Therapeutic macromolecules, delivery

PCI has been shown to increase the biological activity of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane (Table 1). PCI has also been shown to enhance the treatment effect of targeted therapeutic macromolecules. These results show that PCI can induce efficient light-directed delivery of macromolecules into the cytosol, indicating that PCI may have a variety of useful applications for site-specific drug delivery, e.g., in gene therapy, vaccination, and cancer treatment. PCI of BLM has recently been approved for a clinical Phase I trial, where several indications have been included. The first patients with head and neck cancer have recently been treated at... 

Precise information on the enzyme specificities, and particularly the quantity of enzyme activity present in the normal human colon is not easy to find, and underlines the principal that in the development of oral delivery systems either for therapeutic macromolecules or using macromolecules as part of pharmaceutical formulations, then in vitro testing is an essential and valuable tool as described in the next section. 

In the current years the delivery of macromolecules is explored as an alternative route of parenteral preparation, such as injections or infusions, with special attention to oral, buccal, and pulmonary delivery. Different applications of chitosan-based nanoblends for delivery of therapeutic macromolecules are provided herein [53]. 

Interstitial hypertension forms a physiologic barrier to the delivery of therapeutic macromolecules to the cancer cells. 

Impaired delivery of therapeutic macromolecules (e.g., passive immunotherapy)... 

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... 

The physical factors include mechanical stresses and temperature. As discussed above, IFP is uniformly elevated in solid tumors. It is likely that solid stresses are also increased due to rapid proliferation of tumor cells (Griffon-Etienne et al., 1999 Helmlinger et al., 1997 Yuan, 1997). The increase in IFP reduces convective transport, which is critical for delivery of macromolecules. The temperature effects on the interstitial transport of therapeutic agents are mediated by the viscosity of interstitial fluid, which directly affects the diffusion coefficient of solutes and the hydraulic conductivity of tumor tissues. The temperature in tumor tissues is stable and close to the body temperature under normal conditions, but it can be manipulated through either hypo- or hyper-thermia treatments, which are routine procedures in the clinic for cancer treatment. 

The use of photochemical treatment to stimulate translocation of endocytosed macromolecules into the cytosol is a novel technology to improve therapeutic efficacy. The technology as described in this review is derived from photodynamic therapy (PDT) and is named PCI. In both cases a photosensitizer is used in combination with light to exert the treatment effects. The basic mechanisms of the photosensitizers and their tissue interaction in combination with light will be described with emphasis on the properties of the photosensitizers used in PCI before describing the use of PCI for cytosolic delivery of macromolecules. 

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