weeks. The PTX/PEG-HCCs formulation was as effective as PTX in a clinical formulation in redu ...[more]

PMID: 20681596

Similar Datasets

Project description:Therapies targeted to the immune system, such as immunotherapy, are currently shaping a new, rapidly developing branch of promising cancer treatments, offering the potential to change the prognosis of previously non-responding patients. Macrophages comprise the most abundant population of immune cells in the tumor microenvironment (TME) and can undergo differentiation into functional phenotypes depending on the local tissue environment. Based on these functional phenotypes, tumor-associated macrophages (TAMs) can either aid tumor progression (M2 phenotype) or inhibit it (M1 phenotype). Presence of M2 macrophages and a high ratio of M2/M1 macrophages in the TME are clinically associated with poor prognosis in many types of cancers. Herein, we evaluate the effect of macrophage phenotype on the transport and anti-cancer efficacy of albumin-bound paclitaxel (nAb-PTX) loaded into porous silicon multistage nanovectors (MSV). Studies in a coculture of breast cancer cells (3D-spheroid) with macrophages and in vivo models were conducted to evaluate the therapeutic efficacy of MSV-nAb-PTX as a function of macrophage phenotype. Association with MSV increased drug accumulation within the macrophages and the tumor spheroids, shifting the inflammation state of the TME toward the pro-inflammatory, anti-tumorigenic milieu. Additionally, the treatment increased macrophage motility toward cancer cells, promoting the active transport of therapeutic nanovectors into the tumor lesion. Consequently, apoptosis of cancer cells was increased and proliferation decreased in the MSV-nAb-PTX-treated group as compared to controls. The results also confirmed that the tested system shifts the macrophage differentiation toward an M1 phenotype, possessing an anti-proliferative effect toward the breast cancer cells. These factors were further incorporated into a mathematical model to help analyze the synergistic effect of the macrophage polarization state on the efficacy of MSV-nAb-PTX in alleviating hypovascularized tumor lesions. In conclusion, the ability of MSV-nAb-PTX to polarize TAM to the M1 phenotype, causing (1) enhanced penetration of the drug-carrying macrophages to the center of the tumor lesion and (2) increased toxicity to tumor cells may explain the increased anti-cancer efficacy of the system in comparison to nAb-PTX and other controls.

Project description:BACKGROUND:Ovarian cancer is the most leading cause of death and the third most common gynecologic malignancy in women. Traditional chemotherapy has inevitable drawbacks of nonspecific tumor targeting, high toxicity, and poor therapeutic efficiency. In order to overcome such shortcomings, we prepared a novel nano-carrier drug-delivery system to enhance the anti-tumor efficiency. METHODS:In vitro characterizations of nano-carriers were determined by TEM, DLS. Cell viability was measured by MTT method. RT-PCR was performed to measure the expression of FAR? in three ovarian cancer cell lines. The drug-release study and the uptaken study were measured in vitro. The pharmacokinetic and the drug distribution study were verified by HPLC methods in vivo. The enhanced anti-tumor efficiency of FA-NP was evaluated by the tumor inhibitory rate in vivo. RESULTS:Paclitaxel (PTX)-loaded nanoparticles (NPs) (PTX-PEG-PLA-NP and PTX-PEG-PLA-FA-NP) were prepared successfully, and the drug-release study showed that the cumulative release rates of NP groups were much less than free PTX group. The pharmacokinetic study showed that the elimination phase of two kinds of NP groups were much longer than that of PTX group. The drug distribution in different tissues showed that the peak-reach time was 2 h in the PTX group and 6 h in both NP groups. All of these results confirmed the excellent slow-release effects of both kinds of nano-carriers. More importantly, we confirmed that PTX-PEG-PLA-FA-NP had greater uptake by SK-OV-3 cells than PTX-PEG-PLA-NP and free PTX in vitro. A drug-distribution study of tumor-bearing mice demonstrated that the PTX concentration of tumor tissues in the PTX-PEG-PLA-FA-NP group was 3 times higher than the other two groups. PTX-PEG-PLA-FA-NP was uptaken much more by SK-OV-3 cells than PTX-PEG-PLA-NP and free PTX. Eventually, based on the slow-release effect and tumor-targeting characteristics of PTX-PEG-PLA-FA-NP, a cytotoxicity test indicated that PTX-PEG-PLA-FA-NP was much more toxic to SK-OV-3 cells than the controls. The tumor inhibitory rate in the PTX-PEG-PLA-FA-NP group of tumor-bearing mice was about 1.5 times higher than the controls. The tumor targeting and anti-tumor efficiency of PTX-PEG-PLA-FA-NP were confirmed both in vitro and in vivo. CONCLUSIONS:We developed an ovarian cancer targeting nano-carrier drug delivery system successfully, which showed perfect ovarian cancer targeting and anti-tumor effect, thus have the potential to be a new therapy strategy for ovarian cancer patients.

Dataset Information

Effective drug delivery, in vitro and in vivo, by carbon-based nanovectors noncovalently loaded with unmodified Paclitaxel.

Publications

Effective drug delivery, in vitro and in vivo, by carbon-based nanovectors noncovalently loaded with unmodified Paclitaxel.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets