BACKGROUND: Drug targeting using functionalized nanoparticles to advance their transport to the dedicated site became a new standard in novel anticancer methods Anticancer photodynamic therapy also takes benefit from using nanoparticles by means of increasing targeting efficiency and decreased side effect. With this in mind, the silica-based nanoparticles, as drug delivery systems for the second-generation photosensitizer 5,10,15,20-tetrakis(m-hydroxyphenyl) chlorin (temoporfin) were developed. METHODS: In order to determine the stability and therapeutic performance of the selected nanomaterials in physiological fluids, their physicochemical properties (i.e. size, polydispersity, zeta potential) were measured by dynamic light scattering technique and the diameter and the morphology of the individual particles were visualized by a transmission electron microscopy. Their efficacy was compared with commercial temoporfin formulation in terms of in vitro phototoxicity in 4T1 (murine mammary carcinoma) and of in vivo anticancer effect in Nu/Nu mice bearing MDA-MB-231 tumors. RESULTS AND CONCLUSIONS: The two types of silica nanoparticles, porous and non-porous and with different surface chemical modification, were involved and critically compared within the study. Their efficacy was successfully demonstrated and was shown to be superior in comparison with commercial temoporfin formulation in terms of in vitro phototoxicity and cellular uptake as well as in terms of in vivo anticancer effect on human breast cancer model. Temoporfin-loaded silica nanoparticles also passed through the blood-brain barrier showing potential for the treatment of brain metastases.

• Klíčová slova
• Blood-brain barrier, Drug delivery, Photodynamic therapy, Silica nanoparticles, Temoporfin,
• MeSH
• fotochemoterapie metody   MeSH
• fotosenzibilizující látky aplikace a dávkování   farmakologie   MeSH
• lidé MeSH
• mesoporfyriny aplikace a dávkování   farmakologie   MeSH
• myši nahé MeSH
• nádorové buněčné linie MeSH
• nanočástice chemie   MeSH
• nosiče léků chemie   MeSH
• oxid křemičitý chemie   MeSH
• polyethylenglykoly chemie   MeSH
• transmisní elektronová mikroskopie MeSH
• uvolňování léčiv MeSH
• velikost částic MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fotosenzibilizující látky MeSH
• mesoporfyriny MeSH
• nosiče léků MeSH
• oxid křemičitý MeSH
• polyethylenglykoly MeSH
• temoporfin MeSH Prohlížeč

We developed fully biodegradable/metabolizable nanosystem based on polymer surfactant-stabilized thermoresponsive solid lipid nanoparticles with non-covalently bound photosensitizer temoporfin (T-SLNP) with particle size below 50nm. The efficacy of T-SLNP was compared with commercial temoporfin formulation in terms of in vitro phototoxicity in 4T1 (murine mammary carcinoma) and MDA-MB-231(human breast adenocarcinoma) cells and of in vivo anticancer effect in Nu/Nu mice bearing MDA-MB-231 tumors. In vitro study demonstrated faster accumulation kinetics in the cells for our formulation design resulting in higher phototoxicity against the tumor cells. In vivo anticancer efficacy was markedly improved by T-SLNP compared with commercial temoporfin formulation. Owing to controlled and sustained release properties, subcellular size, biocompatibility with tissue and cells, the T-SLNP nanodispersion prepared in this study represents promising drug delivery system applicable in cancer treatment.

• Klíčová slova
• Drug delivery, Nanomedicine, Photodynamic therapy, Solid lipid nanoparticles, Temoporfin,
• MeSH
• experimentální nádory mléčných žláz terapie   MeSH
• fotochemoterapie metody   MeSH
• fotosenzibilizující látky aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• lipidy chemie   MeSH
• mastné alkoholy aplikace a dávkování   terapeutické užití   MeSH
• mesoporfyriny chemie   MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nanočástice chemie   MeSH
• nosiče léků chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fotosenzibilizující látky MeSH
• lipidy MeSH
• mastné alkoholy MeSH
• mesoporfyriny MeSH
• myristyl alcohol MeSH Prohlížeč
• nosiče léků MeSH
• temoporfin MeSH Prohlížeč

Upconverting nanoparticles are interesting materials that have the potential for use in many applications ranging from solar energy harvesting to biosensing, light-triggered drug delivery, and photodynamic therapy (PDT). One of the main requirements for the particles is their surface modification, in our case using poly(methyl vinyl ether-alt-maleic acid) (PMVEMA) and temoporfin (THPC) photosensitizer to ensure the colloidal and chemical stability of the particles in aqueous media and the formation of singlet oxygen after NIR irradiation, respectively. Codoping of Fe2+, Yb3+, and Er3+ ions in the NaYF4 host induced upconversion emission of particles in the red region, which is dominant for achieving direct excitation of THPC. Novel monodisperse PMVEMA-coated upconversion NaYF4:Yb3+,Er3+,Fe2+ nanoparticles (UCNPs) with chemically bonded THPC were found to efficiently transfer energy and generate singlet oxygen. The cytotoxicity of the UCNPs was determined in the human pancreatic adenocarcinoma cell lines Capan-2, PANC-01, and PA-TU-8902. In vitro data demonstrated enhanced uptake of UCNP@PMVEMA-THPC particles by rat INS-1E insulinoma cells, followed by significant cell destruction after excitation with a 980 nm laser. Intratumoral administration of these nanoconjugates into a mouse model of human pancreatic adenocarcinoma caused extensive necrosis at the tumor site, followed by tumor suppression after NIR-induced PDT. In vitro and in vivo results thus suggest that this nanoconjugate is a promising candidate for NIR-induced PDT of cancer.

• Klíčová slova
• pancreatic tumor, photodynamic therapy, temoporfin, upconversion,
• Publikační typ
• časopisecké články MeSH

The development of drug resistance is a major problem which often occurs during anticancer chemotherapies. Photodynamic therapy (PDT) has been studied as an alternative treatment modality for drug-resistant tumors, however the question of resistance to PDT and potential cross-resistance with chemotherapy has yet to be fully answered. To investigate the mechanism of resistance to PDT, we developed an in vitro experimental model system in a mouse mammary carcinoma cell line 4T1. We used two ethylene glycol derivatives of tetraphenylporphyrin, and tetraphenylchlorin derivative, temoporfin, as photosensitizers (PS). PDT-resistant clones were obtained by exposure to a set concentration of PS followed by irradiation with increasing light doses. PDT resistance to soluble glycol porphyrins was mediated mainly by increased drug efflux through ABCB1 (P-glycoprotein) as we demonstrated by specific ABCB1 knockdown experiments, which in turn rescued the sensitivity of resistant cells to PDT. In contrast, resistance raised to temoporfin, which is generally more lipophilic than glycol porphyrins, elicited mechanism based on sequestration of the drug to lysosomes. The resistance that is acquired from a particular PS could be overcome by using a different PS, which is not susceptible to the same mechanism(s) of resistance. Elucidation of the underlying mechanisms in various types of resistance might facilitate improvements in PDT treatment design.

• MeSH
• chemorezistence genetika   MeSH
• ethylenglykoly aplikace a dávkování   chemie   MeSH
• fotochemoterapie MeSH
• fotosenzibilizující látky aplikace a dávkování   chemie   MeSH
• genový knockdown MeSH
• glykoly chemie   MeSH
• lidé MeSH
• mesoporfyriny aplikace a dávkování   chemie   MeSH
• MFC-7 buňky MeSH
• myši MeSH
• nádory mléčné žlázy u zvířat farmakoterapie   genetika   patologie   MeSH
• P-glykoprotein genetika   MeSH
• paclitaxel škodlivé účinky   MeSH
• porfyriny aplikace a dávkování   chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ethylenglykoly MeSH
• fotosenzibilizující látky MeSH
• glykoly MeSH
• mesoporfyriny MeSH
• P-glykoprotein MeSH
• paclitaxel MeSH
• porfyriny MeSH
• temoporfin MeSH Prohlížeč

Photodynamic therapy (PDT) has the potential to cure pancreatic cancer with minimal side effects. Visible wavelengths are primarily used to activate hydrophobic photosensitizers, but in clinical practice, these wavelengths do not sufficiently penetrate deeper localized tumor cells. In this work, NaYF4:Yb3+,Er3+,Fe2+ upconversion nanoparticles (UCNPs) were coated with polymer and labeled with meta-tetra(hydroxyphenyl)chlorin (mTHPC; temoporfin) to enable near-infrared light (NIR)-triggered PDT of pancreatic cancer. The coating consisted of alendronate-terminated poly[N,N-dimethylacrylamide-co-2-aminoethylacrylamide]-graft-poly(ethylene glycol) [P(DMA-AEM)-PEG-Ale] to ensure the chemical and colloidal stability of the particles in aqueous physiological fluids, thereby also improving the therapeutic efficacy. The designed particles were well tolerated by the human pancreatic adenocarcinoma cell lines CAPAN-2, PANC-1, and PA-TU-8902. After intratumoral injection of mTHPC-conjugated polymer-coated UCNPs and subsequent exposure to 980 nm NIR light, excellent PDT efficacy was achieved in tumor-bearing mice.

• MeSH
• akrylamidy chemie   MeSH
• fotochemoterapie * metody   MeSH
• fotosenzibilizující látky * chemie   farmakologie   MeSH
• infračervené záření MeSH
• koloidy chemie   MeSH
• lidé MeSH
• mesoporfyriny * chemie   farmakologie   MeSH
• myši inbrední BALB C MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory slinivky břišní * farmakoterapie   patologie   MeSH
• nanočástice chemie   MeSH
• polyethylenglykoly * chemie   MeSH
• polymery chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylamidy MeSH
• fotosenzibilizující látky * MeSH
• koloidy MeSH
• mesoporfyriny * MeSH
• polyethylenglykoly * MeSH
• polymery MeSH
• temoporfin MeSH Prohlížeč

Since the time when hematoporphyrine derivative (trade name Photofrin) has been introduced into clinical practice in Canada in 1993, a lot of new photosensitizers (PS) have been studied. Some of them successfully passed the clinical trials and are in use in the treatment of cancerous (ALA, temoporfin) and non-cancerous (verteporfin) diseases. The others (motexafin lutecium, talaporfin, phthalocyanines and SnET2) are entering or passing the clinical trials now. The newer PS are also called the second generation PS, when the first generation is composed of Photofrin only. The second generation PS usually possesses better properties, especially concerning absorption at longer wavelengths, shorter skin photosensitivity, better accumulation ratio between tumorous and healthy tissue and pharmacokinetics.

• MeSH
• fotochemoterapie * MeSH
• fotosenzibilizující látky chemie   terapeutické užití   MeSH
• lidé MeSH
• nádory farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• fotosenzibilizující látky MeSH

High photodynamic activity was observed for hexadeca-cationic zinc, magnesium, and metal-free phthalocyanines (Pcs) and tetrapyrazinoporphyrazines with EC50 values as low as 5 nM (MCF-7 cells) for the best compound; this activity was several times better than that of clinically established photosensitizers verteporfin, temoporfin, S3AlOHPc, or protoporphyrin IX. This lead compound was characterized by low dark toxicity (TC50 = 369 μM), high efficiency against other cell lines (HCT 116 and HeLa), and possible activation by light above 680 nm. The excellent photodynamic activity resulted from the rigid spatial arrangement of the quaternized triazole moieties above and below the Pc core, as confirmed by X-ray crystallography. The triazole moieties thus formed two "cationic donuts" that protected the hydrophobic core against aggregation in water. The lysosomes were found to be the site of subcellular localization and were consequently the primary targets of photodynamic injury, resulting in predominantly necrotic cell death.

• MeSH
• fotochemoterapie MeSH
• fotosenzibilizující látky chemická syntéza   chemie   farmakologie   MeSH
• indoly chemická syntéza   chemie   farmakologie   MeSH
• isoindoly MeSH
• krystalografie rentgenová MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• lyzozomy metabolismus   MeSH
• molekulární konformace MeSH
• nádorové buněčné linie MeSH
• nekróza MeSH
• porfyriny chemická syntéza   chemie   farmakologie   MeSH
• pyrazoly chemická syntéza   chemie   farmakologie   MeSH
• triazoly chemická syntéza   chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fotosenzibilizující látky MeSH
• indoly MeSH
• isoindoly MeSH
• phthalocyanine MeSH Prohlížeč
• porfyriny MeSH
• pyrazoly MeSH
• triazoly MeSH

Investigation of a series of tetra(3,4-pyrido)porphyrazines (TPyPzs) substituted with hydrophilic substituents revealed important structure-activity relationships for their use in photodynamic therapy (PDT). Among them, a cationic TPyPz derivative with total of 12 cationic charges above, below and in the plane of the core featured a unique spatial arrangement that caught the hydrophobic core in a cage, thereby protecting it fully from aggregation in water. This derivative exhibited exceptionally effective photodynamic activity on a number of tumor cell lines (HeLa, SK-MEL-28, A549, MCF-7) with effective concentrations (EC50) typically below 5 nM, at least an order of magnitude better than the EC50 values obtained for the clinically approved photosensitizers verteporfin, temoporfin, protoporphyrin IX, and trisulfonated hydroxyaluminum phthalocyanine. Its very low dark toxicity (TC50 > 400 μM) and high ability to induce photodamage to endothelial cells (EA.hy926) without preincubation suggest the high potential of this cationic TPyPz derivative in vascular-targeted PDT.

• MeSH
• buňky 3T3 MeSH
• endoteliální buňky účinky léků   MeSH
• fotochemoterapie MeSH
• fotosenzibilizující látky chemická syntéza   chemie   farmakologie   MeSH
• HeLa buňky MeSH
• kationty chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• metaloporfyriny chemická syntéza   chemie   farmakologie   MeSH
• MFC-7 buňky MeSH
• molekulární struktura MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• pyridiny chemická syntéza   chemie   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fotosenzibilizující látky MeSH
• kationty MeSH
• metaloporfyriny MeSH
• pyridiny MeSH