Passive targeting is the foremost mechanism by which nanocarriers and drug-bearing macromolecules deliver their payload selectively to solid tumors. An important driver of passive targeting is the enhanced permeability and retention (EPR) effect, which is the cornerstone of most carrier-based tumor-targeted drug delivery efforts. Despite the huge number of publications showcasing successes in preclinical animal models, translation to the clinic has been poor, with only a few nano-based drugs currently being used for the treatment of cancers. Several barriers and factors have been adduced for the low delivery efficiency to solid tumors and poor clinical translation, including the characteristics of the nanocarriers and macromolecules, vascular and physiological barriers, the heterogeneity of tumor blood supply which affects the homogenous distribution of nanocarriers within tumors, and the transport and penetration depth of macromolecules and nanoparticles in the tumor matrix. To address the challenges associated with poor tumor targeting and therapeutic efficacy in humans, the identified barriers that affect the efficiency of the enhanced permeability and retention (EPR) effect for macromolecular therapeutics and nanoparticle delivery systems need to be overcome. In this review, approaches to facilitate improved EPR delivery outcomes and the clinical translation of novel macromolecular therapeutics and nanoparticle drug delivery systems are discussed.

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Background Patients with chronic pancreatitis (CP) suffer from pain and receive increased opioid prescriptions with a high risk of opioid use disorder (OUD). We studied the predictors, trends and outcomes of OUD among patients hospitalized with CP. Methods Records with CP (with/without OUD) were extracted from the Nationwide Inpatient Sample (NIS) 2012-2014, and the association of OUD with the burden of CP was calculated. We then charted the trends of OUD and its interaction with concomitant CP from NIS 2007-2014 (SAS 9.4). Results In the period 2012-2014, 4349 (4.99%) of the 87,068 CP patients had concomitant OUD, with higher risk among patients who were young, females, white vs. Hispanics, and individuals with chronic back pain, arthritis, non-opioid substance use, mental health disorders, and those hospitalized in urban centers. OUD was associated with a longer hospital stay (6.9 vs. 6.5 days, P=0.0015) but no significant difference in charges ($47,151 vs. $49,017, P=0.0598) or mortality (1.64% vs. 0.74%, P=0.0506). From 2007-2014, the average yearly rate of OUD was 174 cases per 10,000 hospitalizations (174/10,000), almost 3 times higher among CP vs. non-CP (479/10,000 vs. 173/10,000, P<0.001), and it increased from 2007 to 2014 (135/10,000 to 216/10,000, P<0.001). The yearly increase was 2.7 times higher among patients with CP vs. non-CP (29.9/10,000 vs. 11.3/10,000 hospitalizations/year, P<0.001). Conclusions CP is associated with higher rates and trends of OUD. Patients with CP at high risk of OUD may benefit from alternate analgesic regimens or surveillance for OUD when they are prescribed opioids.