Synthesis, Anticancer Activities, and Cellular Uptake Studies of Lipophilic Derivatives of Doxorubicin Succinate

Doxorubicin (DOX) is one of the most commonly used chemotherapeutic agents for treating human cancer. However, its clinical use has been limited by DOX-induced cardiotoxicity as well as other side effects. In the present study, we designed and synthesized the fullerenol (FU)-DOX conjugates and folic acid (FA)-grafted FU-DOX conjugates for improving the selectivity and activity of DOX in cancer cells. We further characterized the physicochemical properties and examined the release kinetics, cellular uptake, and in vitro anticancer activities of FU-DOX and FA-FU-DOX. The results showed that FU-DOX and FA-FU-DOX had a mean diameter of <200 nm and a low polydispersity. Both FU-DOX and FA-FU-DOX exhibited pH sensitivity and their DOX release rates were higher at pH 5.9 vs. pH 7.4. The cellular uptake studies indicated that FU conjugation enhanced the intracellular accumulation of DOX in human hepatocellular carcinoma (HCC) cell lines (BEL-7402 and HepG2) and the immortalized normal human hepatocytes (L02). The conjugation of FA to FU-DOX further promoted the drug internalization in an FR-dependent manner and enhanced the cytotoxicity against HCC cells. In conclusion, the newly prepared FA-FU-DOX conjugates can optimize the safety and efficacy profile of DOX.

Download Full-text

In Vitro Cellular Uptake Studies of Self-Assembled Fluorinated Nanoparticles Labelled with Antibodies

Nanomaterials ◽

10.3390/nano11081906 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1906

Author(s):

Mona Atabakhshi-Kashi ◽

Mónica Carril ◽

Hossein Mahdavi ◽

Wolfgang J. Parak ◽

Carolina Carrillo-Carrion ◽

...

Keyword(s):

Flow Cytometry ◽

Cellular Uptake ◽

Hydrophobic Interactions ◽

Intrinsic Properties ◽

Wide Range ◽

Self Assembled ◽

Uptake Studies ◽

Targeting Ability ◽

Fluorinated Nanoparticles

Nanoparticles (NPs) functionalized with antibodies (Abs) on their surface are used in a wide range of bioapplications. Whereas the attachment of antibodies to single NPs to trigger the internalization in cells via receptor-mediated endocytosis has been widely studied, the conjugation of antibodies to larger NP assemblies has been much less explored. Taking into account that NP assemblies may be advantageous for some specific applications, the possibility of incorporating targeting ligands is quite important. Herein, we performed the effective conjugation of antibodies onto a fluorescent NP assembly, which consisted of fluorinated Quantum Dots (QD) self-assembled through fluorine–fluorine hydrophobic interactions. Cellular uptake studies by confocal microscopy and flow cytometry revealed that the NP assembly underwent the same uptake procedure as individual NPs; that is, the antibodies retained their targeting ability once attached to the nanoassembly, and the NP assembly preserved its intrinsic properties (i.e., fluorescence in the case of QD nanoassembly).

Download Full-text

EFFECTS OF POLYMERIC NANOPARTICLE SURFACE PROPERTIES ON INTERACTION WITH BRAIN TUMOR ENVIRONMENT

Nano LIFE ◽

10.1142/s1793984413430034 ◽

2013 ◽

Vol 03 (04) ◽

pp. 1343003 ◽

Cited By ~ 7

Author(s):

BRANDON MATTIX ◽

THOMAS MOORE ◽

OLGA UVAROV ◽

SAMUEL POLLARD ◽

LAUREN O'DONNELL ◽

...

Keyword(s):

Human Brain ◽

Surface Charge ◽

Cellular Uptake ◽

Drug Clearance ◽

Cellular Interaction ◽

Normal Tissues ◽

Poly Ethylene ◽

Uptake Studies ◽

Effect Of Surface

Current chemotherapy treatments are limited by poor drug solubility, rapid drug clearance and systemic side effects. Additionally, drug penetration into solid tumors is limited by physical diffusion barriers [e.g., extracellular matrix (ECM)]. Nanoparticle (NP) blood circulation half-life, biodistribution and ability to cross extracellular and cellular barriers will be dictated by NP composition, size, shape and surface functionality. Here, we investigated the effect of surface charge of poly(lactide)-poly(ethylene glycol) NPs on mediating cellular interaction. Polymeric NPs of equal sizes were used that had two different surface functionalities: negatively charged carboxyl ( COOH ) and neutral charged methoxy ( OCH 3). Cellular uptake studies showed significantly higher uptake in human brain cancer cells compared to noncancerous human brain cells, and negatively charged COOH NPs were uptaken more than neutral OCH 3 NPs in 2D culture. NPs were also able to load and control the release of paclitaxel (PTX) over 19 days. Toxicity studies in U-87 glioblastoma cells showed that PTX-loaded NPs were effective drug delivery vehicles. Effect of surface charge on NP interaction with the ECM was investigated using collagen in a 3D cellular uptake model, as collagen content varies with the type of cancer and the stage of the disease compared to normal tissues. Results demonstrated that NPs can effectively diffuse across an ECM barrier and into cells, but NP mobility is dictated by surface charge. In vivo biodistribution of OCH 3 NPs in intracranial tumor xenografts showed that NPs more easily accumulated in tumors with less collagen. These results indicate that a robust understanding of NP interaction with various tumor environments can lead to more effective patient-tailored therapies.

Download Full-text

New derivatives of a natural nordentatin

Open Chemistry ◽

10.1515/chem-2020-0149 ◽

2020 ◽

Vol 18 (1) ◽

pp. 890-897 ◽

Cited By ~ 1

Author(s):

Tin Myo Thant ◽

Nanik Siti Aminah ◽

Alfinda Novi Kristanti ◽

Rico Ramadhan ◽

Hnin Thanda Aung ◽

...

Keyword(s):

Cell Line ◽

Parent Compound ◽

T47d Cell ◽

Positive Control ◽

Inhibition Assay ◽

Anticancer Activities ◽

Methanol Fraction ◽

T47d Cell Line ◽

Ft Ir ◽

Derivatives Of

AbstractNew derivatives were obtained from natural nordentatin (1) previously isolated from the methanol fraction of Clausena excavata by an acylation method. Herein, we report ten new pyranocoumarin derivatives 1a–1j. Their structures were elucidated based on UV-vis, FT-IR, NMR, and DART-MS data. The α-glucosidase inhibition and anticancer activities of nordentatin (1) and its derivatives were also evaluated. The α-glucosidase inhibition assay exhibited that the derivatives 1b, 1d, 1e, 1f, 1h, 1i, and 1j possess higher inhibitory activity for α-glucosidase with IC50 values of 1.54, 9.05, 4.87, 20.25, 12.34, 5.67, and 2.43 mM, whereas acarbose was used as the positive control, IC50 = 7.57 mM. All derivatives exhibited a weak cytotoxicity against a cervical cancer (HeLa) cell line with the IC50 between 0.25 and 1.25 mM. They also showed moderate to low growth inhibition of a breast cancer (T47D) cell line with IC50 values between 0.043 and 1.5 mM, but their activity was lower than that of the parent compound, nordentatin (1) (IC50 = 0.041 mM).

Download Full-text

Synthesis and Evaluation of Anticancer Activities of Novel C-28 Guanidine-Functionalized Triterpene Acid Derivatives

Molecules ◽

10.3390/molecules23113000 ◽

2018 ◽

Vol 23 (11) ◽

pp. 3000 ◽

Cited By ~ 8

Author(s):

Anna Spivak ◽

Rezeda Khalitova ◽

Darya Nedopekina ◽

Lilya Dzhemileva ◽

Milyausha Yunusbaeva ◽

...

Keyword(s):

Human Fibroblasts ◽

Human Tumor ◽

Jurkat Cells ◽

Anticancer Activities ◽

Triterpene Acid ◽

Guanidine Group ◽

Triterpene Acids ◽

Cycle Arrest ◽

Normal Human ◽

Derivatives Of

Triterpene acids, namely, 20,29-dihydrobetulinic acid (BA), ursolic acid (UA) and oleanolic acid (OA) were converted into C-28-amino-functionalized triterpenoids 4–7, 8a, 15, 18 and 20. These compounds served as precursors for the synthesis of novel guanidine-functionalized triterpene acid derivatives 9b–12b, 15c, 18c and 20c. The influence of the guanidine group on the antitumor properties of triterpenoids was investigated. The cytotoxicity was tested on five human tumor cell lines (Jurkat, K562, U937, HEK, and Hela), and compared with the tests on normal human fibroblasts. The antitumor activities of the most tested guanidine derivatives was lower, than that of corresponding amines, but triterpenoids with the guanidine group were less toxic towards human fibroblasts. The introduction of the tris(hydroxymethyl)aminomethane moiety into the molecules of triterpene acids markedly enhanced the cytotoxic activity of the resulting conjugates 15, 15c, 18b,c and 20b,c irrespective of the triterpene skeleton type. The dihydrobetulinic acid amine 15, its guanidinium derivative 15c and guanidinium derivatives of ursolic and oleanolic acids 18c and 20c were selected for extended biological investigations in Jurkat cells, which demonstrated that the antitumor activity of these compounds is mediated by induction of cell cycle arrest at the S-phase and apoptosis.

Download Full-text

Epigallocatechin Gallate-Gold Nanoparticles Exhibit Superior Antitumor Activity Compared to Conventional Gold Nanoparticles: Potential Synergistic Interactions

Nanomaterials ◽

10.3390/nano9030396 ◽

2019 ◽

Vol 9 (3) ◽

pp. 396 ◽

Cited By ~ 10

Author(s):

Suhash Chavva ◽

Sachin Deshmukh ◽

Rajashekhar Kanchanapally ◽

Nikhil Tyagi ◽

Jason Coym ◽

...

Keyword(s):

Gold Nanoparticles ◽

Antitumor Activity ◽

Cancer Cells ◽

Cellular Uptake ◽

Nuclear Translocation ◽

Epigallocatechin Gallate ◽

Drug Carriers ◽

Water Soluble ◽

Tetrazolium Salt ◽

Uptake Studies

Epigallocatechin gallate (EGCG) possesses significant antitumor activity and binds to laminin receptors, overexpressed on cancer cells, with high affinity. Gold nanoparticles (GNPs) serve as excellent drug carriers and protect the conjugated drug from enzymatic metabolization. Citrate-gold nanoparticles (C-GNPs) and EGCG-gold nanoparticles (E-GNPs) were synthesized by reduction methods and characterized with UV-visible spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering (DLS). Cytotoxicity of citrate, EGCG, C-GNPs, and E-GNPs was evaluated by the water-soluble tetrazolium salt (WST-1) assay. Nanoparticle cellular uptake studies were performed by TEM and atomic absorption spectroscopy (AAS). Dialysis method was employed to assess drug release. Cell viability studies showed greater growth inhibition by E-GNPs compared to EGCG or C-GNPs. Cellular uptake studies revealed that, unlike C-GNPs, E-GNPs were taken up more efficiently by cancerous cells than noncancerous cells. We found that E-GNP nanoformulation releases EGCG in a sustained fashion. Furthermore, data showed that E-GNPs induced more apoptosis in cancer cells compared to EGCG and C-GNPs. From the mechanistic standpoint, we observed that E-GNPs inhibited the nuclear translocation and transcriptional activity of nuclear factor-kappaB (NF-κB) with greater potency than EGCG, whereas C-GNPs were only minimally effective. Altogether, our data suggest that E-GNPs can serve as potent tumor-selective chemotoxic agents.

Download Full-text

Design and Evaluation of Licochalcone A Derivatives as Anticancer Agents

Natural Product Communications ◽

10.1177/1934578x1801300609 ◽

2018 ◽

Vol 13 (6) ◽

pp. 1934578X1801300

Author(s):

Goo Yoon ◽

Seung Hoon Cheon ◽

Jung Hyun Shim ◽

Seung Sik Cho

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Anticancer Agents ◽

Cancer Cell Lines ◽

Anticancer Activities ◽

Licochalcone A ◽

Lead Compounds ◽

Further Development ◽

Derivatives Of

New derivatives of licochalcone A were synthesized and evaluated for their potential anticancer activities. Compounds 6 (( E)-N-(4-(3-(5-bromo-4-hydroxy-2-methoxy phenyl) acryloyl) phenyl)-4-isopropylbenzamide) and 8 (1-(3-dimethylamino-phenyl)-3-(2-trifluoromethyl-phenyl)-propenone) showed potent activity against the screened cancer cell lines with that of compound 6 ranging from 6.9 ± 0.2 μM to 22.9 ± 3.1 μM, and that of compound 8 from 4.2 ± 0.5 μM to 11.8 ± 0.7 μM. Both compounds showed stronger cytotoxicity than that of licochalcone A. These two candidates have very different substituents and could be considered as promising lead compounds for further development of potent anticancer agents.

Download Full-text

A Novel Flow-Cytometry-Based Assay for Cellular Uptake Studies of Polyelectrolyte Microcapsules

Small ◽

10.1002/smll.200800596 ◽

2008 ◽

Vol 4 (10) ◽

pp. 1763-1768 ◽

Cited By ~ 62

Author(s):

Maximilian Semmling ◽

Oliver Kreft ◽

Almudena Muñoz Javier ◽

Gleb B. Sukhorukov ◽

Josef Käs ◽

...

Keyword(s):

Flow Cytometry ◽

Cellular Uptake ◽

Polyelectrolyte Microcapsules ◽

Uptake Studies

Download Full-text

The protozoan toxin climacostol and its derivatives: Cytotoxicity studies on 10 species of free-living ciliates

Biologia ◽

10.2478/s11756-010-0071-1 ◽

2010 ◽

Vol 65 (4) ◽

Cited By ~ 16

Author(s):

Federico Buonanno ◽

Claudio Ortenzi

Keyword(s):

Common Species ◽

Aliphatic Chain ◽

Ciliated Protozoan ◽

Anticancer Activities ◽

Free Living ◽

Parent Molecule ◽

Cytotoxicity Studies ◽

Resorcinolic Lipids ◽

Derivatives Of ◽

Freshwater Ciliates

AbstractClimacostol (5-(Z)-non-2-enyl-benzene-1,3-diol) is a natural toxin isolated from the freshwater ciliated protozoan Climacostomum virens and belongs to resorcinolic lipids, a group of compounds that show antimicrobial, antiparasitic, and anticancer activities. We investigated the cytotoxic activity of the chemically synthesized toxin and its alkyl and alkynyl derivatives on C. virens and nine other common species of free-living freshwater ciliates. Our results show that the cytotoxic potency of climacostol can be modulated by the substitution of the double bond present in the aliphatic chain of the toxin with a single or a triple one that was previously obtained during the synthesis of the unsaturated and saturated derivatives of the parent molecule. We demonstrated that the cytotoxicity level of the molecules considered in this study appears to be inversely correlated to the unsaturation level of their aliphatic chains, and that the potency of their action is also related to the target organism.

Download Full-text