Biomaterials Science Blog

The cover story for the July 2014 issue of Biomaterials Science highlights the use of nanovehicle particles for the targeted delivery of chemotherapy drugs to tumor cells in bone.

Bone metastasis, or the spreading of tumor cells from the initial tumor site to bone tissue, marks the stage of cancer progression where the diseased is deemed incurable. Currently, the main method to treat bone metastasis is to utilize aggressive chemotherapy drugs and destroy metastatic tumor cells.  Unfortunately, untargeted chemotherapy treatments result in death of both cancerous and healthy tissue. Treatments could be significantly improved with the technology to specifically target the destruction of tumor cells without affecting the surrounding bone tissue.

Researchers at the University of Utah, University of Iowa, and Wuhan University in China are making this desired technology a reality. Wang et al. have developed a nanovehicle capable of targeting tumor cells within bone tissue.  Nanovehicles (NVs) are essentially nano-sized cargo containers capable of delivering drugs to a desired destination. The cleverly designed NVs are designed to target diseased bone tissue to deliver chemotherapy drugs at a specific site.

The NVs developed in this study have three design features:

(1) The NVs core is made of hydrophilic and hydrophobic block co-polymers able to form a shell-like structure known as a micelle. The micelle serves as the cargo vessel that contains the chemotherapy drug doxorubicin.

(2) The outermost segments of the NVs are negatively charged bone-targeting peptides. The peptide is responsible for the accumulation of NVs in skeletal tissue, and the negative charge prevents cellular uptake of the NVs into healthy tissue.

(3) For uptake into cancer cells, the particle must be positively charged. Therefore, a positively charged peptide linker was added in between the micelle core and the negatively charged bone-targeting region. The peptide linker is cleavable by cathepsin K enzyme (CTSK), which is overexpressed in bone metastatic lesions. When the NV enters a metastatic lesion, the CTSK cleaves off the negatively charged peptides and exposes the positively charged peptides. This charge reversal allows for tumor cells present in the metastatic lesion to uptake the NV.

After extensively characterizing the nanoparticles with NMR and zeta potential measurements, the NVs were used to observe decreased tumor cell viability under CTSK-rich conditions in vitro. More strikingly, in vivo tests of the NVs in a mouse model of bone metastasis showed significant increases in mouse survival and decreases in overall tumor burden.

Collectively, these ingeniously designed nanovehicles show great promise in providing an effective targeted therapy for bone metastasis.

Peptide decoration of nanovehicles to achieve active targeting and pathology-responsive cellular uptake for bone metastasis chemotherapy
X. Wang, Y. Yang, H. Jia, W. Jia, S. Miller, B. Bowman, J. Feng, and F. Zhan
Biomater. Sci., 2014, Advance Article DOI: 10.1039/C4BM00020J

Brian Aguado is currently a Ph.D. Candidate and NSF Fellow in the Biomedical Engineering department at Northwestern University. He holds a B.S. degree in Biomechanical Engineering from Stanford University and a M.S. degree in Biomedical Engineering from Northwestern University. Read more about Brian’s research publications here.

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This study introduces the concept of the “personalized protein corona” as a determinant factor in nano-biomedicine, specifically regarding the biological identity and fate of nanoparticles.

The concept of personalized medicine has become increasingly relevant in healthcare over the past decade. Ever since the human genome was unraveled, the idea of tailoring therapies specific to the individual patient has been at the forefront of medicine. Diagnosis, prognosis and most importantly treatment are thought to eventually be adapted to each individual’s genetic and pathophysiological makeup. Nonetheless, biomaterials for invasive use (e.g. implantation or injection) are still largely being designed for general use. This study argues for a much more specific approach of biomaterials design, looking at the nanoparticles (NPs) in particular.

A collaborative effort headed by Dr. Mahmoudi from Stanford University, US, and the University of Medical Sciences in Tehran, Iran, Hajipour et al. evaluated effects of the altered protein composition of human plasma in different disease states on NP corona formation. Two NP materials were chosen for their analysis, hydrophobic polystyrene and hydrophilic silica, which are widely investigated for biomedical material approaches and currently evaluated for safety purposes. 

 NPs were exposed to plasma solutions of different patient populations to form hard protein coronas, after which the composition of NP protein coronas was analyzed using SDS-page, densitometry and zeta-potential measurements. Interestingly, the authors found that changes in plasma protein composition due to underlying conditions alter the protein decoration on NPs, resulting in an unpredictable biologic identity of the NPs and thus their biological fate. The severity of the condition was also found to impact protein deposition. Intriguingly, even among healthy subjects there was considerable variation in corona composition, creating even more of an impetus for personalized NP design.

Collectively, the researchers found that NP protein corona distinctly depends on particular condition, severity of condition and combination of conditions, with relatively low variation between subjects with similar health profiles. Moving forward, identifying the personalized protein corona for individual patients or at least the expected protein corona in specific patient populations may become an integral aspect of nanoparticle-based biomaterial therapies.

Personalized protein coronas: a “key” factor at the nanobiointerface 
M. J. Hajipour, S. Laurent, A. Aghaie, F. Rezaee and M. Mahmoudi
Biomater. Sci., 2014, Advance Article DOI: 10.1039/c4bm00131a

Robert van Lith is currently a Ph.D. Candidate in the Biomedical Engineering department at Northwestern University, working on novel biomaterials to modulate oxidative stress in tissues. He received an American Heart Association Fellowship and Society for Biomaterials award for his work. He holds B.S. and M.S. degrees in Biomedical Engineering from Eindhoven University of Technology, the Netherlands. Read more about Robert’s research publications here.

This study identifies new surfaces optimized for human pluripotent stem cell expansion using a high-throughput polymer microarray chip.

The biomaterials community is moving toward using high-throughput tools to evaluate cell-material interactions at an unprecedented rate. For instance, polymer microarrays have become popular for identifying candidate surfaces that elicit a desired biological response. Using a single microarray chip, low volumes of polymer solution are deposited in a grid-like format using robotic ink-jet or contact printing. The chip is polymerized to manufacture a polymer microarray. After fabricating the microarray, cells are deposited directly onto the spots of the chip and cultured to determine materials that support a specific cell phenotype.

At the Laboratory of Biophysics and Surface Analysis at the University of Nottingham, Celiz et al. evaluated human pluripotent stem cell growth on a polymer microarray containing 141 varieties of (meth)acrylate and (meth)acrylamide photo-curable polymers. To maximize the diversity of the microarray, monomers containing a variety of nitrogen, fluorine, oxygen, aromatic, and aliphatic side chains were utilized.  Monomers were selected on their ability to be photo-polymerized by UV irradiation. The surface chemistry after polymerization was assessed using ToF-SIMS, and water contact angle measurements determined the surface wettability of each spot.

Partial least squares analysis (PLS) was utilized to correlate surface chemistry and wettability to identify surfaces that would yield high human pluripotent stem cell (hPSC) adhesion. Of the 141 surfaces screened in the array, 47 polymers supported hPSC attachment. Interestingly, no relationship was observed between surface wettability and cell adhesion, indicating wettability of a surface is not sufficient to predict hPSC adhesion. PLS analysis subsequently identified correlations between polymer surface chemistry and experimental hPSC adhesion. Additional experiments confirmed that increased protein adsorption on specific polymer spots was a contributor to cell adhesion to the polymer surface.

Collectively, the polymer array developed in this study was able to operate as a high-throughput tool to identify surfaces amenable to hPSC adhesion. Moving forward, polymer microarrays have the potential to identify a broad library of surfaces capable of supporting sustained hPSC growth and pluripotency.

Chemically diverse polymer microarrays and high throughput surface characterization: a method for discovery of materials for stem cell culture
A. D. Celiz, J. G. W. Smith, A. K. Patel, R. Langer, D. G. Anderson, D. A. Barrett, L. E. Young, M. C. Davies, C. Denning and M. R. Alexander
Biomater. Sci., 2014, Advance Article DOI: 10.1039/C4BM00054D

Brian Aguado is currently a Ph.D. Candidate and NSF Fellow in the Biomedical Engineering department at Northwestern University. He holds a B.S. degree in Biomechanical Engineering from Stanford University and a M.S. degree in Biomedical Engineering from Northwestern University. Read more about Brian’s research publications here.

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Researchers have demonstrated that controlling nanoparticle shape and packing can impact how cancer therapeutics interact with cells.

Photodynamic therapy is an innovative emerging therapy for cancer.  This therapeutic modality consists of introducing light-activated molecules known as ‘photosensitizers’ into cancer cells.  When activated with light, these photosensitizers are able to produce toxic molecules within the cells (also known as reactive oxygen species or ROS) that can eventually cause cancer cell death.  Photosensitizers are often introduced into the cells using nanoparticle carriers. In order for effective cell death to occur, ROS must be formed within the nanoparticles and then diffuse out of the nanoparticles into the cells.

In this article, Chu et al. have designed silica-based nanocarriers that can control how photosensitizers interact with cells. They previously found that when photosensitizer-loaded nanoparticles were packed more densely, the amount of ROS that was released decreased.  In contrast, more loosely packed nanoparticles allowed for greater release of ROS into cells. In this study, the researchers designed a third type of nanoparticle consisting of a gold nanorod coated with dense silica. They found that this third type of nanoparticle released photosensitizers much more efficiently than the either densely packed or loosely packed silica-only particles. They also discovered that the nanorod-based particles produced a different distribution of ROS as compared to the loose or dense silica-only particles. When cells were treated with these nanoparticles, loosely-packed silica particles and the nanorod-based particles demonstrated dramatic decreases in cell-viability due to the action of the photosensitizers. Further, while the silica-based loose and dense particles caused cells to die via a programmed cell death (apoptotic) route, the nanorod-based particles caused cell death via cell injury resulting in premature cell death (necrosis).

These experiments suggest that controlling the composition and shape of the nanoparticles that carry photosensitizers to cancer cells can alter both the number of cancer cells killed as well as the mechanism by which the cells die. This work has implications for future photodynamic therapeutic strategies.

Debanti Sengupta recently completed her PhD in Chemistry from Stanford University.  She is currently a Siebel postdoctoral scholar at the University of California, Berkeley.

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The cerebellum is a region in the brain responsible for regulating motor control and cognitive functions such as attention and language. During development of the cerebellum (and of other tissues), cells interact with the surrounding microenvironment known as the extracellular matrix (ECM). These neuron-ECM interactions regulate neuronal differentiation, growth, formation of synapses, and neurite outgrowth. Specifically, ECM components including collagen and laminin-1 (lam-1) are known to regulate the alignment, migration, and neurite outgrowth of Purkinje cells (PCs). However, the dual signaling roles of collagen and laminin-1 during cerebellar tissue development have not been fully explored.

Dr. Shantanu Sur, a postdoctoral fellow in Prof. Samuel Stupp’s laboratory at Northwestern University, has collaborated with Dr. Thomas Launey at the RIKEN Brain Science Institute in Japan to explore cerebellar tissue development using biomaterial hydrogels. Sur has developed an artificial matrix consisting of collagen and synthetic peptide amphiphile (PA) molecules presenting IKVAV, the peptide on laminin-1 responsible for cell adhesion and neurite outgrowth. Sur et al. evaluated the spatiotemporal expression of lam-1 and collagen in rat cerebellums during PC development (embryonic to post-natal) using histology and immunostaining. Given the changes in the ratio of lam-1 to collagen during PC formation and growth, these results suggest the dynamic involvement of these ECM proteins in forming the neural architecture of the cerebellum.

Using a biomimetic approach to mimic the critical lam-1 to collagen ratio, Sur proceeded to model the dynamic nature of the ECM during PC development with a synthetic collagen-PA hydrogel. Collagen (types I-V) and IKVAV-PA molecules were mixed together in solution at varying concentrations and gelled using ammonia vapor. This simple method allowed Sur to evaluate the density of PC growth, axon guidance, and dendrite morphology in gels using a wide array of collagen and IKVAV-PA concentrations. Strikingly, effects on PC phenotype were observed as a function of the collagen:IKVAV-PA ratio and not the absolute concentrations of each ECM component within the matrix.

Sur comments that the hybrid matrix provides an easily tunable environment to enable the in vitro testing of the role of ECM signals on neuronal maturation. “Our study shows that the optimal ECM-derived cues for neurons change at specific stages of development,” Sur says. “This observation will drive us to work on the design of a dynamic matrix where the extracellular signals delivered to the neuron can be tuned spatiotemporally.” Additionally, the collagen/IKVAV-PA gels may be used to identify cell-ECM interactions during the development of other tissue types, given the simplicity of the technique.

Collectively, this study demonstrates the exciting use of engineered matrices to evaluate spatiotemporal cell-ECM interactions, with the hopes to further elucidate mechanisms of tissue development.

Synergistic regulation of cerebellar Purkinje neuron development by laminin epitopes and collagen on an artificial hybrid matrix construct
Shantanu Sur, Mustafa O. Guler, Matthew J. Webber, Eugene T. Pashuck, Masao Ito, Samuel I. Stupp, and Thomas Launey
Biomater. Sci., 2014, Advance Article, DOI: 10.1039/C3BM60228A

Brian Aguado is currently a Ph.D. Candidate and NSF Fellow in the Biomedical Engineering department at Northwestern University. He holds a B.S. degree in Biomechanical Engineering from Stanford University and a M.S. degree in Biomedical Engineering from Northwestern University. Read more about Brian’s research publications here.

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