Macromolecular drug

Mathiowitz, E., Leong, K., and Langer, R., Macromolecular drug release from biodegradable polyanhydride microspheres, 12th Int. Symp. Control. Rel. Bioact. Mater., 183-184, 1985. 

Another very important site for drug delivery is the central nervous system (CNS). The blood-brain barrier presents a formidable barrier to the effective delivery of most agents to the brain. Interesting work is now advancing in such areas as direct convective delivery of macromolecules (and presumably in the future macromolecular drug carriers) to the spinal cord [238] and even to peripheral nerves [239]. For the interested reader, the delivery of therapeutic molecules into the CNS has also been recently comprehensively reviewed... 

Macromolecular drugs, in general, can be divided into four types (a) polymeric drugs—these represent macromolecules that themselves display pharmacological activity, and polymers that contain therapeutically active groups as an integral part of the main chain ... 

Table 15 Suggested Soluble Macromolecular Drug-Delivery Systems and Their Uses...

With respect to macromolecular drug-carrier approaches, the linear polysaccharide poly a-l,6-maltotriose (pullulan -OH) was combined with l-aminopropan-2-ol via the succinate ester in the following way [1613... 

Maeda H (2001) The enhanced permeability and retention (EPR) effect in tumor vasculature the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul 41 189-207... 

Kim, S. W., Temperature Sensitive Polymers for Delivery of Macromolecular Drugs, in Advanced Biomaterials in Biomedical Engineering and Drug Delivery Systems (N. Ogata, et al., Eds.), pp. 125-133. Springer, Tokyo (1996). 

The past two decades have produced a revival of interest in the synthesis of polyanhydrides for biomedical applications. These materials offer a unique combination of properties that includes hydrolytically labile backbone, hydrophobic bulk, and very flexible chemistry that can be combined with other functional groups to develop polymers with novel physical and chemical properties. This combination of properties leads to erosion kinetics that is primarily surface eroding and offers the potential to stabilize macromolecular drugs and extend release profiles from days to years. The microstructural characteristics and inhomogeneities of multi-component systems offer an additional dimension of drug release kinetics that can be exploited to tailor drug release profiles. 

There are also multiple pathways for liposomes following cellular uptake. They may be delivered to lysosomes, recycled out of the cell, involved in transcytotic passage across an epithelial barrier, or delivered to other cellular compartments such as the Golgi network. Each route offers opportunities for selective delivery of macromolecular drugs and nanosized drugs so the need to comprehend endocytic pathways has never been more apparent (7). Figure 1 summarizes the different pathways of endocytosis. 

Too often results are compromised by a poor experimental set-up of the studies and nontransparent data. Even essential information such as the relevant physicochemical characteristics of the drug in relation to the chosen aerosol system or the fraction that is deposited in the alveoli is often not provided. This makes it impossible to evaluate the impact of such studies. As a result, it is unclear until now to what extent and at what rate macromolecular drugs (> 20 kDa) can be absorbed by the lung. Moreover, the routes by which macromolecules pass through the different pulmonary membranes, especially the alveolar membrane, are unknown. Appropriate experiments and models that provide adequate answers to these questions are required in the coming years. 

In principle, the above-mentioned transport and metabolic functions of the tubule can be used for renal delivery and (re-)activation of (pro-)drugs and macromolecular drug targeting preparations. 

Generally there are two possible ways of synthesis of macromolecular-drug conjugates (Fig. 5) [140] ... 

The ability of a tumor cell to manufacture proteins is a result of intact DNA, RNA and biochemical intracellular mechanisms. Interference with any one of these structures or processes will result in the inability of the cell to produce required proteins. Hence, quantitation of tumor cell protein synthesis over a period of time may constitute a marker allowing determination of the efficacy of a macromolecular drug conjugate. The technique is based on the fact that decreased cell viability in the presence of radiolabeled amino adds correlates to a decrease in radioactivity relative to a control cell population. For example, 3H-leucine [175, 208], a mixture of [14C]-labeled amino acids [205], and 75Se-lenomethionine [54, 209] have been used to evaluate the activity of conjugates. 

Batycky, R.P, Hanes, J., Langer, R., and Edwards, D. A. (1997). A theoretical model of erosion and macromolecular drug release from biodegrading microspheres. J. Pharmaceut. Set, 86, 1464-1477. 

Thus, more work is needed to understand the behavior of macromolecular drugs of this type, and the role played by dissociation or endocytosis (engulfment of the polymer by the cell) in their biological activity. 

Figure 19.1 Physiological pharmacokinetic model for evaluating in vivo disposition of a macromolecular drug. (A) A multi-compartment model in which every tissue compartment is connected with the plasma pool by blood flow. (B) Tissue uptake of a drug from vascular space to tissue parenchyma.

Figure 19.3 summarizes two major clearances governing the biodistribution of most macromolecular drugs—the hepatic uptake clearance and the urinary excretion clearance-of model compounds with diverse... 

Nakanishi, K., M. Masada, and T. Nadai. 1986. Effect of nonsteroidal anti-inflammatory drugs on the absorption of macromolecular drugs in rat rectum. Chem Pharm Bull 34 2628. 

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