[Efficacy and safety analysis of P-GemDOx regimen and stratified prognosis in patients with early extranodal NK/T cell lymphoma].

Objective: To assess the efficacy, safety, and related prognostic factors associated with the P-GemDOx regimen as a first-line treatment for patients with early-stage extranodal natural killer (NK) /T cell lymphoma (ENKTL) . Methods: A retrospective analysis was performed on sixty early-stage ENKTL patients treated with the P-GemDOx regimen who were admitted to the First Affiliated Hospital of Nanjing Medical University between August 2015 and May 2021. The Chi-square test or Fisher's exact test was used to compare group differences, and the Log-rank test was used to compare the differences in survival. Survival outcomes and prognostic factors were examined. Results: After completing 4 to 6 cycles of P-GemDOx chemotherapy, the overall response rate (ORR) was 88.3%, with forty-six patients (76.7% ) achieving complete response (CR). The 4-year progression-free survival (PFS) and overall survival (OS) rates were (66.3±7.1) % and (79.5±6.0) %, respectively. According to the PINK/PINK-E model, there was no significant difference in survival outcomes among risk groups. 23.3% of patients experienced progression of disease within 24 months (POD<24). OS estimates differed significantly (P<0.001) between the POD<24 group (n=14) and the POD≥24 group (n=46). Analysis showed that SUVmax > 12.8 at diagnosis, non-single nasal cavity infiltration, and response less than CR after 4-6 cycles all had a significant association with POD24. We used these data as the basis for predicting POD<24 international prognostic index (POD24-IPI). Patients were stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high risk (two or three risk factors). These groups were associated with 4-year OS rate of 100%, (85.6±9.7) %, and (65.0±10.2) %, respectively (P=0.014). The P-GemDOx regimen was well tolerated, with hematological toxicity being the main side effect. Conclusion: This study demonstrated that the P-GemDOx regimen is effective and safe in the first-line treatment of early-stage ENKTL, and POD24-IPI is a promising prognostic model.

Development and applications of injectable poly(ortho esters) for pain control and periodontal treatment.

Poly(ortho esters) with a low glass transition temperature are semi-solid materials so that therapeutic agents can be incorporated at room temperature, without the use of solvents, by a simple mixing procedure. When molecular weights are limited to < 5 kDa, such materials are directly injectable using a needle size no larger than 22 gauge. Somewhat hydrophilic polymers can be produced by using the diketene acetal 3,9-diethylidene-2,4,8,10-tetraoxaspiro[5.5]undecane and triethylene glycol (TEG), while hydrophobic materials can be produced by using the diketene acetal and 1,10-decanediol. Molecular weight can be reproducibly controlled by using an excess of the diol, or by use of an alcohol that acts as a chain-stopper. Erosion rates can be controlled by varying the amount of latent acid incorporated into the polymer backbone. Toxicology studies using the TEG polymer have been completed and have shown that the polymer is non-toxic. Toxicology studies using the decanediol polymer are underway. Development studies using the TEG polymer aimed at providing a sustained delivery of an analgesic agent to control post-surgical pain are under development and human clinical trials using the decanediol polymer for the treatment of periodontitis are also underway.

Release of BSA from poly(ortho ester) extruded thin strands.

A solventless procedure was used where powdered polymer and micronized protein were intimately mixed and then extruded into 1 mm strands that were cut to the desired length. The polymers used were poly(ortho esters) specifically designed to allow extrusion in the neighborhood of 70 degrees C. At these temperatures many proteins maintain activity in the dry state. In vitro erosion and BSA release results indicate that after a fairly long lag-time, BSA release and polymer erosion occur concomitantly indicating an erosion-controlled process. The lag-time could be eliminated by the addition to the mixture prior to extrusion between 1 and 5 wt% poly(ethylene glycol) or its methoxy derivatives. The lag-time could also be eliminated by using an AB-block copolymer where A is poly(ortho ester) and B is poly(ethylene glycol).

Poly(ortho esters) - their development and some recent applications.

Poly(ortho esters) have been under development since the early 1970s and four families of such polymers have been described. Of most interest are poly(ortho ester) III and poly(ortho ester) IV. Poly(ortho ester) III is a semisolid material that has been shown to be highly biocompatible and is currently being investigated as an adjunct to glaucoma filtering surgery and other ocular applications. However, the polymerization is difficult to control and is not readily scaled up. Poly(ortho ester) IV can be easily prepared in a highly reproducible manner, is very stable provided moisture is rigorously excluded and has also been shown to be highly biocompatible. It is currently under development for a variety of applications, such as ocular delivery, protein release, post-operative pain treatment and post-operative cancer treatment.

Development of a poly(ortho ester) prototype with a latent acid in the polymer backbone for 5-fluorouracil delivery.

A study has been carried out to determine whether the latest family of poly(ortho esters) can be converted into a practical delivery system. This polymer differs from the previously described polymers in that it incorporates a short segment of a latent acid in the polymer backbone. The following issues were specifically addressed: (a) can the erosion and drug release be reproducibly controlled to yield the desired drug release kinetics and erosion rates? (b) Is the polymer stable during radiation sterilization, on storage and on fabrication? (c) Can the polymer be prepared reproducibly at the desired molecular weights and molecular weight distribution? (d) Is the polymer safe for its intended application and does the in vivo erosion proceed to completion? (e) Can the polymer be easily fabricated into desired configurations? Studies have shown that if the synthesis is carefully controlled, the desired molecular weights can be reproducibly prepared, that the polymer is reasonably stable after irradiation at 24 kGy and during storage at room temperature under anhydrous conditions, and that it can be safely thermally fabricated at temperatures in the neighborhood of 120 degrees C. When polymer devices were implanted intraperitoneally in rats the polymer eroded to completion without any overt toxicity as determined by the measured parameters.

Photodynamic crosslinking of proteins. III. Kinetics of the FMN- and rose bengal-sensitized photooxidation and intermolecular crosslinking of model tyrosine-containing N-(2-hydroxypropyl)methacrylamide copolymers.

As part of a study on the role of Tyr residues in the photosensitized intermolecular crosslinking of proteins, we have surveyed the kinetics of the rose bengal- and flavin mononucleotide (FMN)-sensitized photooxidation and crosslinking of a water-soluble N-(2-hydroxypropyl)methacrylamide copolymer with attached 6-carbon side chains terminating in tyrosinamide groups (thus the -OH group of the Tyr is free, but both the amino and carboxyl groups are blocked, simulating the situation of a nonterminal Tyr in a protein). The intermolecular photodynamic crosslinking of the Tyr copolymer can result only from the formation of Tyr-Tyr (dityrosine) bonds, because the copolymer itself is not photooxidizable. Rose bengal, primarily a Type II (singlet oxygen) sensitizer, sensitized the rapid photooxidation of the Tyr residue in the Tyr copolymer only at high pH, where the Tyr phenolic group is ionized; crosslinking did not occur with rose bengal under any of the reaction conditions used. In contrast, FMN, which can sensitize by both Type I (free radical) and Type II processes, sensitized the photooxidation of the Tyr copolymer over the pH range 4-9.5. Also, significant photocrosslinking occurred, but only from pH 4 to 8, with a maximum rate at pH 6. Crosslinking required the presence of oxygen. Studies with inhibitors, D2O as solvent, catalase and superoxide dismutase indicated that the photooxidation and photocrosslinking of the Tyr copolymer with FMN at pH 6 were not mediated by singlet oxygen, superoxide or hydrogen peroxide. It appears that crosslinking involves the abstraction of an H atom from the Tyr phenolic group to give Tyr and FMN radicals. The Tyr radical in one Tyr copolymer can then react with a Tyr radical in another Tyr copolymer to give an intermolecular dityrosine crosslink.

Photodynamic crosslinking of proteins. II. Photocrosslinking of a model protein-ribonuclease A.

Illumination of bovine pancreatic ribonuclease A (RNase A) in solution in the presence of rose bengal as a photosensitizer resulted in the progressive formation of enzyme dimers, trimers, tetramers and higher oligomers, as measured by gel electrophoresis and size exclusion chromatography. Oxygen was necessary for crosslink formation, and azide inhibition studies indicated that singlet oxygen was involved in the process. Chemical modification of His residues (with diethyl pyrocarbonate) and/or Lys residues (with acetic acid N-hydroxysuccinimide ester) in the enzyme decreased crosslinking, suggesting the participation of these two amino acid residues in the reaction. Met and cystine residues did not appear to be involved. Similar studies have shown that model N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing epsilon-aminocaproic acid side chains terminating in His or Lys residues are photodynamically crosslinked via His-His or His-Lys interactions. Treatment of crosslinked RNase A and its His, Lys and Lys-His derivatives for 5 min at 97 degrees C in a dithiothreitol-sodium dodecyl sulfate mixture efficiently ruptured a major part of the photodynamically formed crosslinks; treatment with the detergent alone had no effect. Similar results were obtained with the crosslinked amino acid-containing HPMA copolymers, suggesting that photodynamic crosslinks involving His-His and His-Lys interaction are chemically the same in RNase A and the copolymer model.

Photodynamic crosslinking of proteins. I. Model studies using histidine- and lysine-containing N-(2-hydroxypropyl)methacrylamide copolymers.

One of the mechanisms by which cells might be damaged during the photodynamic therapy (PDT) of tumors is via the covalent crosslinking of proteins to proteins or to other molecules in the cell. It has been suggested that photodynamically generated singlet oxygen interacts with photo-oxidizable amino acid residues such as His, Cys, Trp and Tyr in one protein molecule to generate reactive species, which in turn interact non-photochemically with residues of these types or with free amino groups in another protein molecule to form a crosslink. In some cases, photochemically generated free radicals may be involved in crosslinking. This paper describes studies on the use of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing epsilon-aminocaproic acid side chains terminating in His (P-Acap-His) or Lys (P-Acap-Lys) as models for the photodynamic crosslinking of proteins. The model copolymer P-Acap-His had a weight-averaged molecular weight of about 22,000 and contained four to five His residues per copolymer molecule. The model copolymer P-Acap-Lys had a weight average molecular weight of about 18,000 and contained four to five Lys residues per copolymer molecule. The extent of photocrosslinking, as sensitized by rose bengal, was estimated by measuring the increase in the viscosity of model copolymer solution after various periods of illumination. The extent of intermolecular crosslinking was estimated from the changes in molecular weight distribution of samples before and at the end of illumination as determined by size exclusion chromatography. Photodynamic crosslinking occurred between P-Acap-His molecules and between P-Acap-His and P-Acap-Lys molecules. The higher the concentration of macromolecules in the solution, the higher is the yield of intermolecular crosslinking. Oxygen was necessary for crosslinking, and azide inhibition studies indicated the involvement of singlet oxygen.