Folate receptor-targeted multimodal polymersomes for delivery of quantum dots and doxorubicin to breast adenocarcinoma: In vitro and in vivo evaluation.

In this study, we report the design and delivery of tumor-targeted, quantum dot (QD) and doxorubicin (DOX)-encapsulated PEG-PLGA nanopolymersomes (NPs) for the imaging and chemotherapy of breast cancer. To achieve active cancer targeting, QD and DOX-encapsulated NPs were conjugated with folate for folate-binding protein receptor-guided delivery, which overexpressed in many cancer cells. Hydrophobic DOX and hydrophilic MSA-capped QD were encapsulated in the bilayer and core of the PEG-PLGA nanopolymersomes, respectively. The data show that the formulated NPs sustained DOX release for a period of 12 days. Fluorescence microscopy and MTT assay demonstrated that the developed folate-targeted DOX-QD NPs had higher cytotoxicity than non-targeted NPs and the free form of the drug; moreover, they preferentially accumulated in 4T1 and MCF-7 cells in vitro. In vivo experiments including whole organ tissue-homogenate analysis and organ fluorescence microscopy imaging of BALB/c mice bearing 4T1 breast adenocarcinoma showed that the folate receptor-targeted QD encapsulated NPs accumulate at tumor sites 6h following intravenous injection. Acute toxicity studies of the prepared targeted QD-loaded NPs showed no evidence of long-term harmful histopathological and physiological effects on the treated animals. The in vivo tumor inhibitory effect of folic acid (FA)-QD-DOX NPs demonstrated an augmented therapeutic efficacy of targeted formulation over the non-targeted and free drug. The data obtained illustrate a high potential of the prepared targeted theranostic nanoplatform in the treatment and imaging of breast cancer. This study may open new directions for preparation of QD-based theranostic polymersomes for clinical application.

Alibolandi M ，Abnous K ，Sadeghi F ，Hosseinkhani H ，Ramezani M ，Hadizadeh F ... -  《-》

'One-pot' synthesis of multifunctional GSH-CdTe quantum dots for targeted drug delivery.

Chen X ，Tang Y ，Cai B ，Fan H ... -  《-》

Synthesis of multimodal polymersomes for targeted drug delivery and MR/fluorescence imaging in metastatic breast cancer model.

The objective of the current study is to design and delivery of targeted PEG-PCL nanopolymersomes encapsulated with Gadolinium based Quantum Dots (QDs) and Doxorubicin (DOX) as magnetic resonance-florescence imaging and anti-cancer agent. Diagnostic and therapeutic efficiency of the prepared theranostic formulation was evaluated in vitro and in vivo. Hydrophobic QDs based on indium-copper-gadolinium-zinc sulfide were synthesized and characterized extensively. Hydrophobic QDs and hydrophilic DOX were loaded in PEG-PCL polymersomes through double emulsion method. Drug release pattern was studied in both citrate (pH 5.4) and phosphate (pH 7.4) buffer during 10 days. Both fluorescence and magnetic properties of bare QDs and prepared formulations were studied entirely. AS1411 DNA aptamer was covalently attached to the surface of polymersomal formulation in order to prepare targeted drug delivery system. Cellular cytotoxicity and cellular uptake analysis were performed in both nucleolin positive (MCF7 and 4T1) and nucleolin negative (CHO) cell lines. After in vitro evaluations, anti-tumor efficiency and diagnostic capability of the formulation was investigated in 4T1 tumor baring mice. Scanning emission electron microscopy (SEM) confirmed spherical shape and around 100 nm size of prepared formulations. Transmission electron microscopy (HRTEM) showed crystal shape of QDs with size of 2-3 nm. Drug release study obtained controlled release of encapsulated DOX and stability of formulation in physiologic condition. MTT and flow cytometry results demonstrated that AS1411 aptamer could enhance both toxicity and cellular uptake in nucleolin overexpressing cell lines (P < 0.05). Moreover, aptamer targeted formulation could increase survival rate and tumor inhibitory growth effect in 4T1 tumor baring mice (P < 0.05). Our results verify that aptamer targeted polymersomes loaded with non-toxic QDs as a diagnostic agent and DOX as an anti-cancer drug, could provide a theranostic platform with the purpose of optimization of treatment process and minimization of systemic side effects.

Zavvar T ，Babaei M ，Abnous K ，Taghdisi SM ，Nekooei S ，Ramezani M ，Alibolandi M ... -  《-》

Dextran-poly lactide-co-glycolide polymersomes decorated with folate-antennae for targeted delivery of docetaxel to breast adenocarcinima in vitro and in vivo.

In this study, a tumor-targeted, docetaxel encapsulated dextran-poly lactide-co-glycolide (DEX-PLGA) polymersomes was fabricated for breast cancer chemotherapy. To attain active cancer targeting, docetaxel encapsulated polymersomes was conjugated with folate for folate receptor guided delivery which is overexpressed in various cancer cells including breast adenocarcinoma. Docetaxel was encapsulated in the bilayer of DEX-PLGA or folate-conjugated DEX-PLGA (FA-DEX-PLGA) polymersomes via nanoprecipitation method in order to provide the controlled drug release. The size of polymersomes obtained were 178.53±2.5nm and offered drug encapsulation efficiency and loading content of 78.85±3.81% and 9.32±0.27, respectively. The data demonstrate that the prepared polymersome formulations sustained docetaxel release for a period of 6days. Cellular uptake study and MTT assay showed that the developed folate-targeted docetaxel-loaded polymersomes had higher cytotoxicity than non-targeted ones as well as free form of drug and was accumulated in 4T1 and MCF-7 cells in vitro. The in vivo tumor inhibitory effect of folate-conjugated docetaxel-loaded DEX-PLGA polymersomes (FA-DEX-PLGA-DTX-NPs) demonstrated an increased therapeutic potency of targeted formulation over both non-targeted (DEX-PLGA-DTX-NPs) and free drug. The represented data reveal that the prepared targeted drug delivery system was able to control the docetaxel release, and also enhance the antitumor potency of docetaxel. This study may open new direction for preparation of folate receptor targeted polymersomes based on DEX-PLGA copolymers for translational purposes.

Alibolandi M ，Abnous K ，Hadizadeh F ，Taghdisi SM ，Alabdollah F ，Mohammadi M ，Nassirli H ，Ramezani M ... -  《-》

The chemotherapeutic potential of doxorubicin-loaded PEG-b-PLGA nanopolymersomes in mouse breast cancer model.

Vesicles of mPEG-PLGA block copolymer were developed to deliver a therapeutic quantity of doxorubicin (DOX) for breast cancer treatment. The DOX-loaded nanoparticles (NPs) were prepared by the pH-gradient method and then evaluated in terms of morphology, size, DOX encapsulation efficiency and in vitro drug release mechanism. The PEG-PLGA nanopolymersomes were 134±1.2nm spherical NPs with a narrow size distribution (PDI=0.121). DOX was entrapped in mPEG-PLGA nanopolymersomes with an encapsulation efficiency and a loading content of 91.25±4.27% and 7.3±0.34%, respectively. The DOX-loaded nanopolymersomes were found to be stable, demonstrating no significant change in particle size and encapsulation efficiency (EE%) during the 6-month storage period of the lyophilized powder at 4°C. The nanopolymersomes sustained the release of DOX. In cytotoxicity studies of 4T1 cell line samples, free DOX showed a higher cytotoxicity (IC50=1.76μg/mL) than did DOX-loaded nanopolymersomes (15.82μg/mL) in vitro. In order to evaluate the antitumor efficacy and biodistribution of DOX-loaded nanopolymersomes, murine breast tumors were established on the BALB/c mice, and in vivo studies were performed. The obtained results demonstrated that the prepared drug delivery system was highly effective against a murine breast cancer tumor model and successfully accumulated in the tumor site through an enhanced permeation and retention mechanism. In vivo studies also proved that DOX-loaded nanopolymersomes are stable in blood circulation and could be considered a promising and effective DOX delivery system for breast cancer treatment.

Alibolandi M ，Sadeghi F ，Abnous K ，Atyabi F ，Ramezani M ，Hadizadeh F ... -  《-》