Nanoparticles of 4,7-dichloro-2-quinolinemethylacrylate-based copolymers and their potential cytotoxic activity on human breast carcinoma cells

In this article, an improved synthesis strategy of the potent anticancer compound 4,7-dichloro-2-quinolinemethanol (QM) and its acrylate ester 4,7-dichloro-2-quinolinemethylacrylate (AQM) are described. AQM is copolymerized using free-radical polymerization with N-vinyl-2-pyrrolidone (VP) and the copolymers obtained from different molar ratios of monomers are subjected to nanoprecipitation to produce suspensions of nanoparticles (NPs) in phosphate buffered saline (PBS). The smallest and stable NPs are

prepared with the AQM-VP copolymers 45:55 and 40:60 (118.9 and 128.7 nm in diameter, respectively) at 1 mg mL−1, and along with AQM and QM, are evaluated for their cytotoxic activity on MDA-MB-453 breast carcinoma cells using MTT bioassay. AQM and QM are highly cytotoxic (IC50: 19 and 41 μM, respectively); however, the NPs are not cytotoxic in the range of the assayed concentrations. These results contribute to the search for new polymeric NPs with potential application as QM delivery systems for the treatment of cancer or other diseases treatable with QM.


pH-sensitive polymeric nanoparticles with antioxidant and anti-inflammatory properties against cisplatin-induced hearing loss

Polymeric nanoparticles (NP) based on smart synthetic amphiphilic copolymers are used to transport and controlled release dexamethasone in the inner ear to protect against the ototoxic effect of cisplatin. The NP were based on a mixture of two pseudo-block polymer drugs obtained by free radical polymerization: poly(VI-co-HEI) and poly(VP-co-MVE) or poly(VP-co-MTOS), being VI 1-vinylimidazole, VP N-vinylpyrrolidone, and IBU, MVE and MTOS the methacrylic derivatives of ibuprofen, α-tocopherol and α-tocopheryl succinate, respectively. The NP were obtained by nanoprecipitation with appropriate hydrodynamic properties, and isoelectric points that matched the pH of inflamed tissue. The NP were tested both in vitro (using HEI-OC1 cells) and in vivo (using a murine model) with good results. Although the concentration of dexamethasone administered in the nanoparticles is around two orders of magnitude lower that the conventional treatment for intratympanic administration, the NP protected from the cytotoxic effect of cisplatin when the combination of the appropriate properties in terms of size, zeta potential, encapsulation efficiency and isoelectric point were achieved. To the best of our knowledge this is the first time that pH sensitive NP are used to protect from cisplatin-induced hearing loss by intratympanic administration.

Photothermal and photodynamic activity of polymeric nanoparticles based on α-tocopheryl succinate-RAFT block copolymers conjugated to IR-780

The aim of this work was the generation of a multifunctional nanopolymeric system that incorporates IR- 780 dye, a near-infrared (NIR) imaging probe that exhibits photothermal and photodynamic properties; and a derivate of α-tocopheryl succinate (α-TOS), a mitochondria-targeted anticancer compound. IR-780 was conjugated to the hydrophilic segment of copolymer PEG-b-polyMTOS, based on poly(ethylene glycol) (PEG) and a methacrylic derivative of α-TOS (MTOS), to generate IR-NP, selfassembled nanoparticles (NPs) in aqueous media which exhibit a hydrophilic shell and a hydrophobic core. During assembly, the hydrophobic core of IR-NP could encapsulate additional IR-780 to generate derived subspecies carrying different amount of probe (IR-NP-eIR).

Evaluation of photo-inducible properties of IR-NP and IR-NP-eIR were thoroughly assessed in vitro. Developed nanotheranostic particles showed distinct fluorescence and photothermal behavior after excitation by a laser light emitting at 808 nm. Treatment of MDA-MB-453 cells with IR-NP or IR-NP-eIR resulted in an efficient internalization of the IR-780 dye, while subsequent NIR-laser irradiation led to a severe decrease in cell viability. Photocytoxicity conducted by IR-NP, which could not be attributed to the generation of lethal hyperthermia, responded to an increase in the levels of intracellular reactive oxygen species (ROS). Therefore, the fluorescence imaging and inducible phototoxicity capabilities of NPs derived from IR-780-PEG-bpolyMTOS copolymer confer high value to these nanotheranostics tools in clinical cancer research.


Polymeric nanoparticles loaded with dexamethasone or α-tocopheryl succinate to prevent cisplatin-induced ototoxicity

The aim of this work is the development of highly protective agents to be administered locally within the middle ear to avoid cisplatin-induced ototoxicity, which affects to 100% of the clinical patients at ultrahigh concentrations (16 mg/kg). The protective agents are based on polymeric nanoparticles loaded with dexamethasone or α-tocopheryl succinate as anti-inflammarory and anti-apoptotic molecules.

Dexamethasone and α-tocopheryl succinate are poorly soluble in water and present severe side effects when systemic administered during long periods of time. Their incorporation in the hydrophobic core of nanoparticles with the appropriate hydrodynamic properties provides the desired effects in vitro (lower cisplatin-induced toxicity, decreasing of caspase 3/7 activity, and lower IL-1b release) and in vivo (reducing the hearing loss at the local level). The local administration of the nanoparticles by bullostomy provides an adequate dose of drug without systemic interference with the chemotherapeutic effect of cisplatin.

Martin-Saldana, S. et al. Otoprotective properties of 6 alpha-methylprednisolone-loaded nanoparticles against cisplatin: In vitro and in vivo correlation. Nanomed.-Nanotechnol. Biol. Med. 12, 965–976 (2016). Cite

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