Effect of Photosensitizer Delivery System and Irradiation Parameters on the Efficiency of Photodynamic Therapy of B16 Pigmented Melanoma in Mice

Abstract— Previous studies (Biolo et al., Photochem. Photobiol. 59, 362-365, 1994) showed that liposome-delivered Si(IV)-na-phthalocyanine (SiNc) photosensitizes B16 pigmented melanoma subcutaneously transplanted in C57 mice to the action of 776 nm light. However, the efficacy of the phototreatment was limited by a lack of selectivity of tumor targeting by SiNc as well as by incomplete necrosis of the neoplastic mass. The present investigations show that the use of a different delivery system (Cremophor emulsion vs liposomes of dipalmitoylphosphatidylcholine) causes no significant increase in the selectivity of tumor targeting for three injected doses of SiNc (0.5, 1, 2 mg/kg). However, upon 776 nm light irradiation (300 mW/cm²; 520 J/cm²), the delay in the rate of tumor growth was maximal (7-8 days) for the highest naphthalocyanine dose. On the other hand, a remarkable improvement in the tumor response was obtained by inducing an intratumoral temperature increase to 44°C immediately after PDT. The thermal effect appeared to be due to photoexcitation of melanin by 776 nm light (550 mW/cm²; 520 J/cm²) and subsequent partial conversion of absorbed energy into heat.     

Photosensitizers for tumor therapy: determination of bis(di-isobutyl octadecylsiloxy)silicon 2,3-naphthalocyanine (isoBOSINC) in rat tissue and serum by high-performance liquid chromatography.

Bis(di-isobutyl octadecylsiloxy)silicon 2,3-naphthalocyanine (isoBOSINC) is a synthetic potential photosensitizer for tumor therapy. A new method, which combines solvent extraction and several purification steps, has been developed to determine its presence in tissues. Separation and quantitation of isoBOSINC is done by high-performance liquid chromatography on a silica column with toluene as a mobile phase and using fluorescence detection (lambda ex = 365 nm, lambda em = 750 nm). For recovery studies, isoBOSINC was added to muscles at levels of 0.067 and 0.67 micrograms/g; the mean recoveries were 100%, with coefficients of variation of 6.1 and 6.4%, respectively. For liver samples, the amounts added were 0.67 and 6.7 micrograms/g and for serum 0.67 and 6.70 micrograms/ml. The mean recoveries for liver were 86 and 93%, with coefficients of variation of 7.7 and 4.4%, respectively. For serum, the mean recoveries were 99 and 96%, with coefficients of variation of 2.6 and 6.9%, respectively. Due to its low detection limit and selectivity, the method is appropriate for pharmacokinetic as well as tumor uptake studies following in vivo exposure to isoBOSINC. Preliminary data on tissue distribution of the photosensitizer in normal rats are also presented.     

Evaluation of potassium ferrate(VI) cathode material coated with 2,3-Naphthalocyanine for alkaline super iron battery

The stability of potassium ferrate(VI) (K₂FeO₄) electrodes was dramatically improved by using 2,3-Naphthalocyanine (C₄₈H₂₆N₈) as coating. The electrode material with the coating was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR) and X-ray photoelectron spectroscopy (XPS). K₂FeO₄ electrodes coated with 2,3-Naphthalocyanine provided a superior capacity and stability to uncoated K₂FeO₄ electrodes. Cathodic charge capacity of K₂FeO₄ coated with 2,3-Naphthalocyanine is 42% higher than that of K₂FeO₄ uncoated when discharged at rate of 0.25 C to a cutoff of 0.8 V after storing in the 10 mol/L KOH solution for 3 h.     

The Effect of Fluence Rate on Tumor and Normal Tissue Responses to Photodynamic Therapy

Photodynamic therapy (PDT), carried out at low fluence rates, may enhance tumor response as well as affect treatment selectivity. We have studied the effects of fluence rate on the response of the murine radiation-induced fibrosarcoma (RIF) to PDT using Photofrin® (5 mg/kg). Tumor response was tested over a large range of fluence rates (10-200 mW/cm²) and fluences (25-378 J/ cm²). Low fluence rates were more efficient; -60 J/cm2 at 10 mW/cm² was needed to achieve the same tumor growth delay as -100 J/cm² at 150 mW/cm² and -150 J/cm2 at 200 mW/cm². Despite this increased efficiency, lower fluence rates still required longer treatment times for equivalent anti-tumor effects: 95 min for 57 J/cm² at 10 mW/cm²versus 11 min for 100 J/cm² at 150 mW/cm². Effects of fluence rate on the PDT toxicity to normal tissue were examined through the response of the murine (C311) foot to Photofrin® PDT. Treatment with conditions that produced equivalent tumor responses, i.e. 57 J/cm² at 10 mW/cm² and 100 J/cm² at 150 mW/cm², resulted in a more severe foot response at the higher fluence rate (median peak response: 0.9 at 10 mW/cm², 1.5 at 150 mW/cm²) with more time required for tissue to return to normal (8 days at 10 mW/cm², at least 30 days at 150 mW/cm²). However, when feet were treated with an equal fluence of 100 J/cm2 at various fluence rates, longer healing times accompanied the lower fluence rate treatments. Overall, this paper demonstrates that lower PDT fluence rates are associated with increased efficiency of tumor response. If this increased efficiency is accounted for by lowering treatment fluence, lower fluence rates also may result in a more favorable normal tissue response to treatment.     

Nano Proteolysis Targeting Chimeras (PROTACs) with Anti-Hook Effect for Tumor Therapy

Proteolysis targeting chimera (PROTAC) is an emerging pharmacological modality with innovated post-translational protein degradation capabilities. However, off-target induced unintended tissue effects and intrinsic “hook effect” hinder PROTAC biotechnology to be maturely developed. Herein, an intracellular fabricated nano proteolysis targeting chimeras (Nano-PROTACs) modality with a center-spoke degradation network for achieving efficient dose-dependent protein degradation in tumor is reported. The PROTAC precursors are triggered by higher GSH concentrations inside tumor cells, which subsequently in situ self-assemble into Nano-PROTACs through intermolecular hydrogen bond interactions. The fibrous Nano-PROTACs can form effective polynary complexes and E3 ligases degradation network with multi-binding sites, achieving dose-dependent protein degradation with “anti-hook effect”. The generality and efficacy of Nano-PROTACs are validated by degrading variable protein of interest (POI) such as epidermal growth factor receptor (EGFR) and androgen receptor (AR) in a wide-range dose-dependent manner with a 95 % degradation rate and long-lasting potency up to 72 h in vitro. Significantly, Nano-PROTACs achieve in vivo dose-dependent protein degradation up to 79 % and tumor growth inhibition in A549 and LNCap xenograft mice models, respectively. Taking advantages of in situ self-assembly strategy, the Nano-PROTACs provide a generalizable platform to promote precise clinical translational application of PROTAC.     

Self-Nanoemulsifying Drug Delivery System (SNEDDS) of Apremilast: In Vitro Evaluation and Pharmacokinetics Studies

Psoriatic arthritis is an autoimmune disease of the joints that can lead to persistent inflammation, irreversible joint damage and disability. The current treatments are of limited efficacy and inconvenient. Apremilast (APR) immediate release tablets Otezla^® have 20–33% bioavailability compared to the APR absolute bioavailability of 73%. As a result, self-nanoemulsifying drug delivery systems (SNEDDS) of APR were formulated to enhance APR’s solubility, dissolution, and oral bioavailability. The drug assay was carried out using a developed and validated HPLC method. Various thermodynamic tests were carried out on APR-SNEDDS. Stable SNEDDS were characterized then subjected to in vitro drug release studies via dialysis membrane. The optimum formulation was F9, which showed the maximum in vitro drug release (94.9%) over 24 h, and this was further investigated in in vivo studies. F9 was composed of 15% oil, 60% S_mix, and 25% water and had the lowest droplet size (17.505 ± 0.247 nm), low PDI (0.147 ± 0.014), low ZP (−13.35 mV), highest %T (99.15 ± 0.131) and optimum increases in the relative bioavailability (703.66%) compared to APR suspension (100%) over 24 h. These findings showed that APR-SNEDDS is a possible alternative delivery system for APR. Further studies are warranted to evaluate the major factors that influence the encapsulation efficiency and stability of APR-containing SNEDDS.     

Tumor Tropic Delivery of Hyaluronic Acid-Poly (D,L-lactide-co-glycolide) Polymeric Micelles Using Mesenchymal Stem Cells for Glioma Therapy

Tumor penetration and the accumulation of nanomedicines are crucial challenges in solid tumor therapy. By taking advantage of the MSC tumor-tropic property, we developed a mesenchymal stem cell (MSC)-based drug delivery system in which paclitaxel (PTX)-encapsulating hyaluronic acid-poly (D,L-lactide-co-glycolide) polymeric micelles (PTX/HA-PLGA micelles) were loaded for glioma therapy. The results indicated that CD44 overexpressed on the surface of both MSCs and tumor cells not only improved PTX/HA-PLGA micelle loading in MSCs, but also promoted the drug transfer between MSCs and adjacent cancer cells. It was hypothesized that CD44-mediated transcytosis played a crucial role and allowed deep glioma penetration depending on sequential intra–intercellular delivery via endocytosis–exocytosis. MSC-micelles were able to infiltrate from normal brain parenchyma towards contralateral tumors and led to the eradication of glioma. The survival of orthotopic glioma-bearing rats was significantly extended. In conclusion, the MSC-based delivery of HA-PLGA micelles is a potential strategy for tumor-targeting drug delivery.     

Synthesis and Characterization of Bis(azido)bis(2‐chloropyridine)palladium(II), Bis(azido)bis(3‐chloropyridine)palladium(II), Bis(azido)bis(quinoline)palladium(II), and the Crystal Structure of Bis(azido)bis(quinoline)palladium(II)

Three new monomeric complexes of palladium(II) azide with 2‐chloropyridine ( 1 ), 3‐chloropyridine ( 2 ), and quinoline ( 3 ), have been synthesized by reaction of palladium nitrate and the respective Lewis‐base with sodium azide in a water/acetone mixture. All three compounds were characterized by IR, Raman, and multinuclear NMR spectroscopy. The composition of the complexes were confirmed by elemental analysis. The spectroscopic investigations confirm terminal azide ligands in trans position. Complex 3 was also characterized by crystallographic methods. Each palladium atom of 3 is surrounded in a distorted square planar fashion by 4 nitrogen atoms. The terminal azide ligands are in trans position.     

Mass spectral behavior of some homoleptic and mixed aryldichalcogenide bis(diphenylphosphino)ferrocenenickel(II), palladium(II), and platinum(II), and bis(diisopropylphosphino)ferrocenepalladium(II) complexes

The mass spectral behavior of a number of organometallic complexes containing the Group 10 metals Ni, Pd, and Pt, together with various thiolate ligands were studied. For Pd, two main types of complexes, differing by the substituents on the phosphorus atom were studied. Types I and II were substituted with bis(diphenylphosphino)ferrocene and bis(diisopropylphosphino)ferrocene ligands, respectively. The Ni complexes, except for one, and the Pd Type I complexes had no molecular radical cations (M(+.)) in their EI spectra. On the other hand, all the Pt complexes showed intense M(+.) ions in their EI spectra indicating that these complexes were more stable as radical cations than those of Ni and Pd. The FAB and MALDI spectra of all the complexes displayed intense quasi-molecular ions (MH(+)) and the fragmentations in both modes were similar. The MALDI spectra of several complexes displayed only M(+.) ions while one gave evidence of both MH(+) and M(+.) ions. Several Pd Type II complexes yielded intense M(+.) in their EI spectra.     

Reactivity of dioxoruthenium(VI) porphyrins toward amines. Synthesis and characterization of bis(arylamine)ruthenium(II), bis(arylamido)- and bis(diphenylamido)ruthenium(IV), and oxo(tert-butylimido)ruthenium(VI) porphyrins

Reactions of dioxoruthenium(VI) porphyrins, [Ru(VI)O2(Por)], with p-chloroaniline, trimethylamine, tert-butylamine, p-nitroaniline, and diphenylamine afforded bis(amine)ruthenium(II) porphyrins, [Ru(II)(Por)(L)2] (L-p-ClC6H4NH2, Me3N, Por=TTP, 4-Cl-TPP; L=tBuNH2, Por = TPP, 3,4,5-MeO-TPP, TTP, 4-Cl-TPP, 3,5-Cl-TPP) and bis(amido)ruthenium(IV) porphyrins, [Ru(IV)(Por)(X)2] (X=p-NO2C6H4NH, Por=TTP, 4-Cl-TPP; X = Ph2N, Por = 3,4,5-MeO-TPP, 3,5-Cl-TPP), respectively. Oxidative deprotonation of [Ru(II)(Por)(NH2-p-C6H4Cl)2] in chloroform by air generated bis(arylamido)ruthenium(IV) porphyrins, [RuIV(Por)(NH-p-C6H4Cl)2] (Por=TTP. 4-Cl-TPP). Oxidation of [RuII(Por)-(NH2tBu)2] by bromine in dichloromethane in the presence of tert-butylamine and traces of water produced oxo(imido)ruthenium(VI) porphyrins, [RuVI-O(Por)(NtBu)] (Por=TPP, 3,4,5-MeO-TPP, TTP, 4-Cl-TPP, 3,5-Cl-TPP). These new classes of ruthenium complexes were characterized by 1H NMR, IR, and UV/visible spectroscopy, mass spectrometry, and elemental analysis. The structure of [Ru(IV)(TTP)(NH-p-C6H4Cl)2 . CH2Cl2 was determined by X-ray crystallography. The Ru-N bond length and the Ru-N-C angle of the Ru-NHAr moiety are 1.956(7) A and 135.8(6) degrees, respectively.     

Single crystal electron spin resonance of bis(tetraphenylphosphonium) bis(quinoxaline-2,3-dithiolato)oxovanadate(IV) as a pure compound and diluted in the isomorphous molybdenum(IV) compound

Single crystal e.s.r. spectra at room temperature and Q-band frequencies on [PPh₄]₂ [(Mo/V)O(qdt=₂] (qdt = quinoxaline-2,3-dithiolate) containing ca 3% vanadium gave the spin-Hamiltonian parameters g₁ = 1.977 ± 0.001, g₂ = 1.985 ± 0.001, g₃ = 1.987 ± 0.001, A₁ = (−38.5 ± 0.3) × 10⁻⁴, A₂ = (−45.1 ± 0.3) × 10⁻⁴, A₃ = (−133.2 ± 0.3) × 10⁻⁴ cm⁻¹, and Q′ = −(0.15±0.05) × 10⁻⁴ cm⁻¹. The g and A tensor axes are not coincident. The principal values of the g and A tensors have been analysed via an angular overlap treatment. Proton spin-flip transitions were observed in the spectra at X-band frequencies. Single crystal e.s.r. spectra of undiluted [PPh₄]₂ [VO(qdt)₂] at both X- and Q-band frequencies are interpreted in terms of a two-dimensional weak exchange model with J₀ = −48 ± 2G (ferromagnetic).     

Bis(aldehydes): Versatile precursors for novel bis(14H-dibenzo[a,j]xanthenes), bis(pyrano[3,2-c:5,6-c']dichromenedione), and bis(dihydrobenzo[a]xanthenones) via multicomponent reactions

A synthesis of novel bis(4-(14H-dibenzo[a,j]xanthenes) and bis(dihydro-8H-benzo[a]xanthenones) was performed in good yields via pseudo-multicomponent, or multicomponent reactions, of bis-aldehydes with four equivalents of β-naphthol or with a mixture of two equivalents of each β-naphthol and dimedone in the presence of a catalytic amount of p-toluenesulfonic acid. Bis(pyrano[3,2-c:5,6-c′]dichromenediones) or tetrakis(4-hydroxy-2H-chromen-2-ones) could also be obtained in good yields through pseudo-multicomponent reactions of bis(aldehydes) with four molar ratio of 4-hydroxycoumarin.     

Structure and bonding characteristics of bis(2,3-dicarnomethoxynorbornadiene)dicarbonylmolybdenum and related complexes

A crystal of bis(2,3-dicarbomethoxynorbornadiene)dicarbonylmolybdenum is in space group P2₁/c, with a 11.0406(25), b 14.7281(29), c 15.3310(27), β 110.38(2)° and Z = 4. Very large out-of-plane torsional angles (27–41°) for the vinylic carbomethoxy groups are observed. The bonding properties therefore are analyzed by comparison of spectroscopic data with those of related complexes, i.e. L₂Mo(CO)₂ where L = norbornadiene, 2-p-tosylnorbornadiene, and 2-carbomethoxynorbornadiene. Instead of σ-bond, metal to CC π-coordinations are believed to exist in these complexes. The presence of electron-withdrawing groups on the NBD ligands has increased their chelation strength, but at the same time has weakened the metalCO bonds.     

As(III), Sb(III) and Bi(III) complexes of dehydrodithizone (2,3-diphenyl-2,3-dehydrotetrazolium-5-thiolate)

The solid complexes of dehydrodithizone (2, 3-diphenyl-2,3-dehydrotetrazolium-5-thiolate) (DDTT): (DDTT)₅M(CIO₄)₃ (M=As, Sb, Bi) and (DDTT)₂MX₃ (M=As; X=I-M=Sb, Bi; X=Cl, Br, I) have been isolated. The three perchlorato-complexes have almost identical far i.r. spectra: six metal—ligand bands (five observed for the arsenic derivative) indicate a square pyramidal C_4v symmetry with the stereochemically active electron pair in the sixth position. The ν(MX) frequencies of the halide complexes (DDTT)₂MX3 (M = Sb, Bi; X = Cl, Br) indicate a probable square pyramidal structure with two ligand molecules in the equatorial plane and the stereochemically active electron lone pair in the sixth position. Infrared spectra and the complex stereochemistry indicate that DDTT acts in these complexes, like in other metal complexes, as unidentate sulphur-bonding ligand.     

Synthesis and characterization of 2,3-bis(hydroxyimino)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine and its nickel(II), cobalt(II), copper(II), palladium(II), cadmium(II) and cobalt(III) complexes

Summary 2,3-Bis(hydroxyimino)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (H₂L), prepared from 2,3-diaminopyridine and cyanogen-di-N-oxide has been converted into nickel(II), palladium(II), copper(II), cobalt(II), and cobalt(III) complexes (H₂L) with a 12 metal:ligand ratio. The ligands coordinate through the two N atoms, as do most vicinal dioximes. [(LH)Cl(H₂O)Cd], contains a six-membered chelate ring. [Co(HL)₂(L)Cl] has also been prepared using triphenylphosphine, triphenylarsine, thiophene and chloride as axial ligands. The structure of thevic-dioxime and its complexes are proposed on the basis of elemental analysis, i.r.,¹H-n.m.r. and uv-visible measurements.