Ring-opening polymerization of prodrugs: a versatile approach to prepare well-defined drug-loaded nanoparticles.

The synthesis of polymer-drug conjugates from prodrug monomers consisting of a cyclic polymerizable group that is appended to a drug through a cleavable linker is achieved by organocatalyzed ring-opening polymerization. The monomers polymerize into well-defined polymer prodrugs that are designed to self-assemble into nanoparticles and release the drug in response to a physiologically relevant stimulus. This method is compatible with structurally diverse drugs and allows different drugs to be copolymerized with quantitative conversion of the monomers. The drug loading can be controlled by adjusting the monomer(s)/initiator feed ratio and drug release can be encoded into the polymer by the choice of linker. Initiating these monomers from a poly(ethylene glycol) macroinitiator results in amphiphilic diblock copolymers that spontaneously self-assemble into micelles with a long plasma circulation, which is useful for systemic therapy.

Efficient Design to Monitor the Site-specific Sustained Release of a Non-Emissive Anticancer Drug.

A pH-responsive smart nanocarrier with significant components was synthesized by conjugating the non-emissive anticancer drug methyl orange and polyethylene glycol derived folate moiety to the backbone of polynorbornene. Complete synthesis procedure and characterization methods of three monomers included in the work: norbornene-derived Chlorambucil (Monomer 1), norbornene grafted with polyethylene glycol, and folic acid (Monomer 2) and norbornene attached methyl orange (Monomer 3) connected to the norbornene backbone through ester linkage were clearly discussed. Finally, the random copolymer CHO PEG FOL METH was synthesized by ring-opening metathesis polymerization (ROMP) using Grubbs' second-generation catalyst. Advanced polymer chromatography (APC) was used to find the final polymer's molecular weight and polydispersity index (PDI). Dynamic light scattering, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) were utilized to explore the prodrug's size and morphology. Release experiments of the anticancer drug, Chlorambucil and the coloring agent, methyl orange, were performed at different pH and time. Cell viability assay was carried out for determining the rate of survived cells, followed by the treatment of our final polymer named CHO PEG FOL METH.

Concurrent analysis of cytogenetic damage in vivo: a multiple endpoint-multiple tissue approach.

Simultaneous assessment of in vivo micronucleus and chromosome aberration endpoints has been described in the rat and the mouse. Bone marrow and spleen cells were utilized for genotoxicity assessment. A cellulose column methodology was used in the micronucleus assay (where applicable) to eliminate nucleated cells and facilitate cytogenetic scoring. The test agents--cyclophosphamide, chlorambucil, and acrylamide--produced qualitatively comparable results between micronucleus and chromosome aberration endpoints and varied slightly on a quantitative basis depending on the type of test agent and tissue studied. The results from test agents such as cyclophosphamide, chlorambucil, acrylamide, dimethylnitrosamine, vincristine, and x-rays indicated that bone marrow cytogenetic results are similar to spleen and that the spleen tissue is at least as sensitive as the bone marrow. The concurrent analysis of cytogenetic damage in vivo using a multiple endpoint-multiple tissue approach described here has the following advantages: a) reducing the overall animal usage, b) clarifying marginal micronucleus and/or chromosome aberration data, c) correlating cytogenetic results from multiple endpoints and multiple tissues, and d) helping the investigation of the mechanism of action of test agents and their potential target organs. Also, the multiple endpoint-multiple tissue approach can be extended to other endpoints, tissues, and species (where appropriate and practical) to obtain detailed genotoxicity information.