Macromolecular therapeutics

Maeda H, Wu J, Sawa T, Matsumara Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics a review. J Control Rel 2000 65 271. 

Maeda, H., Seymour L. W., and Miyamoto, Y. Conjugates of anticancer agents and polymers advantages of macromolecular therapeutics in vivo. Bioconjugate Chem., 1992, 3, 351-361. 

Matsumura, Y, and Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy Mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res., 1986, 46, 6387-6392. 

Until recently, the topical ophthalmic use of some interesting and promising either lipophilic or macromolecular therapeutic substances has been limited clinically because of their restrictive physicochemical properties, which has exhibited poor ocular bioavailability. It is possible... 

Gonzalez H, Hwang SJ, Davis ME (1999) New class of polymers for the delivery of macromolecular therapeutics. Bioconjug Chem 10(6) 1068-1074... 

Macromolecular Therapeutics The Cellular Membrane as a Barrier to Therapeutic Effect... 

Fig. 6 Illustration of the PCI principle. The photosensitizer and the macromolecular therapeutics (here visualized by a nanoparticle for gene delivery) are endocytosed as indicated and accumulating in endocytic vesicles. The nanoparticle may be degraded by hydrolytic enzymes in late endosomes or lysosomes, translocated to the cytosol by intrinsic properties of the designed nanoparticle or released into the cytosol by a photochemically induced rupture of the endocytic vesicle as illustrated by the use of a diodelaser. The DNA may thereafter enter the nucleus for transgene expression...

Maeda H, Matsumura Y, Oda T, et al. Cancer selective macromolecular therapeutics tailoring of antitumor protein drugs. In Feeney RE, Whitaker JR, eds. Protein Tailoring for Food and Medical Uses. New York Marcel Dekker, 1986 353-382. 

Greish K, Fang J, Inutsuka T, et al. Macromolecular therapeutics advantages and prospects with special emphasis on solid tumour targeting. Clin Pharmacokinet 2003 43 1089-1105. 

Liposomes are lipid-based vesicles useful in delivering conventional as well as macromolecular therapeutic agents (35). The commercially available liposomal formulations include Doxil (doxorubicin) and Ambisome (amphotericin B), which are available for the treatment of tumors and fungal infections, respectively. Egg yolk and soy lecithins that are mainly composed of phospholipids (< 95%) are commonly used as raw materials for liposome preparation. Of the two, soy lecithins are generally preferred for reasons of... 

Ligand-Binding Assays to Support Disposition Studies of Macromolecular Therapeutics... 

Given the foregoing discussion of some of the unique characteristics of macromolecules that lead to clear differences in their pharmacokinetics compared to those typical of small-molecule drugs, there is a subset of the entire group of bioanalytical assay validation parameters that are of key importance in support of pharmacokinetics of candidate macromolecular therapeutics. Assuming demonstration of accuracy and precision of sufficient quality for the intended application of the assay (e.g., non-GLP discovery support or GLP toxicokinetic support, as discussed above), the most important characteristics of a given assay in support of pharmacokinetic studies are likely to be selectivity, specificity, and reproducibility for analysis of incurred samples. These are all related to the ability of the LBA to detect and quantitate solely, or as closely as possible to solely, the analyte of interest. 

FIGURE 4.3 The impact of matrix on assay performance. The matrix effect (nonspecificity) could be additive or inhibitory. The open circles represent the standard curve when the macromolecular therapeutic was spiked into a buffer matrix. The solid circles represent an additive effect when the standard curve was prepared in 100% matrix, and the closed triangles represent an example where there was an inhibitory effect when the standards were prepared in 100% matrix. 

Stability assessments are often conducted by spiking the macromolecular therapeutic into whole blood, as well as into the resultant matrices after whole blood... 

Of probable interest to the reader of this volume are the many applications of SPR to assays for the detection and characterization of antibodies elicited by therapeutic treatment with biologic macromolecules [166 169]. Given the current intense interest in the development of protein and ODN macromolecules as potential therapeutics, as well as the developing interest in biosimilar protein products, immunogenicity of macromolecules will continue to be investigated for the foreseeable future. Further discussion of assay formats for the detection and characterization of antibodies elicited by treatment with macromolecular therapeutics is presented elsewhere in this volume. 

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