ABSTRACT
Two protoporphyrin IX (PpIX) adamantane derivatives were synthesized and then metallated with zinc. The Zn-PpIX derivatives, exhibiting a high singlet oxygen quantum yield, were tested for their photodynamic activity against the HT-29 cell line. In order to enhance their water-solubility and their cellular bioavailability, these photosensitizers were encapsulated into the hydrophobic cavity of cyclodextrins (CD) previously attached to cellulose nanocrystals (CNCs) via electrostatic interactions. Under illumination, the encapsulated adamantanyl-porphyrins exerted an enhanced in vitro cytotoxicity, as compared with the corresponding free photosensitizers.
Subject(s)
Adamantane/pharmacology , Antineoplastic Agents/pharmacology , Cellulose/pharmacology , Cyclodextrins/pharmacology , Photochemotherapy , Photosensitizing Agents/pharmacology , Protoporphyrins/pharmacology , Adamantane/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Cellulose/chemistry , Cyclodextrins/chemistry , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , HT29 Cells , Humans , Molecular Structure , Nanoparticles/chemistry , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Protoporphyrins/chemistry , Structure-Activity RelationshipABSTRACT
The most prevalent form of Charcot-Marie-Tooth disease (CMT type 1A) is characterized by duplication of the PMP22 gene, peripheral dysmyelination and decreased nerve conduction velocities leading to muscle weakness. Recently, oxidative stress was reported as a feature in CMT1A patients. Curcumin exhibits antioxidant activities and has shown beneficial properties on peripheral nerves. However, curcumin presents unfavorable pharmacokinetics. We developed curcumin-cyclodextrin/cellulose nanocrystals (Nano-Cur) to bypass this limitation. The present study investigated the therapeutic potential of Nano-Cur in vitro in Schwann cells (SCs) and in vivo in the transgenic CMT1A rat model. In vitro, Nano-Cur treatment (0.01⯵M for 8â¯h) reduced reactive oxygen species and improved mitochondrial membrane potential in CMT1A SCs. Moreover, Nano-Cur treatment (0.01⯵M for 1 week) increased the expression of myelin basic protein in SC/neuron co-cultures. Preliminary in vivo experiments carried out in WT rats showed that intraperitoneal (i.p.) injection of Nano-Cur treatment containing 0.2â¯mg/kg of curcumin strongly enhanced the bioavailability of curcumin. Afterwards, in 1-month-old male CMT1A rats, Nano-Cur treatment (0.2â¯mg/kg/day, i.p. for 8 weeks) significantly improved sensori-motor functions (grip strength, balance performance, and mechanical and thermal sensitivities). Importantly, sensory and motor nerve conduction velocities were improved. Further histological and biochemical analyses indicated that myelin sheath thickness and myelin protein expression (myelin protein zero and PMP22) were increased. In addition, oxidative stress markers were decreased in the sciatic nerve and gastrocnemius muscle. Finally, Nrf2 expression and some major antioxidant enzymes were increased in sciatic nerve. Therefore, Nano-Cur significantly improved cellular, electrophysiological, and functional features of CMT1A rats.
Subject(s)
Charcot-Marie-Tooth Disease , Curcumin , Cyclodextrins , Nanoparticles , Animals , Cellulose , Charcot-Marie-Tooth Disease/drug therapy , Charcot-Marie-Tooth Disease/genetics , Curcumin/pharmacology , Humans , Male , Oxidative Stress , Phenotype , Rats , Rats, TransgenicABSTRACT
This paper describes the preparation of two chalcone/ß-cyclodextrin/cellulose-nanocrystals complexes and the study of their antiproliferative activities against two colorectal and two prostatic cancer cell lines. The aim of this work was to enhance hydrosolubility of chalcones thanks to the hydrophilic character of cellulose nanocrystals. These latter were linked, through ionic interactions, to a cationic derivative of ß-cyclodextrins whose lipophilic cavity allowed the encapsulation of hydrophobic chalcones: 3-hydroxy-3',4,4',5'-tetramethoxychalcone (1) and 3',4,4',5'-tetramethoxychalcone (2). First, we showed that encapsulation allowed hydrosolubilization of chalcones. Then, chalcone/ß-cyclodextrin/cellulose-nanocrystals complexes demonstrated enhanced in vitro antiproliferative activities, compared to the corresponding free-chalcones.
Subject(s)
Cellulose/chemistry , Chalcones/chemistry , Nanoparticles/chemistry , beta-Cyclodextrins/chemistry , HumansABSTRACT
We describe the synthesis of cellulose nanocrystals (CNCs) complexed to siRNA. PEI (600Da) was first covalently attached to CNCs by reductive amination reaction, then CNCs-PEI were loaded with siRNA, resulting in the formation of CNCs-PEI-siRNA particles, strongly stabilized by ionic interactions. Efficient cellular uptake of these particles was monitored by ethidium bromide staining. Not only did CNCs-PEI show no cytotoxicity at the studied concentrations, but they also protected siRNA from degradation and favored its delivery into the cells. This siRNA (siRNA killer) is able to silence the expression of cell cycle genes and to induce cell death by apoptosis. Therefore, this study suggests that these CNCs-PEI are promising non-viral nanovehicles for siRNA delivery and for efficient anti-tumor strategy.
Subject(s)
Apoptosis , Cellulose/chemistry , Genetic Vectors , Nanoparticles , Polyethyleneimine/chemistry , RNA, Small Interfering/chemistry , Animals , Cell Line, Tumor , Gene Silencing , MiceABSTRACT
The synthesis of curcumin-cyclodextrin/cellulose nanocrystals (CNCx) nano complexes was performed. CNCx were functionalized by ionic association with cationic ß-cyclodextrin (CD) and CD/CNCx complexes were used to encapsulate curcumin. Preliminary in vitro results showed that the resulting curcumin-CD/CNCx complexes exerted antiproliferative effect on colorectal and prostatic cancer cell lines, with IC50s lower than that of curcumin alone.
