Photosensitizer Release Research Articles

PH-Sensitive mesoporous zirconium diphosphonates for controllable colon-targeted delivery

pH-Sensitive mesoporous zirconium diphosphonates have been successfully synthesized through the surfactant-assisted procedure using the organophosphonate derivative of piperazine, 1,4-bis(phosphomethyl)piperazine (BPMP), and ZrCl4 as the metal precursor. The pH-sensitivity was derived from the reversible protonation–deprotonation of piperazine groups integrated in the mesoporous walls under different pH values, which endows mesoporous zirconium diphosphonates with reversible cationic–neutral surface properties. These pH-sensitive materials can effectively adsorb PDS (dinuclear cobalt phthalocyanine ammonium sulfonate, a photosensitizer of sulfonated phthalocyanine for photodynamic therapy of tumors) through strong electrostatic interaction. The PDS-loaded samples exhibit pH-dependent release behaviors for PDS in physiological buffer solutions as evidenced by the fact that almost no PDS release can be observed in simulated gastric fluid (pH 1.2) and a sustained release of PDS with a slower initial release rate was triggered with the electrostatic interaction disappearing due to the deprotonation of piperazine groups in the mesoporous walls under the weakly basic medium of simulated intestinal fluid (pH 7.5). The pH-sensitive mesoporous zirconium diphosphonates as smart carriers for pH-controllable release of anionic photosensitizer can be used to develop an oral colon-targeted drug delivery system in which the drug molecules will be trapped without release when passing through the stomach, and be released completely in a sustained-release method in the colon followed by a minimal drug release in the small intestine.

Thrombin-sensitive photodynamic agents: A novel strategy for selective synovectomy in rheumatoid arthritis

Protease-sensitive macromolecular prodrugs have attracted interest for bio-responsive drug delivery to sites with up-regulated proteolytic activities such as inflammatory or cancerous lesions. Here we report the development of a novel polymeric photosensitizer prodrug (T-PS) to target thrombin, a protease up-regulated in synovial tissues of rheumatoid arthritis (RA) patients, for minimally invasive photodynamic synovectomy. In T-PS, multiple photosensitizer units are tethered to a polymeric backbone via short, thrombin-cleavable peptide linkers. Photoactivity of the prodrug is efficiently impaired due to energy transfer between neighbouring photosensitizer units. T-PS activation by exogenous and endogenous thrombin induced an increase in fluorescence emission by a factor of 16 after in vitro digestion and a selective fluorescence enhancement in arthritic lesions in vivo, in a collagen-induced arthritis mouse model. In vitro studies on primary human synoviocytes showed a phototoxic effect only after enzymatic digestion of the prodrug and light irradiation, thus demonstrating the functionality of T-PS induced PDT. The developed photosensitizer prodrugs combine the passive targeting capacity of macromolecular drug delivery systems with site-selective photosensitizer release and activation. They illuminate lesions with pathologically enhanced proteolytic activity and induce cell death, subsequent to irradiation.

In vivo transport and pharmacokinetic behavior of tumour photosensitizers.

The mechanisms by which photodynamic sensitizers are transported in the bloodstream influence their distribution among normal and tumour tissues, as well as their partitioning among the various compartments of tumour tissues. Column chromatographic analysis and density gradient ultracentrifugation of sera obtained from both patients and experimental animals show that hydrophilic photosensitizers (e.g. haematoporphyrin, and tetrasulphonated porphyrins and phthalocyanines) are largely transported by albumin and globulins and mainly deposited in the vascular stroma of tumours. More hydrophobic photosensitizers (haematoporphyrin oligomers, porphyrin esters, monosulphonated or unsubstituted phthalocyanines) are preferentially incorporated in the lipid core of lipoproteins. Tightly aggregated dyes partly circulate as unbound pseudomicellar structures which can be entrapped in the interstitial regions of the tumour, localize in macrophages, or enter neoplastic cells via pinocytotic processes. Low density lipoproteins (LDL), which are endocytosed by neoplastic cells through a specific receptor-mediated pathway, display the most selective release of photosensitizers to tumours. The binding of the injected photosensitizer to LDL can be enhanced by preincorporation of the dye in liposomal vesicles which are in a quasi-solid state at the body temperature.

Zinc(II) phthalocyanine loaded PLGA nanoparticles for photodynamic therapy use

Sophisticated delivery systems, such as nanoparticles, represent a growing area in biomedical research. Nanoparticles (Np) were prepared using a solvent emulsion evaporation method (SEEM) to load zinc(II) phthalocyanine (ZnPc). Np were obtained using poly ( d, l latic-co-glycolic acid) (PLGA). ZnPc is a second generation of photoactive agents used in photodynamic therapy. ZnPc loaded PLGA nanoparticles were prepared by SEEM, characterized and available in cellular culture. The process yield and encapsulation efficiency were 80 and 70%, respectively. The nanoparticles have a mean diameter of 285 nm, a narrow size distribution with polydispersive index of 0.12, smooth surface and spherical shape. ZnPc loaded nanoparticles maintains its photophysical behavior after encapsulation. Photosensitizer release from nanoparticles was sustained with a moderate and burst effect of 15% for 3 days. The photocytotoxicity of ZnPc loaded PLGA Np was evaluated on P388-D1 cells what were incubated with ZnPc loaded Np (5 μM) by 6 h and exposed to red light (675 nm) for 120 s, and light dose of 30 J/cm 2. After 24 h of incubation, the cellular viability was determined, obtaining 61% of cellular death. All the physical–chemical, photophysical and photobiological measurements performed allow us conclude that ZnPc loaded PLGA nanoparticles is a promising drug delivery system for photodynamic therapy.

Synthesis, Characterization, Biodegradation, and in Vitro Photodynamic Activities of Silicon(IV) Phthalocyanines Conjugated Axially with Poly(ε-caprolactone)

A new series of phthalocyanine-containing biodegradable poly(ε-caprolactone)s have been synthesized by ring-opening polymerization of ε-caprolactone and/or 5-ethylene ketal ε-caprolactone using silicon phthalocyanine dihydroxide as the initiator and tin(II) 2-ethylhexanoate as the catalyst. The polymers have been spectroscopically characterized, and their molecular weights have been determined by gel permeation chromatography (GPC). All the polymers exhibit typical electronic absorption and fluorescence characteristics for nonaggregated phthalocyanines. The singlet oxygen quantum yields of selected polymers have been determined and found to be slightly lower than that of unsubstituted zinc(II) phthalocyanine in N,N-dimethylformamide (DMF). Nanoparticles with an average hydrodynamic radius 〈Rh〉 of ∼87 nm have been prepared from the homo-poly(ε-caprolactone) 3a and 3b (bulk) via a microphase inversion method. The ketal-containing analogues 5−7 are able to form nanoparticles with a smaller dimension (〈Rh〉 = 26−46 nm) in the absence of surfactants. The biodegradation of these systems with Lipase PS has been monitored by a combination of static and dynamic laser light scattering together with fluorescence spectroscopy, which shows that phthalocyanine rings are released during degradation. The polymers exhibit a high phototoxicity toward the HepG2 cancer cell line. The results suggest that this novel polymer-based colloidal system is potentially useful for the delivery and release of photosensitizers in photodynamic therapy.

UV-sensitive P compounds: release mechanism, seasonal fluctuation and inhibitory effects on alkaline phosphatase activity in a shallow Chinese freshwater lake (Donghu Lake)

Filtrable phosphorus compounds in a shallow Chinese freshwater lake (Donghu Lake) were fractionated by Sephadex G-25 gel-filtration chromatography. Some portions of those compounds released soluble reactive phosphorus upon irradiation with low dose ultraviolet light. Catalase and a hydroxyl radical scavenger (mannitol) markedly prevented photosensitive phosphorus release. The observed effects may be explained by the action of oxidizing reagents such as hydroxyl radicals, produced in photochemical reactions between UV irradiation and humic substances in the water. There was a strong seasonality in UV-sensitive P (UVSP) release. Michaels constants (K-m) of total alkaline phosphatase in the lake water showed a direct positive relation to UVSP. Plot of K-m against the UVSP/phosphomonoester ratio reveals a strong relationship between the two variables. These results suggest that in some situations UVSP may be a competitive inhibitor of alkaline phosphatase activity in the lake. The competitive inhibition of fractionated UVSP on alkaline phosphatase reagent (Sigma) apparently supports this hypothesis.

Iron redox effects on photosensitive phosphorus release from dissolved humic materials

Factors controlling the release of P from dissolved humic material (DHM)‐iron complexes were studied in an acid bog lake. Gel‐permeation chromatography of lake water labeled with 32PO43− was used to separate high‐ and low‐molecular‐weight fractions of P compounds. Fe3+ additions and irradiation with ultraviolet (UV) light increased the release of a labeled compound coeluting with orthophosphate from void volume fractions. Oxidation rates of Fe2+ in whole‐lake water were much slower than photoreduction rates, which suggests that, in UV light, Fe accumulated as Fe2+. Fe2+ concentrations decreased concomitant with a June increase in Chl a in the lake water. Biotic uptake of Fe2+ may deplete the ambient pool of both Fe2+ and Fe3+ in summer and make photosensitive processes less important at this time.

Prolactin cell activity in female and male Syrian hamsters: an apparent sexually dimorphic response to light deprivation and pinealectomy.

In order to determine the role of the pineal gland in mediating the effects of long-term light deprivation on prolactin (PRL) cell activity in a highly photosensitive species, PRL synthesis, storage and release were determined in both female and male Syrian hamsters that were either blind, blind and pinealectomized or left intact for 14 weeks. PRL release was determined in vivo by measuring the amount of immunoreactive (RIA) PRL in the serum of the animals in each group with a heterologous RIA for hamster PRL. Binding resulted in a 98 and 88% reduction in serum PRL levels in female and male hamsters, respectively. Pinealectomy largely prevented the suppressive effects of blinding on PRL release; however, PRL levels in blind pinealectomized animals were intermediate between those in intact and blind animals. PRL synthesis was evaluated by assessing the amount of 3H-leucine incorporated into PRL by anterior pituitaries in vitro. In female hamsters 14 weeks of light deprivation resulted in an 87% decrease in the incorporation of 3H-leucine into newly synthesized PRL whereas in males only a 40% reduction occurred. While pinealectomy completely prevented the inhibitory effects of blinding on PRL synthesis in males, it was less effective in female hamsters inasmuch as PRL synthesis was still nearly 50% lower in blind pinealectomized animals than in controls. Stored PRL, as represented by the total amount of RIA-PRL in vitro, was 96% lower in blind female hamsters as compared with intact controls; in blind male hamsters, stored PRL was reduced by 77%.(ABSTRACT TRUNCATED AT 250 WORDS)