Poly (lactide-co-glycolide) acid nanoencapsulation of a synthetic coumarin: Cytotoxicity and bio-distribution in mice, in cancer cell line and interaction with calf thymus DNA as target

• Published in: Toxicology and applied pharmacology Vol. 253; no. 3; pp. 270 - 281
• Main Authors: Bhattacharyya, Soumya Sundar, Paul, Saili, De, Arnab, Das, Durba, Samadder, Asmita, Boujedaini, Naoual, Khuda-Bukhsh, Anisur Rahman
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15.06.2011; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; ANIMALS; ANTICOAGULANTS; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Apoptosis - drug effects; ATOMIC FORCE MICROSCOPY; Biological and medical sciences; BIOLOGICAL MATERIALS; BLOOD; BLOOD-BRAIN BARRIER; BODY; BODY FLUIDS; BRAIN; CALVES; CARCINOMAS; CARDIOVASCULAR SYSTEM; CATTLE; Cell Line, Tumor; Cell Survival - drug effects; CENTRAL NERVOUS SYSTEM; Chemotherapy; Circular Dichroism; Circular dichroism spectroscopy; COUMARIN; Coumarins - administration & dosage; Coumarins - pharmacokinetics; Coumarins - pharmacology; DIGESTIVE SYSTEM; DISEASES; DNA; DNA - chemistry; DNA-drug interaction; DOMESTIC ANIMALS; DRUGS; ELECTRON MICROSCOPY; EPITHELIOMAS; ESTERS; GLANDS; HEART; HEMATOLOGIC AGENTS; HETEROCYCLIC COMPOUNDS; HETEROCYCLIC OXYGEN COMPOUNDS; Humans; In Situ Nick-End Labeling; INTERACTIONS; KIDNEYS; Lactic Acid - administration & dosage; Lactic Acid - pharmacokinetics; LACTONES; LIGHT SCATTERING; LIVER; LUNGS; LYMPHATIC SYSTEM; MAMMALS; MATERIALS; Medical sciences; MELANOMAS; MICE; MICROSCOPY; Nanocapsules - administration & dosage; NANOSTRUCTURES; NEOPLASMS; NERVOUS SYSTEM; NUCLEIC ACIDS; ORGANIC COMPOUNDS; ORGANIC OXYGEN COMPOUNDS; ORGANS; PARTICLE SIZE; PARTICLES; Pharmacology. Drug treatments; PLGA; Polyglycolic Acid - administration & dosage; Polyglycolic Acid - pharmacokinetics; PYRANS; RESPIRATORY SYSTEM; Reverse Transcriptase Polymerase Chain Reaction; RODENTS; RUMINANTS; SCANNING ELECTRON MICROSCOPY; SCATTERING; SIZE; THYMUS; Tissue Distribution; VERTEBRATES; Circular dichroism spectroscopy; Scanning electron microscopy; Atomic force microscopy; DNA-drug interaction; PLGA; Blood brain barrier; Antineoplastic agent; Targeting; Coumarine derivatives; Central nervous system; Ox; Cytotoxicity; Nanoencapsulation; Encephalon; Target; Circular dichroism spectrometry; Established cell line; Drug interaction; Ungulata; Tumor cell; Thymus gland; Rodentia; Calf; Coumarin; In vitro; Biological activity; Vertebrata; Lactic acid polymer; Mammalia; Cell line; Synthetic product; Mouse; Animal; DNA; Distribution; Plant origin; Artiodactyla
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2011.04.010

Several naturally occurring coumarin compounds, including scopoletin (7 hydroxy-6 methoxycoumarin), of plant origin have been reported to have anti-cancer potentials. A related but chemically synthesized coumarin, 4-methyl-7-hydroxy coumarin (SC), was also shown to have similar anti-cancer potentials. In the present study, to test if nano-encapsulated SC could be a more potent anti-cancer agent, we encapsulated SC with poly lactide-co-glycolide acid (PLGA) nanoparticles (Nano Coumarin; NC) and tested its potentials with a variety of protocols. NC demonstrated greater efficiency of drug uptake and showed anti-cancer potentials in melanoma cell line A375, as revealed from scanning electronic and atomic force microscopies. To test its possible interaction with target DNA, the combined data of circular dichroism spectra (CD) and melting temperature profile (Tm) of calf thymus DNA treated with NC were analyzed. Results indicated a concentration dependent interaction of NC with calf thymus DNA, bringing in effective change in structure and conformation, and forming a new complex that increased its stability. Particle size and morphology of NC determined through polydispersity index and zeta potential using dynamic light scattering qualified NC to be a more potent anti-cancer agent than SC. Further, SC and NC showed negligible cytotoxic effects on normal skin cells and peripheral blood mononuclear cells of mice. Distribution assay of PLGA nanoparticles in different tissues like brain, heart, kidneys, liver, lungs, and spleen in mice revealed the presence of nanoparticles in different tissues including brain, indicating that the particles could cross the blood brain barrier, significant information for drug design. Nanoencapsulated coumarin (NC) were characterized for their size and morphology by scanning electron (SEM) and atomic force microscopies (AFM).The physical interaction of the NC with calf thymus DNA was studied through circular dichroism (CD) spectroscopies, using UV−visible titration and thermal denaturation studies. NC had a concentration dependent interaction with calf thymus DNA, could form a new complex with double helical DNA, increased the Tm value and altered CD spectra of DNA and showed stronger anti-cancer effect than synthetic coumarin. [Display omitted] ► Strategy for PLGA nano-encapsulation of a bioactive synthetic coumarin, 4methyl 7hydroxy coumarin (SC) is formulated. ► Anti-cancer potentials of nano-encapsulated SC (NC) are evaluated in skin papilloma cells A375 through standard protocols. ► Data of CD and Tm indicate concentration dependent interactions of NC bringing conformational changes in target DNA. ► Particle size of NC and physico-chemical interactions with target DNA show NC as a more potent anti-cancer drug than SC. ► NC has less cytotoxic effects, and can cross the blood brain barrier – important features for strategic drug design.