In recent years several review articles and books have been published on the use of porphyrin-based compounds in photodynamic therapy (PDT). This critical review is focused on (i) the basic concept of PDT, (ii) advantages of long-wavelength absorbing photosensitizers (PS), (iii) a brief discussion on recent advances in developing PDT agents, and (iv) the various synthetic strategies designed at the Roswell Park Cancer Institute, Buffalo, for developing highly effective long-wavelength PDT agents and their utility in constructing the conjugates with tumor-imaging and therapeutic potential (Theranostics). The clinical status of certain selected PDT agents is also summarized (205 references).

Glycosaminoglycan (GAG) biosynthesis requires numerous biosynthetic enzymes and activated sulfate and sugar donors. Although the sequence of biosynthetic events is resolved using reconstituted systems, little is known about the emergence of cell-specific GAG chains (heparan sulfate, chondroitin sulfate, and dermatan sulfate) with distinct sulfation patterns. We have utilized a library of click-xylosides that have various aglycones to decipher the mechanism of GAG biosynthesis in a cellular system. Earlier studies have shown that both the concentration of the primers and the structure of the aglycone moieties can affect the composition of the newly synthesized GAG chains. However, it is largely unknown whether structural features of aglycone affect the extent of sulfation, sulfation pattern, disaccharide composition, and chain length of GAG chains. In this study, we show that aglycones can switch not only the type of GAG chains, but also their fine structures. Our findings provide suggestive evidence for the presence of GAGOSOMES that have different combinations of enzymes and their isoforms regulating the synthesis of cell-specific combinatorial structures. We surmise that click-xylosides are differentially recognized by the GAGOSOMES to generate distinct GAG structures as observed in this study. These novel click-xylosides offer new avenues to profile the cell-specific GAG chains, elucidate the mechanism of GAG biosynthesis, and to decipher the biological actions of GAG chains in model organisms.Proteoglycans play a major role in various cellular/physiological processes, including blood clotting, growth factor signaling, embryogenesis, axon growth and guidance, angiogenesis, and others (1-4). Proteoglycans consists of a core protein and glycosaminoglycan (GAG) 2 chains. GAG chains account for Ͼ50% of the total molecular weight and are primarily responsible for physiological activity of the proteoglycans (5, 6). GAG chains are composed of repeating disaccharide units of a hexosamine residue and a hexuronic acid residue. The three major types of GAG chains found in the proteoglycans are heparan sulfate (HS), chondroitin sulfate (CS) and dermatan sulfate (DS). These GAG chains are differentiated by the type of hexosamine (glucosamine/galactosamine), the percentage of uronic acid epimers (glucuronic/iduronic acid), the extent of sulfation, and the nature of glycosidic linkage (␣-/␤-). One of the key steps in the proteoglycan biosynthesis is the xylosylation of certain specific serine residues of the core protein (7-10), which occurs in the late endoplasmic reticulum and/or cis-Golgi compartments (11-13). This key event is an essential prelude for the construction of the proteoglycan linkage region (14) that is followed by sequence of events resulting in the assembly of mature GAG chains by alternative addition of hexosamine and glucuronic acid residues. The maturation of GAG chains occurs in the medial and trans-Golgi compartments and involves the following events: N-sulfation of glucosamine units by N-deacetylase-...

We describe here the development of multifunctional nanocarriers, based on amine functionalized biodegradable polyacrylamide nanoparticles (NPs), for cancer theranostics, including active tumor targeting, fluorescence imaging and photodynamic therapy. The structural design involves adding primary amino groups and biodegradable crosslinkers during the NP polymerization, while incorporating photodynamic and fluorescent imaging agents into the NP matrix, and conjugating PEG and tumor-targeting ligands onto the surface of the NPs. The as-synthesized NPs are spherical, with an average diameter of 44 nm. An accelerated biodegradation study, using sodium hydroxide or porcine liver esterase, indicated a hydrogel polymer matrix chain collapse within several days. By using gel permeation chromatography, small molecules were detected, after the degradation. In vitro targeting studies on human breast cancer cells indicate that the targeted NPs can be transported efficiently into tumor cells. Incubating the multifunctional nanocarriers into cancer cells enabled strong fluorescence imaging. Irradiation of the photosensitizing drug, incorporated within the NPs, with light of a suitable wavelength, causes significant but selective damage to the impregnated tumor cells, but only inside the illuminated areas. Overall, the potential of polymeric-based NPs as biodegradable, multifunctional nanocarriers, for cancer theranostics, is demonstrated here.

Near-infrared (NIR) organic dyes have become important for many biomedical applications, including in vivo optical imaging. Conjugation of NIR fluorescent dyes to photosensitizing molecules (photosensitizers) holds strong potential for NIR fluorescence image guided photodynamic therapy (PDT) of cancer. Therefore, we were interested in investigating the photophysical properties, in vivo tumor-affinity and fluorescence imaging potential of a series of heterocyclic polymethine dyes, which could then be conjugated to certain PDT agents. For our present study, we selected a series of symmetrical polymethine dyes containing a variety of bis-N-substituted indole or benzindole moieties linked by linear conjugation with and without a fused substituted cyclohexene ring. The N-alkyl side chain at the C-terminal position was functionalized with sulfonic, carboxylic acid, methyl ester or hydroxyl groups. Although, among the parent cyanine dyes investigated, the commercially available, cyanine dye IR783 (3) (bis-indole-N-butylsulfonate)-polymethine dye with a cyclic chloro-cyclohexene moiety showed best fluorescence-imaging ability, based on its spectral properties (λAbs=782 nm, λFl=810 nm, ε = 261,000 M-1cm-1, ΦFl≈0.08) and tumor affinity. In addition to 3, parent dyes IR820 and Cypate (6) were also selected and subjected to further modifications by introducing desired functional groups, which could enable further conjugation of the cyanine dyes to an effective photosensitizer HPPH developed in our laboratory. The synthesis and biological studies (tumor-imaging and PDT) of the resulting bifunctional conjugates are discussed in succeeding paper (Part-2 of this study).

The design and synthesis of spirocycles is a challenging task because it involves the creation of a quaternary center, which itself is considered to be one of the most difficult tasks among synthetic transformations. Some recent approaches based on metathesis, cycloaddition and transition-metal-mediated transformations to spirocycles are described here.