The conjugation of therapeutics to water-soluble biomedical polymers increases the aqueous solubility of hydrophobic drugs, prolongs in vivo drug retention time, reduces systemic toxicity, and enhances therapeutic efficacy. , Polymer drug conjugates can preferentially accumulate in solid tumor tissues due to the hyperpermeability of tumor blood vessels or the so-called "enhanced permeability and retention (EPR) effect."3,4 Polymer drug conjugates can also down-regulate or overcome multiple drug resistance. , Because of these unique properties, polymer drug conjugates exhibit higher therapeutic efficacy than the corresponding therapeutics alone. Several polymer drug conjugates are currently used in clinical cancer treatment, and more are in the pipeline of clinical development. For example, styrene-maleic acid copolymer neocarzinostatin conjugate (SMANCS) is used for liver cancer treatment in Japan;7 pegylated adenosine deaminase8 and asparaginase9,10 are used for enzyme replacement therapy for immunodeficiency and for the treatment of acute lymphoblastic leukemia, respectively. Many other polymer drug conjugates, including pegylated interferon a,11 PEG-camptothecin conjugate,12 poly(l-glutamic acid) paclitaxel conjugate,13 poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA)-cis-platinate conjugate,14 and PHPMA-doxorubicin conjugate15,16 are in various phases of clinical trials.

The in vivo behavior, including pharmacokinetics, biodistribution, drug delivery efficiency and therapeutic efficacy, of polymer drug conjugates has been traditionally evaluated by using blood and urine sampling, biopsy-based methods, and symptom-based observations. These methods are sometimes invasive and cannot accurately provide real time information on the interaction of polymers with various organs and tissues, the targeting and delivery efficiency of the drug delivery system, and therapeutic response. A large number of animals are also required in preclinical development. Sometimes, the data obtained by conventional biopsies may be misleading, which might be one of the causes of the efficacy discrepancy between preclinical development in animal models and human clinical trials and the failure of some clinical trials due to improper selection of drug candidates.

In vivo drug delivery by polymer drug conjugates involves circulation of the conjugates in the blood; interaction with the major organs including the liver, heart, lungs, spleen and kidneys, etc.; transport to target tissue; and uptake by target cells and drug release. Direct and continuous evaluation of drug delivery efficiency and tissue interaction of polymeric drug conjugates is critical to develop more efficacious drug delivery systems. Recent advancements in biomedical imaging technology have provided the essential tools for noninvasive and continuous in vivo evaluation for drug delivery. Nuclear medicine, including positron emission tomography (PET) and single photon emission computed tomography (SPECT), is a clinical imaging modality with high detection sensitivity (ca. 10~9 M). Magnetic resonance imaging (MRI) is a noninvasive clinical imaging modality with high spatial resolution. Both imaging modalities are able to noninvasively visualize in vivo drug delivery with polymeric drug conjugates. The polymer conjugates can be labeled with imaging probes and noninvasively and continuously monitored with the imaging modalities. The number of experimental animals can be dramatically reduced in the preclinical development of the conjugates. Biomedical imaging will provide real-time information of the in vivo behavior of polymeric drug conjugates. In this chapter, we will focus on noninvasive visualization of in vivo drug delivery with paramagnetic polymeric conjugates and contrast-enhanced MRI.

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