Jenolyn F. Alexander
Houston Methodist Hospital
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Jenolyn F. Alexander.
ACS Nano | 2014
Veronika Kozlovskaya; Jenolyn F. Alexander; Yun Wang; Thomas Kuncewicz; Xuewu Liu; Biana Godin; Eugenia Kharlampieva
We report on naturally inspired hydrogel capsules with pH-induced transitions from discoids to oblate ellipsoids and their interactions with cells. We integrate characteristics of erythrocytes such as discoidal shape, hollow structure, and elasticity with reversible pH-responsiveness of poly(methacrylic acid) (PMAA) to design a new type of drug delivery carrier to be potentially triggered by chemical stimuli in the tumor lesion. The capsules are fabricated from cross-linked PMAA multilayers using sacrificial discoid silicon templates. The degree of capsule shape transition is controlled by the pH-tuned volume change, which in turn is regulated by the capsule wall composition. The (PMAA)15 capsules undergo a dramatic 24-fold volume change, while a moderate 2.3-fold volume variation is observed for more rigid PMAA–(poly(N-vinylpyrrolidone) (PMAA–PVPON)5 capsules when solution pH is varied between 7.4 and 4. Despite that both types of capsules exhibit discoid-to-oblate ellipsoid transitions, a 3-fold greater swelling in radial dimensions is found for one-component systems due to a greater degree of the circular face bulging. We also show that (PMAA–PVPON)5 discoidal capsules interact differently with J774A.1 macrophages, HMVEC endothelial cells, and 4T1 breast cancer cells. The discoidal capsules show 60% lower internalization as compared to spherical capsules. Finally, hydrogel capsules demonstrate a 2-fold decrease in size upon internalization. These capsules represent a unique example of elastic hydrogel discoids capable of pH-induced drastic and reversible variations in aspect ratios. Considering the RBC-mimicking shape, their dimensions, and their capability to undergo pH-triggered intracellular responses, the hydrogel capsules demonstrate considerable potential as novel carriers in shape-regulated transport and cellular uptake.
Cancer Letters | 2013
Kenji Yokoi; Biana Godin; Carol J. Oborn; Jenolyn F. Alexander; Xuewu Liu; Isaiah J. Fidler; Mauro Ferrari
Pancreatic cancer is a highly fatal disease characterized by a dominant stroma formation. Exploring new biological targets, specifically those overexpressed in stroma cells, holds significant potential for the design of specific nanocarriers to attain homing of therapeutic and imaging agents to the tumor. In clinical specimens of pancreatic cancer, we found increased expression of CD59 in tumor associated endothelial cells as well as infiltrating cells in the stroma as compared to uninvolved pancreas. We explored this dual targeting effect using orthotopic human pancreatic cancer in nude mice. By immunofluorescence analysis, we confirmed the increased expression of Ly6C, mouse homolog of CD59, in tumor associated endothelial cells as well as in macrophages within the stroma. We decorated the surface of porous silicon nanocarriers with Ly6C antibody. Targeted nanocarriers injected intravenously accumulated to tumor associated endothelial cells within 15min. At 4h after administration, 9.8±2.3% of injected dose/g tumor of the Ly6C targeting nanocarriers accumulated in the pancreatic tumors as opposed to 0.5±1.8% with non-targeted nanocarriers. These results suggest that Ly6C (or CD59) can serve as a novel dual target to deliver therapeutic agents to the stroma of pancreatic tumors.
Advanced Healthcare Materials | 2015
Jenolyn F. Alexander; Veronika Kozlovskaya; Jun Chen; Thomas Kuncewicz; Eugenia Kharlampieva; Biana Godin
Blood-borne objects display a nonspherical shape with in-flow dimensions much larger than the vascular endothelial fenestrations, yet, at the diseased state, are able to traverse through these fenestrations owing to their elasticity. The role of physical parameters including shape and elasticity in the behavior of objects found in the tumor microenvironment needs to be understood to ultimately enhance chemotherapy and minimize its side effects. In this study, sphere- and cube-shaped biocompatible elastic microparticles (EM) made via layer-by-layer assembly of hydrogen-bonded tannic acid/poly(N-vinylpyrrolidone) (TA/PVPON) as hollow polymer shells and their rigid core-shell precursors (RM) are explored. In contrast to rigid five-bilayer (TA/PVPON) core shells, hollow elastic shells are unrecognized by J774A.1 macrophages, yet interact with endothelial and breast cancer cells. Internalization of cubical shells is fivefold more efficient by HMVEC (human microvascular endothelial cells) and sixfold and 2.5-fold more efficient by MDA-MB-231 and by SUM159 (breast cancer cells), respectively, compared to spherical shells. The interaction of cubical (TA/PVPON)5 shells with endothelial cells is similar under 10 s(-1) (characteristic of tumor vasculature) and 100 s(-1) shear rate (normal vasculature) while it is decreased at 100 s(-1) shear rate for the spherical shells. Our data suggest that cubical geometry promotes interaction of particles with breast cancer cells, while elasticity prevents engulfment by phagocytic cells in the tumor microenvironment.
Cancer Research | 2016
Tomonori Tanei; Fransisca Leonard; Xuewu Liu; Jenolyn F. Alexander; Yuki Saito; Mauro Ferrari; Biana Godin; Kenji Yokoi
Current treatments for liver metastases arising from primary breast and lung cancers are minimally effective. One reason for this unfavorable outcome is that liver metastases are poorly vascularized, limiting the ability to deliver therapeutics from the systemic circulation to lesions. Seeking to enhance transport of agents into the tumor microenvironment, we designed a system in which nanoparticle albumin-bound paclitaxel (nAb-PTX) is loaded into a nanoporous solid multistage nanovector (MSV) to enable the passage of the drug through the tumor vessel wall and enhance its interaction with liver macrophages. MSV enablement increased nAb-PTX efficacy and survival in mouse models of breast and lung liver metastasis. MSV-nAb-PTX also augmented the accumulation of paclitaxel and MSV in the liver, specifically in macrophages, whereas paclitaxel levels in the blood were unchanged after administering MSV-nAb-PTX or nAb-PTX. In vitro studies demonstrated that macrophages treated with MSV-nAb-PTX remained viable and were able to internalize, retain, and release significantly higher quantities of paclitaxel compared with treatment with nAb-PTX. The cytotoxic potency of the released paclitaxel was also confirmed in tumor cells cultured with the supernatants of macrophage treated with MSV-nAB-PTX. Collectively, our findings showed how redirecting nAb-PTX to liver macrophages within the tumor microenvironment can elicit a greater therapeutic response in patients with metastatic liver cancer, without increasing systemic side effects.
Cancer Letters | 2014
Kenji Yokoi; Tomonori Tanei; Biana Godin; Anne L. van de Ven; Aika Matsunoki; Jenolyn F. Alexander; Mauro Ferrari
Enhanced permeation and retention (EPR) effect, the mechanism by which nanotherapeutics accumulate in tumors, varies in patients based on differences in the tumor and organ microenvironment. Surrogate biomarkers for the EPR effect will aid in selecting patients who will accumulate higher amounts of nanotherapeutics and show better therapeutic efficacy. Our data suggest that the differences in the vascular permeability and pegylated liposomal doxorubicin (PLD) accumulation are tumor type as well as organ-specific and significantly correlated with the relative ratio of MMP-9 to TIMP-1 in the circulation, supporting development of these molecules as biomarkers for the personalization of nanoparticle-based therapy.
Journal of Materials Chemistry B | 2013
Srimeenakshi Srinivasan; Jenolyn F. Alexander; Wouter Driessen; Fransisca Leonard; Hu Ye; Xuewu Liu; Wadih Arap; Renata Pasqualini; Mauro Ferrari; Biana Godin
There has been extensive research on the use of nanovectors for cancer therapy. Targeted delivery of nanotherapeutics necessitates two important characteristics; the ability to accumulate at the disease locus after overcoming sequential biological barriers and the ability to carry a substantial therapeutic payload. Successful combination of the above two features is challenging, especially in solid porous materials where chemical conjugation of targeting entities on the particle surface will generally prevent successful loading of the therapeutic substance. In this study, we propose a novel strategy for decorating the surface of mesoporous silicon particles with targeting entities (bacteriophage) and gold nanoparticles (AuNP) while maintaining their payload carrying potential. The resulting Bacteriophage Associated Silicon Particles (BASP) demonstrates efficient encapsulation of macromolecules and therapeutic nanoparticles into the porous structures. In vitro targeting data show enhanced targeting efficiency with about four orders of magnitude lower concentration of bacteriophage. In vivo targeting data suggest that BASP maintain their integrity following intravenous administration in mice and display up to three fold higher accumulation in the tumor.
Nanoscale | 2016
Fransisca Leonard; Louis T. Curtis; Pooja Yesantharao; Tomonori Tanei; Jenolyn F. Alexander; Min Wu; John Lowengrub; Xuewu Liu; Mauro Ferrari; Kenji Yokoi; Hermann B. Frieboes; Biana Godin
Hypovascularization in tumors such as liver metastases originating from breast and other organs correlates with poor chemotherapeutic response and higher mortality. Poor prognosis is linked to impaired transport of both low- and high-molecular weight drugs into the lesions and to high washout rate. Nanoparticle albumin-bound-paclitaxel (nAb-PTX) has demonstrated benefits in clinical trials when compared to paclitaxel and docetaxel. However, its therapeutic efficacy for breast cancer liver metastasis is disappointing. As macrophages are the most abundant cells in the liver tumor microenvironment, we design a multistage system employing macrophages to deliver drugs into hypovascularized metastatic lesions, and perform in vitro, in vivo, and in silico evaluation. The system encapsulates nAb-PTX into nanoporous biocompatible and biodegradable multistage vectors (MSV), thus promoting nAb-PTX retention in macrophages. We develop a 3D in vitro model to simulate clinically observed hypo-perfused tumor lesions surrounded by macrophages. This model enables evaluation of nAb-PTX and MSV-nab PTX efficacy as a function of transport barriers. Addition of macrophages to this system significantly increases MSV-nAb-PTX efficacy, revealing the role of macrophages in drug transport. In the in vivo model, a significant increase in macrophage number, as compared to unaffected liver, is observed in mice, confirming the in vitro findings. Further, a mathematical model linking drug release and retention from macrophages is implemented to project MSV-nAb-PTX efficacy in a clinical setting. Based on macrophage presence detected via liver tumor imaging and biopsy, the proposed experimental/computational approach could enable prediction of MSV-nab PTX performance to treat metastatic cancer in the liver.
Archive | 2011
Silvia Ferrati; Agathe K. Streiff; Srimeenakshi Srinivasan; Jenolyn F. Alexander; Nikhil Bhargava; Andrew Peters; Nelly E Song; Ennio Tasciotti; Biana Godin; Mauro Ferrari; Rita E. Serda
Mass transport within body compartments and across biological barriers negatively impacts drug delivery but also presents opportunities to optimally design drug carriers that benefit from novel differentials presented in pathological tissue. As an example, cancer presents unique alterations in vascular permeability, osmotic pressure, cellular zip-codes, and numerous other physical parameters that can be used to achieve preferential accumulation of imaging and therapeutic agents at the cancer lesion. This chapter describes the journey of drug delivery from the site of administration to the appropriate subcellular compartment within the target cell. Design parameters for optimal fabrication of nanoparticle-based carriers, including size, shape, elemental composition, surface staging, and hierarchical ordering of multi-particle complexes are presented. The overall objective of this chapter is to enhance our understanding of mass transport in order to facilitate the development of carriers for therapy and diagnostics of various pathological conditions.
Archive | 2016
Matthew Ware; Jenolyn F. Alexander; Huw D. Summers; Biana Godin
One of the main objectives in nanomedicine is to enable specific delivery of therapeutics and imaging agents to the disease loci. While previously the main tool for targeting was incorporating entities with biological recognition on the surface of the nanovector, recently, the focus has shifted to the ability of the physical characteristics of particles to guide them crossing numerous barriers to the site of action. In this chapter we will focus on how the geometry of nanovectors affects their interaction with biological milieu, and as a result their therapeutic and diagnostic potential. The chapter is divided into sections describing interactions of various particles with extracellular components, whole cells and various cell organelles. In the intracellular interactions subsection, we focus on the initial interaction between particle and cell membrane, the uptake mechanism and intracellular trafficking of particles with various geometries. Furthermore, the importance of charge density and the zeta potential parameter is discussed. The chapter concludes with a discussion of challenges and outlook on future developments of theranostic particle delivery using particle geometry as the rational design feature.
Cancer Research | 2013
Kenji Yokoi; Tomonori Tanei; Biana Godin; Anne L. van de Ven; Jenolyn F. Alexander; Mauro Ferrari
Pegylated liposomal doxorubicin (PLD) for cancer therapy is advantageous over conventional chemotherapy with doxorubicin, because of the preferential delivery of drugs to tumors owing to the enhanced permeation and retention (EPR) effect. The biological barriers include abnormal structure of tumor vessels in heterogeneous tumor microenvironments shall influence the EPR effect and result in heterogeneous tumor perfusion of PLD and therapeutic efficacy. Although 4T1, murine breast cancer cells and 3LL, murine lung cancer cells had similar sensitivity to PLD in vitro, only 4T1 tumors responded to therapy with PLD in vivo. There were no significant differences of the microvessel density and blood perfusion in these tumors. In contrast, PLD extravasated and accumulated into 4T1 tumors significantly more than 3LL tumors, indicating vascular permeability was higher in 4T1 tumors. Coverage of endothelial cells by collagen type IV, which constitutes basement membrane of the vessels, was significantly lower in 4T1 tumors as compared to those in 3LL tumors. Differential analysis of protein expression by 4T1 and 3LL cells in vitro revealed that MMP-9 (collagenase) production was significantly higher in 4T1 cells as compared to 3LL cells. MMP-9 expression was also higher in 4T1 tumors as well as in sera of mice bearing 4T1 tumors as compared to 3LL tumors and sera of mice bearing 3LL tumors and normal mice respectively. Batimastat, MMPs inhibitor, injected in vivo increased the coverage of endothelial cells by basement membrane and abrogated the accumulation of PLD into the 4T1 tumors, indicating MMP-9 can play a pivotal role in controlling the vascular permeability. Interestingly, 4T1 tumors were accumulated with PLD only when tumors were growing in the brain and mammary fat pad, but not in the liver. Coverage of the endothelial cells by basement membrane was significantly higher in the tumors growing in the liver as compared to the other two locations. The levels of TIMP-1, endogenous inhibitor of MMPs, were significantly higher in the mice bearing 4T1 in the liver as compared to the mice bearing the tumors in the other locations. These data indicate the levels as well as balance between MMP-9 and TIMP-1 can determine the vascular permeability to PLD. Therefore the these enzymes in the circulation can serve as surrogate markers for the vascular permeability to PLD and there is a possibility to personalize the therapy by selecting patients who will likely accumulated with PLD into tumors to increase clinical outcome. Citation Format: Kenji Yokoi, Tomonori Tanei, Biana Godin, Anne van de Ven, Jenolyn Alexander, Mauro Ferrari. Tumor type and organ type dependent differences of vascular permeability to pegylated liposomal doxorubicin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4973. doi:10.1158/1538-7445.AM2013-4973