Nano-sized drug carriers: Extravasation, intratumoral distribution, and their modeling.

Navigating intratumoral drug distribution has proven to be one of the most challenging aspects of drug delivery. The barriers are significant and varied; increased diffusional distances, elevated interstitial fluid pressure, regions of dense extracellular matrix and high cell density, and overall heterogeneity. Such a long list imposes significant requirements on nano-sized carriers. Unfortunately, other capabilities are eclipsed by the distribution requirements. A drug can do no good until it reaches its target. Numerous strategies to improve drug distribution have been developed, taking account of various unique characteristics of solid tumors, including some mechanisms that are still not fully understood. Most of these strategies were from small animal tumor models which are our primary tool for understanding cancer physiology. The small animal tumor model is the most versatile and effective means of understanding tumor transport, but its prevalence belies some of its weaknesses. Tumors grown under lab conditions are developed much more quickly than naturally developed cancers, potentially impacting tumor heterogeneity, blood vessel development, extracellular matrix organization, cell diversity, and many other features of structure and physiology that may impact transport. These problems come in addition to the difficulties of making precise measurements within a living tumor. Resolving these problems is best done by improving our analysis methods, and by finding complementary models that can clarify and expound the details. In this review, we will first discuss some of the strategies employed to improve transport and then highlight some of the new models that have recently been developed in the Bae lab and how they may aid in the study of tumor transport in the future.

Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery.

Enhanced permeability in tumours is thought to result from malformed vascular walls with leaky cell-to-cell junctions. This assertion is backed by studies using electron microscopy and polymer casts that show incomplete pericyte coverage of tumour vessels and the presence of intercellular gaps. However, this gives the impression that tumour permeability is static amid a chaotic tumour environment. Using intravital confocal laser scanning microscopy we show that the permeability of tumour blood vessels includes a dynamic phenomenon characterized by vascular bursts followed by brief vigorous outward flow of fluid (named 'eruptions') into the tumour interstitial space. We propose that 'dynamic vents' form transient openings and closings at these leaky blood vessels. These stochastic eruptions may explain the enhanced extravasation of nanoparticles from the tumour blood vessels, and offer insights into the underlying distribution patterns of an administered drug.

Uterine perfusion model for analyzing barriers to transport in fibroids.

This project uses an ex vivo human perfusion model for studying transport in benign, fibrous tumors. The uterine arteries were cannulated to perfuse the organ with a buffer solution containing blood vessel stain and methylene blue to analyze intratumoral transport. Gross examination revealed tissue expansion effects and a visual lack of methylene blue in the fibroids. Some fibroids exhibited regions with partial methylene blue penetration into the tumor environment. Histological analysis comparing representative sections of fibroids and normal myometrium showed a smaller number of vessels with decreased diameters within the fibroid. Imaging of fluorescently stained vessels exposed a stark contrast between fluorescence within the myometrium and relatively little within the fibroid tissues. Imaging at higher magnification revealed that fibroid blood vessels were indeed perfused and stained with the lipophilic membrane dye; however, the vessels were only the size of small capillaries and the blood vessel coverage was only 12% that of the normal myometrium. The majority of sampled fibroids had a strong negative correlation (Pearson's r=-0.68 or beyond) between collagen and methylene blue staining. As methylene blue was able to passively diffuse into fibroid tissue, the true barrier to transport in these fibroids is likely high interstitial fluid pressure, correlating with high collagen content and solid stress observed in the fibroid tissue. Fibroids had an average elevated interstitial fluid pressure of 4mmHg compared to -1mmHg in normal myometrium. Our findings signify relationships between drug distribution in fibroids and between vasculature characteristics, collagen levels, and interstitial fluid pressure. Understanding these barriers to transport can lead to developments in drug delivery for the treatment of uterine fibroids and tumors of similar composition.

A second golden age of aeroacoustics?

In 1992, Sir James Lighthill foresaw the dawn of a second golden age in aeroacoustics enabled by computer simulations (Hardin JC, Hussaini MY (eds) 1993 Computational aeroacoustics, New York, NY: Springer (doi:10.1007/978-1-4613-8342-0)). This review traces the progress in large-scale computations to resolve the noise-source processes and the methods devised to predict the far-field radiated sound using this information. Keeping focus on aviation-related noise sources a brief account of the progress in simulations of jet noise, fan noise and airframe noise is given highlighting the key technical issues and challenges. The complex geometry of nozzle elements and airframe components as well as the high Reynolds number of target applications require careful assessment of the discretization algorithms on unstructured grids and modelling compromises. High-fidelity simulations with 200-500 million points are not uncommon today and are used to improve scientific understanding of the noise generation process in specific situations. We attempt to discern where the future might take us, especially if exascale computing becomes a reality in 10 years. A pressing question in this context concerns the role of modelling in the coming era. While the sheer scale of the data generated by large-scale simulations will require new methods for data analysis and data visualization, it is our view that suitable theoretical formulations and reduced models will be even more important in future.

EPR: Evidence and fallacy.

The enhanced permeability and retention (EPR) of nanoparticles in tumors has long stood as one of the fundamental principles of cancer drug delivery, holding the promise of safe, simple and effective therapy. By allowing particles preferential access to tumors by virtue of size and longevity in circulation, EPR provided a neat rationale for the trend toward nano-sized drug carriers. Following the discovery of the phenomenon by Maeda in the mid-1980s, this rationale appeared to be well justified by the flood of evidence from preclinical studies and by the clinical success of Doxil. Clinical outcomes from nano-sized drug delivery systems, however, have indicated that EPR is not as reliable as previously thought. Drug carriers generally fail to provide superior efficacy to free drug systems when tested in clinical trials. A closer look reveals that EPR-dependent drug delivery is complicated by high tumor interstitial fluid pressure (IFP), irregular vascular distribution, and poor blood flow inside tumors. Furthermore, the animal tumor models used to study EPR differ from clinical tumors in several key aspects that seem to make EPR more pronounced than in human patients. On the basis of this evidence, we believe that EPR should only be invoked on a case-by-case basis, when clinical evidence suggests the tumor type is susceptible.

Mind the gap: a survey of how cancer drug carriers are susceptible to the gap between research and practice.

With countless research papers using preclinical models and showing the superiority of nanoparticle design over current drug therapies used to treat cancers, it is surprising how deficient the translation of these nano-sized drug carriers into the clinical setting is. This review article seeks to compare the preclinical and clinical results for Doxil®, PK1, Abraxane®, Genexol-PM®, Xyotax™, NC-6004, Mylotarg®, PK2, and CALAA-01. While not comprehensive, it covers nano-sized drug carriers designed to improve the efficacy of common drugs used in chemotherapy. While not always available or comparable, effort was made to compare the pharmacokinetics, toxicity, and efficacy between the animal and human studies. Discussion is provided to suggest what might be causing the gap. Finally, suggestions and encouragement are dispensed for the potential that nano-sized drug carriers hold.

Odyssey of a cancer nanoparticle: from injection site to site of action.

No chemotherapeutic drug can be effective until it is delivered to its target site. Nano-sized drug carriers are designed to transport therapeutic or diagnostic materials from the point of administration to the drug's site of action. This task requires the nanoparticle carrying the drug to complete a journey from the injection site to the site of action. The journey begins with the injection of the drug carrier into the bloodstream and continues through stages of circulation, extravasation, accumulation, distribution, endocytosis, endosomal escape, intracellular localization and-finally-action. Effective nanoparticle design should consider all of these stages to maximize drug delivery to the entire tumor and effectiveness of the treatment.

pH-Sensitive polymeric micelle-based pH probe for detecting and imaging acidic biological environments.

To overcome the limitations of monomeric pH probes for acidic tumor environments, this study designed a mixed micelle pH probe composed of polyethylene glycol (PEG)-b-poly(L-histidine) (PHis) and PEG-b-poly(L-lactic acid) (PLLA), which is well-known as an effective antitumor drug carrier. Unlike monomeric histidine and PHis derivatives, the mixed micelles can be structurally destabilized by changes in pH, leading to a better pH sensing system in nuclear magnetic resonance (NMR) techniques. The acidic pH-induced transformation of the mixed micelles allowed pH detection and pH mapping of 0.2-0.3 pH unit differences by pH-induced "on/off"-like sensing of NMR and magnetic resonance spectroscopy. The micellar pH probes sensed pH differences in nonbiological phosphate buffer and biological buffers such as cell culture medium and rat whole blood. In addition, the pH-sensing ability of the mixed micelles was not compromised by loaded doxorubicin. In conclusion, PHis-based micelles could have potential as a tool to simultaneously treat and map the pH of solid tumors in vivo.

Improved implementation of Kirkwood-Buff solution theory in periodic molecular simulations.

Kirkwood-Buff (KB) solution theory is a means to obtain certain thermodynamic derivatives from knowledge of molecular distributions. In actual practice the required integrals over radial distribution functions suffer inaccuracies due to finite-distance truncation effects and their use in closed systems. In this work we discuss how best to minimize these inaccuracies under traditional KB theory. In addition we implement a method for calculating KB quantities in molecular simulations with periodic boundary conditions and particularly within the canonical ensemble. The method is based on a finite-Fourier-series expansion of molecular concentration fluctuations and leads to more reliable results for a given computational effort. The procedure is validated and compared to the original method for a nonideal liquid mixture of Lennard-Jones particles intended to imitate a real system, carbon tetrafluoride, and methane.