Millard M. Judy

4-alkylamino-3-bromo-N-alkyl-1,8-naphthalimides: new photochemically activatable antiviral compounds

The synthesis of several 3-bromo-4-alkylamino-N-alkyl-1,8-naphthalimides is described. These compounds have been shown to be effective, non-oxygen based photochemical inactivators of enveloped viruses, including herpes simplex virus and HIV.

In vitro PHOTODYNAMIC INACTIVATION OF Herpes simplex VIRUS WITH SAPPHYRINS: 22 π-ELECTRON PORPHYRIN-LIKE MACROCYCLES

Abstract— The photodynamic inactivation of HSV‐1, a virus having a membranous envelope, with both a decaalkyl sapphyrin and its dicarboxy‐substituted analog was studied. The decaalkyl sapphyrin was as efficient in the inactivation of HSV‐1 on a per macrocycle basis as DHE, whereas the efficiency of the dicarboxy‐substituted sapphyrin was approximately two orders of magnitude less. Fluorescence studies of sapphyrins binding to liposomes and VSV suggested that the decaalkylsapphyrin bound monomerically to cholesterol‐rich regions of the viral envelope, whereas its charged analog localized in a more polar environment.

Photodynamic inactivation of simian immunodeficiency virus

A photodynamic flow system employing a dihematoporphyrin ether (DHE) was tested for its ability to inactivate the in vitro infectivity of simian immunodeficiency virus (SICMac) at 630 +/- 5 nm with a light fluence of 5 J/cm2. Cell-free SIVMac was inactivated by photoactivated hematoporphyrin derivative in a dose-dependent fashion. Since SIVMac is closely related to human immunodeficiency virus type 2 (HIV-2) and we have previously reported the successful photodynamic inactivation of HIV-1 in cell-free medium as well as in whole human blood, this technology has the potential for the eradication of transfusion-associated acquired immunodeficiency diseases caused by the above-mentioned retroviruses.

Gel electrophoretic studies of photochemical cross-linking of type I collagen with brominated 1,8-naphthalimide dyes and visible light

Insoluble Type I collagen from bovine Achilles tendon (Sigma C9879) was suspended in a 3 mM solution of the dye diEd66Br dissolved in Cremophor ELR (BASF) to give a molecular concentration ratio. Fifty-microliter aliquots in 5-mm-diameter wells were exposed to 458 J/cm2 (225 mW/cm2, 1800 sec) of 457.9-nm light from an argon ion laser; similar aliquots with and without dye were kept in the dark to serve as controls. Following pelleting of the collagen by centrifugation and 3x washing in phosphate-buffered saline, aliquots of light-treated and control sample pellets were (1) digested in collagenase (Sigma C9891) or (2) extracted in 0.5 M acetic acid, followed by centrifugative ultrafiltration (10-kd cutoff) in 0.01 M acetic acid. Aliquots of the supernatant of the acid-extracted collagen also were digested in pepsin. Electrophoretic protein migration in 8% to 25% gradient polyacrylamide gels following SDS solubilization disclosed numerous, densely packed, essentially contiguous protein bands. These studies indicate that the dye and light treatment of insoluble Type I collagen (1) results in cross-linking of collagen molecules and (2) does not denature the trimer conformation sufficiently to enable significant digestion by pepsin.

Photochemical bonding of skin with 1,8-naphthalimide dyes

Our ongoing studies out to one year postoperatively of healing in sheep menisci and condylar articular cartilage prompt the study of photochemical bonding of other connective tissues with our 1,8-naphthalimide dyes. Here we report our ex-vivo experiments in photochemical bonding of the dermis of rabbit dorsal skin with 1,8-naphthalimide dyes, in which effects of varying the externally applied pressure during the welding and of the addition of an albumin-collagen protein filler are studied.

Healing results in meniscus and articular cartilage photochemically welded with 1,8-naphthalimide dyes

Meniscal tears and partial thickness defects in articular cartilage do not heal spontaneously. In this paper results are described of studies of a procedure for evoking the healing response in such lesions by a non-thermal tissue sparing photochemical weld using 1,8-naphthalimide dyes. Fifteen essentially mature Barbados sheep 40 - 60 pounds in weight received a 2 - 3 mm flap tear by incision in the red white zone of the medial meniscus oriented parallel to the table of the tibia. The animals were divided into four groups; Group I, no treatment; Group II, treatment by laser activated photoactive dyes; Group III, treatment by suturing; Group IV, treatment by laser irradiation only; Group V, treatment by photoactive dyes only. In another group of 12 sheep partial thickness flap tear was created by incision in the articular cartilage of the femoral condyle. These were divided into four groups as for the meniscus study, omitting the sutured control. Welds were made using the dimeric dye MBM Gold BW 012-012-012 at 12 mM in PBS, 457.9 nm argon ion laser radiation at 800 mW/cm2, 7.5 minutes (360 J/cm2) with approximately 2 kg/cm2 externally applied pressure. Animals were sacrificed at 24 hr, 4 weeks, 3 and 6 months postoperatively. Gross appearance of menisci and cartilage in all welded knees was normal and all welds resisted deformation or loosening under forceful probing. Histology of studies of both tissues out to 6 moths disclosed close bonding of welded area, continuing healing response in the form of cellular recruitment and protein deposition and the absence of inflammatory response. Tissue erosion and arthritic changes were evident in all unwelded controls.

Preferential localization of varying forms of photoactive 1,8-naphthalimide compounds within the atheromatous arterial wall

We are currently working with a novel class of photoactivated 4‐amino substituted 1,8‐naphthalimide compounds for tissue bonding. With promising results in other tissues, we are pursuing potential vascular applications. This study focused on determining the appropriate compound formulation(s), concentration, and exposure times to optimize penetration of the heterogeneous arterial wall.

Repair of articular cartilage and meniscal tears by photoactive dyes: in-vivo study

We describe healing results of our 6 month study of a repair procedure which evokes the healing response in meniscal tears and partial thickness defects in articular cartilage by a non-thermal tissue sparing photochemical weld using 1,8-naphthalimide dyes. Welds of incisional flaps in adult sheep meniscus and femoral articular cartilage were made using the dye MBM Gold 012011012 at 12 mM in PBS, 457.9nm Argon ion laser radiation at 800 mW/cm2, 7.5 minutes with approximately 1 kg/cm2 externally applied pressure. Gross appearance of tissues in all welded knees appeared normal. Hematoxylin and eosin stained sections disclosed close bonding of welded areas and continuing healing response as cellular recruitment.

High-intensity ablative/coagulative side-delivery endoscopic devices

The optical beam profile, power transmission efficiency, and tissue effects on the Idaho potato model of 1.064-micrometer Nd:YAG radiation were determined using a fiber with the 3M High-Power Side-Firing Tip. The results suggest that a single mechanically and thermally robust beam-focusing tip may be used for both ablation and coagulation in the treatment of benign prostate hypertrophy.

Photodynamic research at Baylor University Medical Center Dallas, Texas

We received our first CO2 laser at Baylor University Medical Center in December 1974, following a trip to Israel in January of that year. Discussion with the customs office of the propriety of charging an 18% import tax lasted for nine months. We lost that argument. Baylor has been using lasers of many types for many procedures since that time. About ten years ago, through the kindness of Tom Dougherty and Roswell Park, we started working with photodynamic therapy, first with hematoporphyrin I and later with dihematoporphyrin ether (II). In February 1984, we were invited to a conference at Los Alamos, New Mexico, U.S.A. on medical applications of the free electron laser as part of the Star Wars Program. A grant application from Baylor was approved that November, but funding did not start for many months. This funding contributed to the development of a new research center as part of Baylor Research Institute. Many of the projects investigated at Baylor dealt with applications of the free electron laser (FEL), after it became available. A staff was assembled and many projects are still ongoing. I would like to outline those which are in some way related to photodynamic therapy.