Paclitaxel-Loaded Folate-Targeted Albumin-Alginate Nanoparticles Crosslinked with Ethylenediamine. Synthesis and In Vitro Characterization

Ana María Martínez-Relimpio; Marta Benito; Elena Pérez-Izquierdo; César Teijón; Rosa María Olmo; María Dolores Blanco

doi:10.3390/polym13132083

Paclitaxel-Loaded Folate-Targeted Albumin-Alginate Nanoparticles Crosslinked with Ethylenediamine. Synthesis and In Vitro Characterization

Polymers ◽

10.3390/polym13132083 ◽

2021 ◽

Vol 13 (13) ◽

pp. 2083

Author(s):

Ana María Martínez-Relimpio ◽

Marta Benito ◽

Elena Pérez-Izquierdo ◽

César Teijón ◽

Rosa María Olmo ◽

...

Keyword(s):

Folic Acid ◽

Cell Membrane ◽

Cell Viability ◽

Folate Receptor ◽

Antineoplastic Drugs ◽

Secondary Effects ◽

In Vitro Characterization ◽

Nanometric Range ◽

Mcf 7

Among the different ways to reduce the secondary effects of antineoplastic drugs in cancer treatment, the use of nanoparticles has demonstrated good results due to the protection of the drug and the possibility of releasing compounds to a specific therapeutic target. The α-isoform of the folate receptor (FR) is overexpressed on a significant number of human cancers; therefore, folate-targeted crosslinked nanoparticles based on BSA and alginate mixtures and loaded with paclitaxel (PTX) have been prepared to maximize the proven antineoplastic activity of the drug against solid tumors. Nanometric-range-sized particles (169 ± 28 nm–296 ± 57 nm), with negative Z-potential values (between −0.12 ± 0.04 and −94.1± 0.4), were synthesized, and the loaded PTX (2.63 ± 0.19–3.56 ±0.13 µg PTX/mg Np) was sustainably released for 23 and 27 h. Three cell lines (MCF-7, MDA-MB-231 and HeLa) were selected to test the efficacy of the folate-targeted PTX-loaded BSA/ALG nanocarriers. The presence of FR on the cell membrane led to a significantly larger uptake of BSA/ALG–Fol nanoparticles compared with the equivalent nanoparticles without folic acid on their surface. The cell viability results demonstrated a cytocompatibility of unloaded nanoparticle–Fol and a gradual decrease in cell viability after treatment with PTX-loaded nanoparticle–Fol due to the sustainable PTX release.

Download Full-text

Paclitaxel-loaded Folate-targeted Albumin-Alginate Nanoparticles Crosslinked with Ethylenediamine. Synthesis and In Vitro Characterization.

10.20944/preprints202105.0671.v1 ◽

2021 ◽

Author(s):

A.M. Martínez ◽

M. Benito ◽

E. Pérez ◽

C. Teijón ◽

R.M. Olmo ◽

...

Keyword(s):

Folic Acid ◽

Cell Membrane ◽

Cell Viability ◽

Folate Receptor ◽

Antineoplastic Drugs ◽

Secondary Effects ◽

In Vitro Characterization ◽

Nanometric Range ◽

Mcf 7

Among the different ways to reduce the secondary effects of antineoplastic drugs in cancer treatment, the use of nanoparticles has demonstrated good results due to the protection of the drug and the possibility of releasing compounds to a specific therapeutic target. The α-isoform of folate receptor (FR) is overexpressed on a significant number of human cancers; therefore, folate-targeted crosslinked nanoparticles based on BSA and alginate mixtures and loaded with paclitaxel (PTX) have been prepared to maximizing the proven antineoplastic activity of the drug against solid tumors. Nanometric-range sized particles (169 ± 28nm - 296 ± 57nm), with negative Z-potential values (between -0.12 ± 0.04 and -94.1± 0.4), were synthesized. The loaded PTX (2.63±0.19 - 3.56 ±0.13 µg PTX/mg Np) was sustainably released along 23 and 27h. Three cell lines (MCF-7, MDA-MB-231 and HeLa) were selected to test the efficacy of the folate-targeted PTX-loaded BSA/ALG nanocarriers. The presence of FR on cell membrane led to a significant larger uptake of BSA/ALG-Fol nanoparticles regarding to the equivalent nanoparticles without folic acid on its surface. The cell viability results demonstrated a cytocompatibility of unloaded nanoparticle-Fol and a gradual decrease in cell viability after treatment with PTX-loaded nanoparticles-Fol due to the sustainable PTX release.

Download Full-text

Novel Difolate Targeting Nano-Level Ultrasound Contrast Agent for Therapy of Breast Cancer Tumor Cells

Science of Advanced Materials ◽

10.1166/sam.2021.4038 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1295-1303

Author(s):

Guangheng Liu ◽

Xiangfeng Yang ◽

Qiming Niu ◽

Wenkui Sun

Keyword(s):

Breast Cancer ◽

Contrast Agent ◽

Tumor Cells ◽

Folate Receptor ◽

Ultrasound Contrast Agent ◽

Hydroxyl Group ◽

Binding Ability ◽

Ultrasound Contrast ◽

Mcf 7

ABSTRACTA new type of difolate targeting nano-level ultrasound contrast agent ((folate molecule, FOL)2-TUAs) was prepared, so as to investigate its targeted binding effect with human breast cancer mammary carcinoma cells (MCF-7) in vitro. L-2-aminoadipic acid (L-2-AD) as a branch unit was inserted at the hydroxyl end of distearoyl phosphatidylethanolamine (DISP)-PEG2000-COOH to construct a tree structure. At this time, the free hydroxyl group in the distearoyl phosphatidylethanolamine (DISP)-PEG2000-COOH structure modified the FOL with the help of N-Hydroxysuccinimide/N,N'-dicyclohexylcarbodiimide (NHS/DCC). Each 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DISP-PEG2000) connected two FOLs to generate difolate targeted nanomaterials. Nano laser particle size (PS) and Zeta potential analyzer (ZPA) were applied to analyze the physical characteristics of the material such as PS and dispersion, and the enhanced development effect in vitro was detected by the ultrasonic diagnostic instrument. Besides, the targeted binding ability of the contrast agent based on this material to folate receptor (FR) overexpressing MCF-7 cells was analyzed by flow cytometry (FCM) and fluorescence microscope. In the experiment, hydrogen-1 nuclear magnetic resonance (1H NMR) demonstrated that (FOL)2-TUAs was successfully synthesized. The surface of this material was round and uniformly distributed without aggregation. According to the relative number of FOL molecules, non-targeted nano-agent (U-TUA), monofolate targeted nano-agent (FOL-TUA), and difolate targeted nano-agent ((FOL)2-TUA) were obtained. The in vitro imaging showed that different materials exhibited enhanced imaging effects in ultrasonic diagnostic equipment. FCM and fluorescence microscopy both indicated that the difolate TUA could achieve a good binding to MCF-7 cells. Most of the nano-agents were attached to the cell membrane, surrounded by red fluorophore, namely increasing the FOL content of DISP-PEG2000 chain could enhance the targeted binding ability of tumor cells.

Download Full-text

Evaluating biological activity of folic acid-modified and 10-hydroxycamptothecin-loaded mesoporous silica nanoparticles

10.22541/au.163364394.48960944/v1 ◽

2021 ◽

Author(s):

Mei-Xia Zhao ◽

Di-Feng Chen ◽

Xue-Jie Zhao ◽

Lin-Song Li ◽

Yong-Fang Liu

Keyword(s):

Folic Acid ◽

Mesoporous Silica ◽

Silica Nanoparticles ◽

Folate Receptor ◽

Mesoporous Silica Nanoparticles ◽

Drug Carriers ◽

Transmission Electron ◽

Before And After ◽

Drug Efficiency

Targeted nanocarrier can selectively deliver anti-tumor drugs to cancer sites improving drug efficiency. Accordingly, a targeted nanocarrier (MSN-FA) was synthesized based on folic acid (FA) modified mesoporous silica nanoparticles (MSNs). These loaded with 10-hydroxycamptothecin (HCPT) to obtain the nano-drug MSN-FA@HCPT. These nanocarriers were characterized by transmission electron microscopy (TEM), zeta potential, ultraviolet-visible spectroscopy (UV-Vis), fourier transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). Notably, the nanocarriers were nearly spherical before and after loading HCPT and exhibited good dispersibility. Also, folate receptor (FR) over-expressing HeLa cells and FR deficient HepG2 cells were used to evaluate in vitro cellular uptake and cytotoxicity of MSN-FA@HCPT and MSN@HCPT. Interestingly, FA-modified nanocarriers enhanced the cytotoxicity of HCPT by improving drug targeting to tumor cells. Also, apoptotic and mitochondrial membrane potential (MMP) reducing effects of MSN-FA@HCPT were more prominent than the MSNs without FA modification. MSN-FA@HCPT can be excellent drug carriers with profound biomedical applications.

Download Full-text

Optimisation of Folate-Mediated Liposomal Encapsulated Arsenic Trioxide for Treating HPV-Positive Cervical Cancer Cells In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms20092156 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2156 ◽

Cited By ~ 5

Author(s):

Akhtar ◽

Ghali ◽

Wang ◽

Bell ◽

Li ◽

...

Keyword(s):

Cervical Cancer ◽

Folic Acid ◽

Cancer Cells ◽

Arsenic Trioxide ◽

Folate Receptor ◽

Hpv Infection ◽

Cytotoxicity Studies ◽

Cervical Cancer Cells ◽

Infected Cells

High-risk human papilloma virus (HPV) infection is directly associated with cervical cancer development. Arsenic trioxide (ATO), despite inducing apoptosis in HPV-infected cervical cancer cells in vitro, has been compromised by toxicity and poor pharmacokinetics in clinical trials. Therefore, to improve ATO’s therapeutic profile for HPV-related cancers, this study aims to explore the effects of length of ligand spacers of folate-targeted liposomes on the efficiency of ATO delivery to HPV-infected cells. Fluorescent ATO encapsulated liposomes with folic acid (FA) conjugated to two different PEG lengths (2000 Da and 5000 Da) were synthesised, and their cellular uptake was examined for HPV-positive HeLa and KB and HPV-negative HT-3 cells using confocal microscopy, flow cytometry, and spectrophotometer readings. Cellular arsenic quantification and anti-tumour efficacy was evaluated through inductively coupled plasma-mass spectrometry (ICP-MS) and cytotoxicity studies, respectively. Results showed that liposomes with a longer folic acid-polyethylene glycol (FA-PEG) spacer (5000 Da) displayed a higher efficiency in targeting folate receptor (FR) + HPV-infected cells without increasing any inherent cytotoxicity. Targeted liposomally delivered ATO also displayed superior selectivity and efficiency in inducing higher cell apoptosis in HPV-positive cells per unit of arsenic taken up than free ATO, in contrast to HT-3. These findings may hold promise in improving the management of HPV-associated cancers.

Download Full-text

Assessment of Intracellular Delivery Potential of Novel Sustainable Poly(δ-decalactone)-Based Micelles

Pharmaceutics ◽

10.3390/pharmaceutics12080726 ◽

2020 ◽

Vol 12 (8) ◽

pp. 726

Author(s):

Kuldeep Kumar Bansal ◽

Ezgi Özliseli ◽

Gaurav Kumar Saraogi ◽

Jessica M. Rosenholm

Keyword(s):

Drug Delivery ◽

Folic Acid ◽

Folate Receptor ◽

In Vitro Cytotoxicity ◽

Uptake Efficiency ◽

Drug Delivery Carrier ◽

Intracellular Drug Delivery ◽

Copolymer Micelles ◽

Model Drug

Biodegradable polymers from renewable resources have attracted much attention in recent years within the biomedical field. Lately, poly(δ-decalactone) based copolymer micelles have emerged as a potential drug delivery carrier material as a sustainable alternative to fossil-based polymers. However, their intracellular drug delivery potential is not yet investigated and therefore, in this work, we report on the synthesis and cellular uptake efficiency of poly(δ-decalactone) based micelles with or without a targeting ligand. Folic acid was chosen as a model targeting ligand and Rhodamine B as a fluorescent tracer to demonstrate the straightforward functionalisation aspect of copolymers. The synthesis of block copolymers was accomplished by a combination of facile ring-opening polymerisation and click chemistry to retain the structure uniformity. The presence of folic acid on the surface of micelles with diameter ~150 nm upsurge the uptake efficiency by 1.6 fold on folate receptor overexpressing MDA-MB-231 cells indicating the attainment of targeting using ligand functionality. The drug delivery capability of these carriers was ascertained by using docetaxel as a model drug, whereby the in vitro cytotoxicity of the drug was significantly increased after incorporation in micelles 48 h post incubation. We have also investigated the possible endocytosis route of non-targeted micelles and found that caveolae-mediated endocytosis was the preferred route of uptake. This work strengthens the prospect of using novel bio-based poly(δ-decalactone) micelles as efficient multifunctional drug delivery nanocarriers towards medical applications.

Download Full-text

Adriamycin Loaded and Folic Acid Coated Zn-MOF for Tumor-Targeted Chemotherapy of Cervical Cancer

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2019.2178 ◽

2019 ◽

Vol 9 (11) ◽

pp. 1535-1541

Author(s):

Jing Sun ◽

Xiang-E Long ◽

Rong Li ◽

Chao-Feng Hu ◽

Xiao-Hong Ge

Keyword(s):

Folic Acid ◽

Drug Targeting ◽

Folate Receptor ◽

Metal Organic Framework ◽

Drug Carriers ◽

Spherical Particles ◽

Metal Organic ◽

Cervical Tumors

The drug delivery systems (DDSs) introduced in recent years have been wide recognized to greatly evaluate the efficacy of drugs. With the aim to increase drug targeting to tumors as well as decrease the side effect of both drug and drug carriers, this study has developed a hybrid DDS by incorporation zinc based metal-organic framework (Zn-MOF) and folic acid (FA). Moreover, adriamycin (Adr) as a model anticancer drug was loaded into the FA/Zn-MOF nanoparticle. The as-prepared FA/ZnMOF/Adr was expected to serve as a tumor targeting DDS that capable of effectively delivering Adr to cervical tumors. Characterization revealed that FA/Zn-MOF/Adr was nanosized spherical particles with high stability and biocompatibility. Most importantly, the FA/Zn-MOF/Adr could realize positive targeting to FA overexpressed HeLa cells through folate receptor (FR). Therefore, FA/Zn-MOF/Adr resulted enhanced in vitro and in vivo anticancer benefits than than free Adr or FA unmodified Zn-MOF/Adr.

Download Full-text

Rapid synthesis and in vitro and in vivo evaluation of folic acid derivatives labeled with fluorine-18 for PET imaging of folate receptor-positive tumors

Nuclear Medicine and Biology ◽

10.1016/j.nucmedbio.2011.03.004 ◽

2011 ◽

Vol 38 (7) ◽

pp. 1019-1028 ◽

Cited By ~ 19

Author(s):

I. Al Jammaz ◽

B. Al-Otaibi ◽

S. Amer ◽

S.M. Okarvi

Keyword(s):

Folic Acid ◽

Pet Imaging ◽

Folate Receptor ◽

Rapid Synthesis ◽

In Vivo Evaluation

Download Full-text

Folate Receptor-Mediated Cancer Cell Specific Gene Delivery Using Folic Acid-Conjugated Oligochitosans

Journal of Nanoscience and Nanotechnology ◽

10.1166/jnn.2006.465 ◽

2006 ◽

Vol 6 (9) ◽

pp. 2860-2866 ◽

Cited By ~ 53

Author(s):

Dongwon Lee ◽

Richard Lockey ◽

Shyam Mohapatra

Keyword(s):

Folic Acid ◽

Gene Transfer ◽

Gene Delivery ◽

Cancer Cells ◽

Transfection Efficiency ◽

Folate Receptor ◽

Weight Ratio ◽

Specific Gene ◽

Transfer Potential

Chitosan-mediated gene delivery has gained an increasing interest due to its ability to treat cancers and genetic diseases. However, low transfection efficiency and lack of target specificity limit its application for gene and drug delivery. In the present work, folic acid was covalently conjugated to chitosan as a targeting ligand in an attempt to specifically deliver DNA to folate receptor-overexpressing cancer cells. Folic acid-conjugated chitosan (FACN) was successfully synthesized and characterized by 1H-NMR and is biocompatible. In vitro gene transfer potential of FACN was evaluated in human epithelial ovarian cancer OV2008 cells and human breast cancer MCF-7 cells. FACN at a weight ratio of 10 : 1 exhibited significantly (< 0.01) enhanced gene transfer potential in folate receptor-overexpressing cancer cells as compared to unmodified chitosan. Transfection of FACN/pDNA nanocomplexes is competitively inhibited by free folic acid, suggesting the specific gene delivery of FACN/pDNA nanocomplexes is achieved through folate receptor-mediated endocytosis. Taken together, these results demonstrate that FACN provides a promising carrier for cancer gene therapy.

Download Full-text

Modeling of antiproliferative effects of Salvia officinalis L. essential oil optimized using Box–Behnken design

10.21203/rs.3.rs-44076/v1 ◽

2020 ◽

Author(s):

Imen Kallel ◽

Ahmed Bayoudh ◽

Bochra Gargouri ◽

Lamia Khannous ◽

Asma Elaguel ◽

...

Keyword(s):

Essential Oil ◽

Cell Viability ◽

Cell Lines ◽

Human Cancer ◽

Salvia Officinalis ◽

Dependent Manner ◽

Box Behnken Design ◽

Cytotoxicity Activity ◽

Mcf 7

Abstract Background Salvia officinalis L. essential oil (SoEO) was mostly traditionally used to medicate various diseases as cancer. Then, the present work aims were: (1) to model the cytotoxicity effects of Salvia officinalis L. essential oil (SoEO) related to the human cancer cell lines kind (MCF-7 and HeLa) ; (2) to optimize the hydro-distillation extraction conditions of SoEO; and, (3) to determine the in vitro scavenging capacity of the free radicals DPPH•, NO•, ABTS+, and the ability to reduce Fe3+. Methods The cytotoxicity and anti-proliferative abilities were evaluated by measuring cell viability and then modeled. Two human cell lines: MCF-7 and HeLa were used. The optimization of SoEO extraction by hydro-distillation was carried out with Response Surface Methodology (RSM) using the Box–Behnken design Results The cytotoxicity activity against both tumor cell lines MCF-7 and HeLa was considerably important with IC50 = 3.125 and 8.920 µg/mL, respectively. All treated cell lines showed a significant reducing in cell viability in response to the increasing oil concentration. The relative behaviors of both cell lines under SoEO treatment were modeled. The obtained optimal extraction yield was Y = 1.85 g/100 g d.b. The main identified fractions were camphene (23.7%), α-thujone (19.62%), 1,8-cineole (10.6%), viridiflorol (5.9%), borneol (5.72%); β-thujone (5.4%); caryophyllene (3,83%). Also, SoEO was mostly able to scavenge DPPH• free radical, ABTS+ radical and hydrogen peroxide in an amount dependent manner (IC50 = 0.97, 0.279 and 0.05 mg/mL, respectively). Conclusion The present work provides a preliminary platform for further investigation of the possible mechanism of S. officinalis essential oils and their individual compounds in cytotoxic and antitumor activity.

Download Full-text