Page - (000371) - in Biomedical Chemistry: Current Trends and Developments

surface renders the nanocarriers capable of evading the recognition and opsonization by the RES, consequently reducing their clearance from the systemic circulation, prolonging the circulation time, and ultimately promoting the accumulation in the tumor site through the EPR effect (Arias, 2011; Danhier, 2010; Maruyama, 2011; Sawant, 2012; Sultana, 2013). The aforementioned formulations strategies have been explored on the engineering of nanoparticulate drug delivery platforms that exclusively exploit a passive mechanism for targeting cancer and, in fact, a bench-to-bedside translation can already be considered as a reality with many of those being approved for commercialization or undergoing clinical trials for treating a wide range of cancers (Table 3.5.2). 3.5.3.1.3 Challenges and Future Prospects of Passive Targeting Despite the potential of the passive targeting that has been discussed above, this mechanism presents some limitations and faces some challenges, being now considered as a more complex and heterogeneous phenomenon than previously assumed (Prabhakar, 2013).The inter- and intratumoral variability of the tumors result in significant differences on the physiology of the tumor microvasculature and microenvironment and, consequently, on the therapeutic response to passive targeted nanomedicines (Jain, 2010). In addition, the capability of the loaded therapeutic agents to succesfully reach their pharmacological target, thus exerting their therapeutic effect, does not solely depend on the biodistribution of the nanocarrier and its accumulation in the tumor site. An effective drug delivery might be hindered by an increased interstitial fluid pressure which induces the eflux of therapeutics back in the systemic circulation, as well as by the inability of the drug molecules to homogeneously diffuse inside the tumor mass (Dreher, 2006; Sawant, 2012). Therefore, the screening of individual tumor genetic profiles and their particular predisposition for the EPR effect, paralellely to the specific fine-tuning of the drug release profiles based on the bahavior of the drugs in the tumor microenvironment, may become crucial when designing and engineering personalized and optimized