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Biomedical subjects

J D Spikes

Publications and source records attributed to J D Spikes.

At least 19 recordsLinked to original sources
PubMed1994

A polymeric drug delivery system for the simultaneous delivery of drugs activatable by enzymes and/or light.

Three water soluble copolymers based on N-(2-hydroxypropyl)methacrylamide were prepared. Copolymer I contains adriamycin, a chemotherapeutic agent, attached via enzymatically degradable oligopeptide (glycylphenylalanylleucylglycine; G-F-L-G) side chains. The other two copolymers contained the photosensitizer, meso-chlorin e6 monoethylene diamine disodium salt (Mce6). In Copolymer II, the chlorin is attached via the degradable G-F-L-G sequence, and it was bound by the nondegradable glycyl spacer in Copolymer III. Initially, the copolymers were characterized separately in vitro and in vivo. Combinations of the copolymer bound chemotherapeutic agent and each of the copolymer bound photosensitizers were then assessed for antitumor effect in vivo. Localization/retention studies (A/J mice; Neuro 2A neuroblastoma solid tumor) were performed with the two copolymers containing Mce6 as well as the free drug. Results of these experiments demonstrated a very different tumor uptake profile for the two copolymers. While the free drug was rapidly cleared from tumor tissue, the copolymer containing Mce6 attached via the non-degradable bond was retained for an extended period; drug concentrations in the tumor were high even after 5 days. On the other hand, a high concentration of the copolymer containing Mce6 bound via the degradable sequence was taken up by the tumor, yet its concentration in the tumor was substantially diminished at 48 h after administration. This shows indirect evidence of in vivo cleavage of Mce6 from the copolymer in the lysosomal compartment which is supported by direct evidence of cleavage by cathepsin B (a lysosomal enzyme) in vitro. Antitumor effects were assessed on Neuro 2A neuroblastoma induced in A/J mice for all three copolymers. Photodynamic therapy (PDT) proved the copolymer with Mce6 bound via the degradable oligopeptide sequence to be a more effective photosensitizer in vivo than the other chlorin containing copolymer. The difference in activity was consistent with the results obtained by photophysical analyses in which the free drug had a higher quantum yield of singlet oxygen generation than the polymer bound drug in buffer. The quantum yield of singlet oxygen generation increased with the enzymatic cleavage of the chlorin from the copolymer. Conditions were subsequently determined for which chemotherapy or PDT would show some antitumor effect, yet be incapable of curing tumors. Finally, combination therapy experiments were performed in which the copolymer bound adriamycin was mixed with either of the copolymer bound chlorin compounds and injected intravenously (i.v.) into the tail veins of mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Acrylamides↗
PubMed1993

Photosensitizing properties of mono-L-aspartyl chlorin e6 (NPe6): a candidate sensitizer for the photodynamic therapy of tumors.

There is a large amount of interest in chlorins as photosensitizers for the photodynamic therapy of tumors because of their strong absorption in the red, where light penetration into mammalian tissues is efficient. Mono-L-aspartyl chlorin e6 (NPe6), in phosphate buffer of pH 7.4, had absorption peaks at 400 and 654 nm with molar absorption coefficients of 180,000 and 40,000 M-1 cm-1 respectively. In buffer, the NPe6 triplet had a peak at 440 nm and a lifetime under argon of approximately 300 microseconds. The triplet was efficiently quenched by ground state oxygen (kQ = 1.9 x 10(9) M-1 s-1) with the formation of singlet oxygen, as identified by its near infrared luminescence. The quantum yield of singlet oxygen production was 0.77. A number of substrates were efficiently photo-oxidized by NPe6, including furfuryl alcohol, cysteine, histidine, tryptophan and human serum albumin. These reactions were efficiently inhibited by azide (which did not quench NPe6 triplets), indicating that they are probably mediated by singlet oxygen. Thus, NPe6 has a desirable array of photoproperties for a sensitizer to be used in the clinical photodynamic therapy of tumors.

Antineoplastic Agents↗
PubMed1993

Photobleaching of mono-L-aspartyl chlorin e6 (NPe6): a candidate sensitizer for the photodynamic therapy of tumors.

Most sensitizers used for the photodynamic therapy (PDT) of tumors photobleach on illumination. Thus, it is of interest to examine the photobleaching behavior of new sensitizers proposed for use in PDT. This report surveys the quantum yields and kinetics of the photobleaching of mono-L-aspartyl chlorin e6(NPe6), a hydrophilic chlorin that has many of the photoproperties desirable in a sensitizer for clinical PDT. It is a very effective sensitizer for the PDT of several types of model tumors in animals and is now in Phase I clinical trials. The quantum yield of NPe6 photobleaching in pH 7.4 phosphate buffer in air was 8.2 x 10(-4); this is greater than the yields for typical porphyrin photosensitizers. For example, the yields for hematoporphyrin and uroporphyrin are 4.7 x 10(-5) and 2.8 x 10(-5), respectively. The yield decreased significantly in organic solvents of low dielectric constant. The Sn derivative of NPe6 was more light stable than NPe6 (yield = 5.7 x 10(-6), while the Zn derivative was more sensitive (yield = 1.9 x 10(-2). Oxygen appeared to be necessary for the photobleaching of NPe6; however, bleaching was not inhibited by 100 mM azide, an efficient quencher of singlet oxygen. The photooxidizable substrates cysteine, dithiothreitol and furfuryl alcohol increased the quantum yield of photobleaching two- to four-fold, while the electron acceptor, metronidazole, increased it almost six-fold. Photobleaching yields for several other chlorins were also measured.

Animals↗
PubMed1992

Quantum yields and kinetics of the photobleaching of hematoporphyrin, Photofrin II, tetra(4-sulfonatophenyl)-porphine and uroporphyrin.

Porphyrins used as sensitizers for the photodynamic therapy (PDT) of tumors are progressively destroyed (photobleached) during illumination. If the porphyrin bleaches too rapidly, tumor destruction will not be complete. However, with appropriate sensitizer dosages and bleaching rates, irreversible photodynamic injury to the normal tissues surrounding the tumor, which retain less sensitizer, may be significantly decreased. This paper surveys the quantum yields and kinetics of the photobleaching of four porphyrins: hematoporphyrin (HP), Photofrin II (PF II), tetra(4-sulfonatophenyl)porphine (TSPP) and uroporphyrin I (URO). The initial quantum yields of photobleaching, as measured in pH 7.4 phosphate buffer in air, were: 4.7 x 10(-5), 5.4 x 10(-5), 9.8 x 10(-6), and 2.8 x 10(-5) for HP, PF II, TSPP and URO respectively; thus, the rates of photobleaching are rather slow. Low oxygen concentration (2 microM) significantly reduced the photobleaching yields. However, D2O increased the yields only slightly, and the singlet oxygen quencher, azide, had no effect, even at 0.1 M. Photosensitizing porphyrins in body fluids, cells and tissues may be closely associated with various photooxidizable molecules and electron acceptors and donors. Therefore, selected model compounds in these categories were examined for their effects on porphyrin photobleaching. A number inhibited and/or accelerated photobleaching, depending on the compound, the porphyrin and the reaction conditions. For example, 1.0 mM furfuryl alcohol increased the photobleaching yields of HP and URO more than 5-fold, with little effect on PF II or TSPP. In contrast, the electron acceptor, methyl viologen, increased the photobleaching yield of TSPP more than 10-fold, with little accelerating effect on the other porphyrins. These results suggest that the mechanism(s) of the photobleaching of porphyrin photosensitizers in cells and tissues during PDT may be complex.

Dihematoporphyrin Ether↗
PubMed1991

Presence of blood significantly decreases transmission of 630 nm laser light.

Application of 630 nm light in the presence of blood is often necessary during photodynamic therapy, particularly for proposed intravascular applications. The effect of blood on transmission of 630 nm light was studied using a three dimensional irradiation model and an integrating sphere for measuring light transmitted in any direction through blood layers of different hematocrit (25 to 75) and thickness (.15 to .98 mm). There was an inverse relationship between transmission and hematocrit and transmission and blood thickness, p = .000 for both. At a physiologic hematocrit of 46, transmission through blood layers of .98, .41, .28, and .15 mm were 21%, 33%, 29%, and 58% respectively. These blood thicknesses or more are likely in the clinical environment, and can be expected to result in significant transmission losses. The marked absorption of 630 nm light by blood indicates that removal of the blood or correction for power loss should be employed when 630 nm light is applied in a blood containing environment.

Absorption↗
PubMed1990

Photothermal sensitizers: possible use in tumor therapy.

Photothermal damage of tissues or endotissular compartments may be induced by pulsed irradiation of either endogenous chromophores (e.g. hemoglobin, melanin) or externally added dyes; the latter should have short triplet lifetimes and mainly decay from electronically excited states by nonradiative pathways. Potential photothermal sensitizers are some metallo derivatives of porphyrins and porphyrinoid compounds, azo dyes and triphenylmethane derivatives. These dyes have the additional property of significant absorbance at wavelengths longer than 600 nm, which can penetrate deep into biological tissues. Spatial confinement of the photothermal process depends on the absorption coefficient of the photoexcited chromophore and its thermal relaxation time. Present evidence indicates that the selective photothermal damage of macromolecules or subcellular organelles requires pulsed excitation at picosecond or nanosecond regimes, while microsecond or millisecond domains are effective in the case of cells or similar structures. The possible use of photothermal sensitization in the treatment of tumors is briefly discussed.

Animals↗
PubMed1990

Chlorins as photosensitizers in biology and medicine.

The photodynamic therapy (PDT) of tumors involves illumination of the tumorous area following the administration of a tumor-localizing photodynamic sensitizer. Hematoporphyrin derivative (HPD) and Photofrin II (a purified form of HPD), the main sensitizers used clinically for PDT to date, are complex mixtures of porphyrins; furthermore, these preparations absorb light very poorly in the red region of the spectrum (wavelengths greater than 600 nm) where light penetration into mammalian tissues is greatest. Thus there is considerable interest in identifying new sensitizers that localize more effectively in tumors, absorb more strongly at longer wavelengths and can be prepared in high purity. Much of this interest has been directed towards chlorins (reduced porphyrins), which typically absorb strongly in the red. This review summarizes research that has been carried out on selected types of chlorins, some of which may have important applications as sensitizers for PDT.

Animals↗
PubMed1989

The chemistry, photophysics and photosensitizing properties of phthalocyanines.

Phthalocyanines (Pcs) and naphthalocyanines (Ncs) are being extensively studied as photosensitizers for photodynamic therapy (PDT) of cancer. They strongly absorb clinically useful red light, with maxima around 670 nm and 770 nm respectively. Chelated with appropriate diamagnetic metal ions, they exhibit high triplet yields and long triplet lifetimes. Energy transfer from the triplet dye to ground-state oxygen to yield singlet oxygen appears to be the main photosensitizing pathway in biological systems. Underivatized Pcs and Ncs can be incorporated in liposomes for in vivo administration. Sulphonation renders the dyes water soluble but also enhances dimerization to yield photochemically inactive aggregates. Tumour retention and cell membrane penetration of the dyes are strongly affected by the polarity of the macrocycle as well as the nature of the central metal ion and axial ligands. Among the sulphonated dyes, amphiphilic mono- and disulphonated derivatives exhibit particularly good cell membrane-penetrating properties, although the more highly sulphonated dyes show better tumour retention in vivo. At least in vitro, Pc dyes are more photoactive than the corresponding Nc dyes, which probably reflects the lower photostability of the latter.

Indoles↗
PubMed1983

A preliminary comparison of the photosensitizing properties of porphyrins in aqueous solution and liposomal systems.

The preliminary studies reported here show that at least some lipid soluble porphyrins can easily be incorporated into the membranes of liposomes prepared with different phospholipids; such porphyrins do not leach out of the membranes when the liposomes are stored in aqueous media. In this environment, the lipid soluble porphyrins are very effective photodynamic sensitizers for lipophilic substrates in the liposome membrane, for external amino acids and proteins, and for mammalian cells.

Drug Stability↗