Targeted drug delivery to tumor sites is one of the ultimate goals in drug delivery. Recent progress in nanoparticle engineering has certainly improved drug targeting, but the results are not as good as expected. This is largely due to the fact that nanoparticles, regardless of how advanced they are, find the target as a result of blood circulation, like the conventional drug delivery systems do. Currently, the nanoparticle-based drug delivery to the target tumor tissues is based on wrong assumptions that most of the nanoparticles, either PEGylated or not, reach the target by the enhanced permeation and retention (EPR) effect. Studies have shown that so-called targeting moieties, i.e., antibodies or ligands, on the nanoparticle surface do not really improve delivery to target tumors. Targeted drug delivery to tumor sites is associated with highly complex biological, mechanical, chemical and transport phenomena, of which characteristics vary spatiotemporally. Yet, most of the efforts have been focused on design and surface manipulation of the drug carrying nanoparticles with relatively little attention to other aspects. This article examines the current misunderstandings and the main difficulties in targeted drug delivery.

Delivery of therapeutic agents selectively to tumor tissue, which is referred as “targeted delivery,” is one of the most ardently pursued goals of cancer therapy. Recent advances in nanotechnology enable numerous types of nanoparticles (NPs) whose properties can be designed for targeted delivery to tumors. In spite of promising early results, the delivery and therapeutic efficacy of the majority of NPs are still quite limited. This is mainly attributed to the limitation of currently available tumor models to test these NPs and systematically study the effects of complex transport and pathophysiological barriers around the tumors. In this study, thus, we developed a new in vitro tumor model to recapitulate the tumor microenvironment determining the transport around tumors. This model, named tumor-microenvironment-on-chip (T-MOC), consists of 3-dimensional microfluidic channels where tumor cells and endothelial cells are cultured within extracellular matrix under perfusion of interstitial fluid. Using this T-MOC platform, the transport of NPs and its variation due to tumor microenvironmental parameters have been studied including cut-off pore size, interstitial fluid pressure, and tumor tissue microstructure. The results suggest that T-MOC is capable of simulating the complex transport around the tumor, and providing detailed information about NP transport behavior. This finding confirms that NPs should be designed considering their dynamic interactions with tumor microenvironment.

The importance and advantages of three-dimensional (3D) cell cultures have been well-recognized. Tumor cells cultured in a 3D culture system as multicellular tumor spheroids (MTS) can bridge the gap between in vitro and in vivo anticancer drug evaluations. An in vitro 3D tumor model capable of providing close predictions of in vivo drug efficacy will enhance our understanding, design, and development of better drug delivery systems. Here, we developed an in vitro 3D tumor model by adapting the hydrogel template strategy to culture uniformly sized spheroids in a hydrogel scaffold containing microwells. The in vitro 3D tumor model was to closely simulate an in vivo solid tumor and its microenvironment for evaluation of anticancer drug delivery systems. MTS cultured in the hydrogel scaffold are used to examine the effect of culture conditions on the drug responses. Free MTS released from the scaffold are transferred to a microfluidic channel to simulate a dynamic in vivo microenvironment. The in vitro 3D tumor model that mimics biologically relevant parameters of in vivo microenvironments such as cell-cell and cell-ECM interactions, and a dynamic environment would be a valuable device to examine efficiency of anticancer drug and targeting specificity. These models have potential to provide in vivo correlated information to improve and optimize drug delivery systems for an effective chemotherapy.

Magnetic nanoparticles can be used for a variety of biomedical applications. They can be used in the targeted delivery of therapeutic agents in vivo, in the hyperthermic treatment of cancers, in magnetic resonance (MR) imaging as contrast agents and in the biomagnetic separations of biomolecules. In this study, a characterization of the movement and heating of three different types of magnetic nanoparticles in physiological systems in vitro is made in a known external magnetic field and alternating field respectively. Infra-red (IR) imaging and MR imaging were used to visualize these nanoparticles in vitro. A strong dependence on the size and the suspending medium is observed on the movement and heating of these nanoparticles. First, two of the particles (mean diameter d = 10 nm, uncoated Fe3O4 and d = 2.8 µm, polystyrene coated Fe3O4+γ-Fe2O3) did not move while only a dextran coated nanoparticle (d = 50 nm, γ-Fe2O3) moved in type 1 collagen used as an in vitro model system. It is also observed that the time taken by a collection of these nanoparticles to move even a smaller distance (5 mm) in collagen (∼100 min) is almost ten times higher when compared to the time taken to move twice the distance (10 mm) in glycerol (∼10 min) under the same external field. Second, the amount of temperature rise increases with the concentration of nanoparticles regardless of the microenvironments in the heating studies. However, the amount of heating in collagen (maximum change in temperature ΔTmax∼9 °C at 1.9 mg Fe ml−1 and 19 °C at 3.7 mg Fe ml−1) is significantly less than that in water (ΔTmax∼15 °C at 1.9 mg Fe ml−1 and 33 °C at 3.7 mg Fe ml−1) and glycerol (ΔTmax∼13.5 °C at 1.9 mg Fe ml−1 and 30 °C at 3.7 mg Fe ml−1). Further, IR imaging provides at least a ten times improvement in the range of imaging magnetic nanoparticles, whereby a concentration of (0–4 mg Fe ml−1) could bevisualized as compared to (0–0.4 mg Fe ml−1) by MR imaging. Based on these in vitro studies, important issues and parameters that require further understanding and characterization of these nanoparticles in vivo are discussed.

In order to cryopreserve functional engineered tissues (ETs), the microstructure of the extracellular matrix (ECM) should be maintained as well as the cellular viability since the functionality is closely related to the ECM microstructure. Since the post-thaw ECM microstructure is determined by the deformation of ETs during cryopreservation, freezing-induced deformation of ETs was measured with a newly developed quantum dot (QD)-mediated cell image deformetry system using dermal equivalents as a model tissue. The dermal equivalents were constructed by seeding QD-labeled fibroblasts in type I collagen matrices. After 24 hour incubation, the ETs were directionally frozen by exposing them to a spatial temperature gradient (from 4 °C to −20 °C over a distance of 6 mm). While being frozen, the ETs were consecutively imaged, and consecutive pairs of these images were two-dimensionally cross-correlated to determine the local deformation during freezing. The results showed that freezing induced the deformation of ET, and its magnitude varied with both time and location. The maximum local dilatation was 0.006 s −1 and was always observed at the phase change interface. Due to this local expansion, the unfrozen region in front of the freezing interface experienced compression. This expansion-compression pattern was observed throughout the freezing process. In the unfrozen region, the deformation rate gradually decreased away from the freezing interface. After freezing/thawing, the ET experienced an approximately 28% decrease in thickness and 8% loss in weight. These results indicate that freezing-induced deformation caused the transport of interstitial fluid and the interstitial fluid was extruded. In summary, the results suggest that complex cell-fluid-matrix interactions occur within ETs during freezing, and these interactions determine the post-thaw ECM microstructure and eventual post-thaw tissue functionality.