Macromolecular and Related Delivery

Polymer-based drug delivery systems also favorably alter the pharmacokinetics and biodistribution of conjugated drugs and accumulate in tumor interstitium following extravasation.41 Examples include SMANCS (a conjugate of the polymer styrene-co-maleic acid/anhydride and neocarzinos-tatin for treatment of hepatocellular carcinoma), conjugates of various cytotoxic agents (e.g., paclitaxel, doxorubicin, platinate, and campthothecin) with polyglutamate and nonbiodegradable hydroxypropyl methacrylamide.

Other related polymer-based systems in cancer drug delivery include micelles42,43 and dendri-mers.44 For example, PluronicsĀ® (copolymers of ethylene oxide and propylene oxide) are capable of forming micelles, and some members of Pluronic copolymers can overcome multidrug resist-ance.42 However, it is becoming clear that Pluronic copolymers can induce complement activation, even at concentrations below their critical micelle concentration, which may increase the risk of pseudoallergy in sensitive patients.45

Dendrimers are highly branched macromolecules with controlled near monodisperse three-dimensional architecture emanating from a central core.44 Polymer growth starts from a central core molecule and growth occurs in an outward direction by a series of polymerization reactions. Hence, precise control over size can be achieved by the extent polymerization, starting from a few nanometers. Cavities in the core structure and folding of the branches create cages and channels. The surface groups of dendrimers are amenable to modification and can be tailored for specific applications. Therapeutic and diagnostic agents are usually attached to surface groups on dendri-mers by chemical modification. For example, a recent study has used tagged-dendrimers for in vivo evaluation of tumor-associated matrix metalloproteinase-7 (matrilysin) activity.46

Other macromolecular systems for cancer targeting and treatment include various forms of monoclonal and bispecific monoclonal antibodies against tumor-associated antigens.47 These can further be coupled to drugs, toxins, enzymes (as in antibody-directed enzyme pro-drug therapy), cytokines, radionuclides, etc.

2.4 CONCLUSIONS

The chaotic blood flow in tumor vasculature and the heterogeneous vascular permeability of tumor blood vessels are among the key barriers controlling passive delivery of macromolecular and particulate delivery systems into the interstitium of solid tumors. Already compromised by abnormal hydrostatic pressure gradients, compressive mechanical forces generated by tumor cell proliferation cause intratumoral vessels to compress and collapse, thus creating further barriers for passive targeting. Interestingly, tumor-specific cytotoxic therapy, reducing tumor cell number, may result in more efficient delivery by decompressing these same vessels,48 but this enhanced perfusion could provide a route for metastasis. Pathohysiologoical barriers, however, are not fully developed in micrometastases, and also pose a lesser problem in the diagnostic oncology as well as in drug delivery to well-perfused and low-pressure regions in larger tumors. Some of the problems may possibly be overcome by design of long-circulating multifunctional carriers (carriers that contain appropriate combinations of cytotoxic agents, diagnostic, and barrier-avoiding components) with biochemical triggering mechanisms.16 The vascular barrier of the solid tumor is also its Achilles' heel; the nutritionally demanding tumor cells are entirely dependent upon a functional vasculature.

For this reason, interest has also been focused on the concept of tumor vasculature as a target rather than a barrier and is reviewed in this compendium and elsewhere.49-51

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