Book Chapter Citations

  • Drug Delivery: Intravaginal, Advantages and Challenges
    Gu, Jijin; Ho, Emmanuel A
    In Encyclopedia of Biomedical Polymers and Polymeric Biomaterials, 1st Ed.; Mishra, M., Ed.; Taylor & Francis: New York, 2015; Vol. 4, 2712-2725

    The Encyclopedia of Biomedical Polymers & Polymeric Biomaterials presents state-of-the-art research and development on the synthesis, properties, and applications of novel polymers in a vital area. This groundbreaking work includes an extremely large number of contributors for a reference publication in biomedical polymers and polymeric biomaterials. With multiple articles on many subjects, the encyclopedia offers a broad-based perspective on a multitude of topics, as well as detailed research information, figures, tables, illustrations, and references.

  • Publication in Refereed Journals

  • Controlling Differentiation of Adult Stem Cells Via Cell-Derived Nanoparticles: Implications in Bone Repair
    Shruthi Polla Ravi,Yasmeen Shamiya, Aishik Chakraborty, Ali Coyle, Alap Ali Zahid, Jin Wang, Michael S. H. Boutilier, Emmanuel A. Ho, Arghya Paul
    ACS Applied Nano Materials, Dec 6, 2022

  • Reagent free detection of SARS-CoV-2 using an antibody-based microwave sensor in a microfluidic platform
    Weijia Cui, Pei Zhao, Jin Wang, Ning Qin, Emmanuel A. Ho, Carolyn L. Ren
    Lab on a Chip, Apr 19, 2022

  • Fused deposition modeling three-dimensional printing of flexible polyurethane intravaginal rings with controlled tunable release profiles for multiple active drugs
    Yufei Chen, Yannick L Traore, Lyndon Walker, Sidi Yang,Emmanuel A. Ho
    Drug Delivery and Translational Research, Feb 24, 2022

  • Translational advancements in transdermal and mucosal delivery
    Emmanuel A. Ho, Ryan F Donnelly
    Drug Delivery and Translational Research, Feb 8, 2022

  • Doxorubicin nanoformulations on therapy against cancer: An overview from the last 10 years
    Natália A.D'Angelo, Mariana A.Noronha, Mayra C.C.Câmara, Isabelle S.Kurnik, Chuying Feng, Victor H.S.Araujo, João H.P.M.Santos, Valker Feitosa, João V.D.Molino, Carlota O.Rangel-Yagui, Marlus Chorilli, Emmanuel A. Ho, André M.Lopes
    Materials Science and Engineering: C, Dec 23, 2021

  • Low-Dose Acetylsalicylic Acid Reduces T Cell Immune Activation: Potential Implications for HIV Prevention
    Julie Lajoie, Monika M Kowatsch, Lucy W Mwangi, Geneviève Boily-Larouche, Julius Oyugi, Yufei Chen, Makobu Kimani, Emmanuel A. Ho, Joshua Kimani, Keith R Fowke
    Frontiers in Immunology, November 18, 2021

  • Segmented intravaginal ring for the combination delivery of hydroxychloroquine and anti-CCR5 siRNA nanoparticles as a potential strategy for preventing HIV infection
    Yannick L Traore, Yufei Chen, Fernanda Padilla, Emmanuel A. Ho
    Drug Delivery and Translational Research, April 17, 2021

  • Sustainable Materials for Fused Deposition Modeling 3D Printing Applications
    Jennifer P. Rett, Yannick L. Traore, Emmanuel A. Ho
    Advanced Engineering Materials, March 24, 2021

  • Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
    Daniel J. Klionsky, Emmanuel A. Ho,et al.
    Autophagy, Feb 8, 2021

  • Microfluidic Technology for Antibacterial Resistance Study and Antibiotic Susceptibility Testing: Review and Perspective
    Ning Qin , Pei Zhao, Emmanuel A. Ho,Gongming Xin, and Carolyn L. Ren
    ACS Sensors, Dec 18, 2020

  • Challenges in the development and establishment of exosome-based drug delivery systems
    Jin Wang, Derek Chen and Emmanuel A. Ho,
    Journal of Controlled Release, Oct 12, 2020

  • Anti-α4β7 monoclonal antibody–conjugated nanoparticles block integrin α4β7 on intravaginal T cells in rhesus macaques
    Sidi Yang, Geraldine Arrode-Bruses, Ines Frank, Brooke Grasperge, James Blanchard, Agegnehu Gettie, Elena Martinelli and Emmanuel A. Ho,
    Science Advances, Aug 21, Vol. 6, N0. 34, 2020

  • Autophagy induction and PDGFR-β knockdown by siRNA-encapsulated nanoparticles reduce chlamydia trachomatis infection.
    Sidi Yang, Yannick L. Traore, Celine Jimenez and Emmanuel A. Ho
    Sceintific Reports, Feb 04, 2019

  • Design and development of pH-responsive polyurethane membranes for intravaginal release of nanomedicines
    Seungil Kim, Yannick L. Traore, Emmanuel A. Ho and Song Liu
    Acta Biomaterialia, Oct 5, 2018

  • Current State of Microbicide Development
    Yannick L. Traore, Yufei Chen, Emmanuel A. Ho
    Clinical Pharmacology & Therapeutics, Aug 14, 2018

  • Switchable On-Demand Release of a Nanocarrier from a Segmented Reservoir Type Intravaginal Ring Filled with a pH-Responsive Supramolecular Polyurethane Hydrogel
    Seungil Kim, Yannick L. Traore, Yufei Chen, Emmanuel A. Ho, and Song Liu
    ACS Applied Bio Materials, Aug 14, 1(3)652–662,2018

  • Implant delivering hydroxychloroquine attenuates vaginal T lymphocyte activation and inflammation
    Yufei Chen, Yannick L. Traore, Sidi Yang, Julie Lajoie, Keith R. Fowke, Daniel W. Rickey Emmanuel A. Ho,
    Journal of Controlled Release, May 10, 277:102-113, 2018

  • A new strategy for battling bacterial resistance: turning potent, non-selective and potentially non-resistance-inducing biocides into selective ones
    Sadegh Ghanbar, Miral Fumakia, Emmanuel A. Ho, and Song Liu
    Nanomedicine: Nanotechnology, Biology, and Medicine, Feb 14, 14(2), 471-481, 2018

  • Dynamic mechanical behaviour of nanoparticle loaded biodegradable PVA films for vaginal drug delivery
    Yannick L. Traore, Miral Fumakia, Jijin Gu, and Emmanuel A. Ho
    Journal of Biomaterials Applications, March, 32(8):1119-1126, 2018

  • Disposition, metabolism and histone deacetylase and acetyltransferase inhibition activity of tetrahydrocurcumin and other curcuminoids
    Julia T. Novaes, Ryan Lillico, Casey L. Sayre, Kalyanam Nagabushanam, Muhammed Majeed, Yufei Chen, Emmanuel A. Ho, Ana Luise de P. Oliveira, Stephanie E. Martinez, Samaa Alrushaid, Neal M. Davies, Ted M. Lakowski
    Pharmaceutics, Oct 12, 9(4),45, 2017

  • Self-assembled nanoparticles made from a new PEGylated poly(aspartic acid) graft copolymer for intravaginal delivery of poorly water-soluble drugs
    Seungil Kim, Yannick L. Traore, Jae Sang Lee, Ji-Heung Kim, Emmanuel A. Ho, Song Liu
    Journal of Biomaterials Science, Polymer Edition, Aug 30, 28(17):2082-2099, 2017

  • Development of antibody-modified chitosan nanoparticles for the targeted delivery of siRNA across the blood-brain barrier as a strategy for inhibiting HIV replication in astrocytes
    Jijin Gu, Karam Al-Bayati, Emmanuel A. Ho
    Drug Delivery and Translational Research, Mar 17,7(4):497-506, 2017

  • Reversibly pH-responsive Polyurethane Membranes for On-demand Intravaginal Drug Delivery
    Seungil Kim, Yufei Chen, Emmanuel A. Ho, Song Liu
    Acta Biomaterialia, Jan 1, 47:100-112, 2017

  • Nanoparticles encapsulated with LL37 and serpin A1 promotes wound healing and synergistically enhances antibacterial activity
    Miral D. Fumakia, Emmanuel A. Ho
    Molecular Pharmaceutics, Jul 5, 13(7):2318-31, 2016

  • Evaluating the impact of hydroxychloroquine-loaded polyurethane intravaginal rings on lactobacilli
    Yannick Leandre Traore, Yufei Chen, Anne-Marie Bernier, Emmanuel A. Ho
    Antimicrobial Agents and chemotherapy, Dec;59(12):7680-6, 2015

  • Protein/peptide-based entry/fusion inhibitors as anti-HIV therapies: challenges and future direction
    Miral Fumakia, Sid Yang, Jijin Gu, Emmanuel A. Ho
    Reviews in Medical Virology, Aug 26, 26(1):4-20, 2015

  • Biodegradable film for the targeted delivery of siRNA-loaded nanoparticles to vaginal immune cells
    Jijin Gu, Sid Yang, Emmanuel A. Ho
    Molecular Pharmaceutics, Aug 3;12(8):2889-903, 2015

  • Pharmacological effects of a C-phycocyanin-based multicomponent nutraceutical in an in-vitro canine chondrocyte model of osteoarthritis
    Stephanie E. Martinez, Yufei Chen, Emmanuel A. Ho, Steven A. Martinez, Neal M. Davies
    Canadian Journal of Veterinary Research, Jul;79(3):241-9, 2015

  • Expression and regulation of bone morphogenetic protein 4 in hepatocellular carcinoma
    Xiaotong Wang, Qingguo Wang, Weisi Kong, Gerald Y. Minuk, Frank J. Burczynski, Emmanuel A. Ho, Yuewen Gong
    Integrative Cancer Science and Therapeutics, Volume 2(1): 70-74, 2015

  • Development of an analytical method for the rapid quantitation of peptides used in microbicide formulations
    Yufei Chen, Sid Yang, Emmanuel A. Ho
    Chromatographia, 77(23-24):1713-1720, 2014

  • Development of polyether urethane intravaginal rings for the sustained delivery of hydroxychloroquine
    Yufei Chen, Yannick Leandre Traore, Amanda Li, Keith R. Fowke, Emmanuel A. Ho
    Drug Design, Development and Therapy, Oct;8: 1801-1815, 2014

    Hydroxychloroquine (HCQ) has been shown to demonstrate anti-­inflammatory properties and direct anti-HIV activity. In this study, we describe for the first time the fabrication and in vitro evaluation of two types of intravaginal ring (IVR) devices (a surfaced-modified matrix IVR and a reservoir segmental IVR) for achieving sustained delivery (>14 days) of HCQ as a strategy for preventing male-to-female transmission of HIV. Both IVRs were fabricated by hot-melt injection molding. Surface-modified matrix IVRs with polyvinylpyrrolidone or poly(vinyl alcohol) coatings exhibited significantly reduced burst release on the first day (6.45% and 15.72% reduction, respectively). Reservoir IVR segments designed to release lower amounts of HCQ displayed near-zero-order release kinetics with an average release rate of 28.38 µg/mL per day for IVRs loaded with aqueous HCQ and 32.23 µg/mL per day for IVRs loaded with HCQ mixed with a rate-controlling excipient. Stability studies demonstrated that HCQ was stable in coated or noncoated IVRs for 30 days. The IVR segments had no significant effect on cell viability, pro-inflammatory cytokine production, or colony formation of vaginal and ectocervical epithelial cells. Both IVR systems may be suitable for the prevention of HIV transmission and other sexually transmitted infections.

  • Novel intravaginal nanomedicine for the targeted delivery of saquinavir to CD4+ immune cells
    Sidi Yang, Yufei Chen, Kaien Gu, Alicia Dash, Casey L. Sayre, Neal M. Davies, Emmanuel A. Ho
    International Journal of Nanomedicine, Aug;8: 2847-2858, 2013

    The goal of this study was to develop and characterize an intravaginal nanomedicine for the active targeted delivery of saquinavir (SQV) to CD4+ immune cells as a potential strategy to prevent or reduce HIV infection. The nanomedicine was formulated into a vaginal gel to provide ease in self-administration and to enhance retention within the vaginal tract. SQV-encapsulated nanoparticles (SQV-NPs) were prepared from poly(lactic-co-glycolic acid)(PLGA) and conjugated to antihuman anti-CD4 antibody. Antibody-conjugated SQV-NPs (Ab-SQV-NPs) had an encapsulation efficiency (EE%) of 74.4% ± 3.7% and an antibody conjugation efficiency (ACE%) of 80.95% ± 1.10%. Over 50% of total loaded SQV was released from NPs over 3 days. NPs were rapidly taken up by Sup-T1 cells, with more than a twofold increase in the intracellular levels of SQV when delivered by Ab-SQV-NPs in comparison to controls 1 hour post-treatment. No cytotoxicity was observed when vaginal epithelial cells were treated for 24 hours with drug-free Ab-NPs (1,000 µg/mL), 1% HEC placebo gel (200 mg/mL), or 1% HEC gel loaded with drug-free Ab-NPs (5 mg NPs/g gel, 200 mg/mL of gel mixture). Overall, we described an intravaginal nanomedicine that is nontoxic and can specifically deliver SQV into CD4+ immune cells. This platform may demonstrate potential utility in its application as postexposure prophylaxis for the treatment or reduction of HIV infection, but further studies are required.

  • Targeting the metabolism of leukemia stem cells as a novel therapeutic strategy
    Emmanuel A. Ho and Neal M. Davies
    Drugs in Context, DOI: 10.7573/dic.212252, 2013

  • Intravaginal rings as a novel platform for mucosal vaccination
    Emmanuel A. Ho
    Journal of Molecular Pharmaceutics & Organic Process Research, 1:e103.doi:10.4172/jmpopr.1000e103, 2013

  • Advancements in the field of intravaginal siRNA delivery
    Sidi Yang, Yufei Chen, Roien Ahmadie, Emmanuel A. Ho
    Journal of Controlled Release, Jan 5;167(1):29-39, 2013

    The vaginal tract is a suitable site for the administration of both local and systemic acting drugs. There are numerous vaginal products on the market such as those approved for contraception, treatment of yeast infection, hormonal replacement therapy, and feminine hygiene. Despite the potential in drug delivery, the vagina is a complex and dynamic organ that requires greater understanding. The recent discovery that injections of double stranded RNA (dsRNA) in Caenorhabditis elegans (C. elegans) results in potent gene specific silencing, was a major scientific revolution. This phenomenon known as RNA interference (RNAi), is believed to protect host genome against invasion by mobile genetic elements such as transposons and viruses. Gene silencing or RNAi has opened new potential opportunities to study the function of a gene in an organism. Furthermore, its therapeutic potential is being investigated in the field of sexually transmitted infections such as human immunodeficiency virus (HIV) and other diseases such as age-related macular degeneration (AMD), diabetes, hypercholesterolemia, respiratory disease, and cancer. This review will focus on the therapeutic potential of siRNA for the treatment and/or prevention of infectious diseases such as HIV, HPV, and HSV within the vaginal tract. Specifically, formulation design parameters to improve siRNA stability and therapeutic efficacy in the vaginal tract will be discussed along with challenges, advancements, and future directions of the field.

  • Characterization of long-circulating cationic nanoparticle formulations consisting of a two-stage PEGylation step for the delivery of siRNA in a breast cancer tumor model
    Emmanuel A. Ho, Maryam Osooly, Dita Strutt, Dana Masin, Youngjoo Yang, Hong Yan, Marcel Bally
    Journal of Pharmaceutical Sciences, Jan; 102 (1) 227-36, 2013

    Polyethylene glycol (PEG) has been used widely in liposomal formulations as a strategy to inhibit opsonization by plasma proteins and to prolong liposome plasma circulation time. PEG can be incorporated onto the surface of liposomes either during the spontaneous self-assembling process or inserted after vesicle formation. The advantages of employing the PEG postinsertion method include improved drug encapsulation efficiency and the ability to incorporate PEG conjugates for enhanced cell binding and uptake. In this study, we propose to evaluate a cationic lipid nanoparticle formulation containing two PEGylation steps: pre- and post-siRNA insertion. Our results indicate that formulations consisting of the extra PEG post-insertion step significantly increased siRNA circulation in the plasma by two-folds in comparison with the formulations consisting of only the single PEGylation step. Moreover, this formulation was able to efficiently carry siRNA to the tumor site, increase siRNA stability and significantly downregulate luciferase mRNA expression by >50% when compared with the controls in an intraperitoneal and subcutaneous breast cancer tumor model. Overall, our cationic lipid nanoparticle formulation displayed enhanced plasma circulation, reduced liver accumulation, enhanced tumor targeting, and effective gene knockdown--demonstrating excellent utility for the delivery of siRNA.

  • Characterization of cationic liposome formulations designed to exhibit extended plasma residence times and tumor vasculature targeting properties
    Emmanuel A. Ho, Euan Ramsay, Mihaela Ginj, Malathi Anantha, Isaiah Bregman, Jonathan Sy, Janet Woo, Maryam Osooly-Talesh, Donald T. Yapp, Marcel B. Bally
    Journal of Pharmaceutical Sciences, Jun;99(6):2839-53, 2010

    Cationic liposomes exhibit a propensity to selectively target tumor-associated blood vessels demonstrating potential value as anti-cancer drug delivery vehicles. Their utility however, is hampered by their biological instability and rapid elimination following i.v. administration. Efforts to circumvent rapid plasma elimination have, to date, focused on decreasing cationic lipid content and incorporating polyethylene glycol (PEG)-modified lipids. In this study we wanted to determine whether highly charged cationic liposomes with surface-associated PEG could be designed to exhibit extended circulation lifetimes, while retaining tumor vascular targeting properties in an HT29 colorectal cancer xenograft model. Cationic liposomes prepared of DSPC, cationic lipids (DODAC, DOTAP, or DC-CHOL), and DSPE-PEG(2000) were studied. Our results demonstrate that formulations prepared with 50 mol% DODAC or DC-CHOL, and 20 mol% DSPE-PEG(2000) exhibited circulation half-lives ranging from 6.5 to 12.5 h. Biodistribution studies demonstrated that DC-CHOL formulations prepared with DSPE-PEG(2000) accumulated threefold higher in s.c. HT29 tumors than its PEG-free counterpart. Fluorescence microscopy studies suggested that the presence of DSPE-PEG(2000) did not adversely affect liposomal tumor vasculature targeting. We show for the first time that it is achievable to design highly charged, highly pegylated (20 mol% DSPE-PEG(2000)) cationic liposomes which exhibit both extended circulation lifetimes and tumor vascular targeting properties.

  • Drug release mechanism of paclitaxel from a chitosan-lipid implant system: effect of swelling, degradation and morphology
    Patrick Lim Soo, Jaepyoung Cho, Justin Grant, Emmanuel A. Ho, Micheline Piquette-Miller, Christine Allen
    European Journal of Pharmaceutics and Biopharmaceutics, May;69(1):149-57, 2008

    Localized and sustained delivery of anti-cancer agents to the tumor site has great potential for the treatment of solid tumors. A chitosan–egg phosphatidylcholine (chitosan–ePC) implant system containing PLA-b-PEG/PLA nanoparticles has been developed for the delivery of paclitaxel to treat ovarian cancer. Production of volumes of ascites fluid in the peritoneal cavity is a physical manifestation of ovarian cancer. In vitro release studies of paclitaxel from the implant were conducted in various fluids including human ascites fluid. A strong correlation (r2 = 0.977) was found between the release of paclitaxel in ascites fluid and PBS containing lysozyme (pH 7.4) at 37 °C. The drug release mechanism for this system was proposed based on swelling, degradation and morphology data. In addition, in vitro release of paclitaxel was found to be a good indicator of the in vivo release profile (correlation between release rates: r2 = 0.965). Release of paclitaxel was found to be sustained over a four-week period following implantation of the chitosan–ePC system into the peritoneal cavity of healthy Balb/C mice. Also, the concentrations of paclitaxel in both plasma and tissues (e.g. liver, kidney and small intestine) were found to be relatively constant.

  • Novel drug delivery strategies for the treatment of ovarian cancer
    Emmanuel A. Ho, Christine Allen and Micheline Piquette-Miller
    Expert Review of Obstetrics & Gynecology, 2(5):587-593, 2007

  • KLF6 and HSF4 transcriptionally regulate multidrug resistance transporters during inflammation
    Emmanuel A. Ho, Micheline Piquette-Miller
    Biochemical and Biophysical Research Communications, Feb 16;353(3):679-85, 2007

    Endotoxin-induced inflammation alters the hepatic expression of the drug efflux transporter genes mdr1b (Abcb1b) and mrp3 (Abcc3) in rats. In this study, we identified a novel kruppel-like zinc finger protein 6 (KLF6) cis-element on the rat mdr1b promoter which is important for basal activity and IL-1beta and endotoxin-mediated induction in gene transcription. Interestingly, KLF6 also functioned as a negative transcriptional regulator, inhibiting TNF-alpha-mediated induction of mdr1b. Furthermore, novel CCAAT/enhancer binding protein beta (C/EBPbeta) and heat shock factor 4 (HSF4) transcription binding sites were identified on the rat mrp3 promoter. Deletion of the HSF4 element significantly increased transcriptional activity of the mrp3 gene when exposed to TNF-alpha. Endotoxin treatment significantly affected transcriptional activity only in C/EBPbeta and HSF4 double deletion mrp3 promoter constructs. In summary, KLF6 and HSF4 are stimuli-specific regulatory elements which may be important in the control of the rat mdr1b and mrp3 genes during health and disease.

  • Impact of intraperitoneal, sustained delivery of paclitaxel on the expression of P-glycoprotein in ovarian tumors
    Emmanuel A. Ho, Patrick Lim Soo, Christine Allen, Micheline Piquette-Miller
    Journal of Controlled Release, Jan 22;117(1):20-7, 2007

    Recently, we developed a novel implantable drug delivery system which can provide sustained intraperitoneal (i.p.) delivery of paclitaxel (PTX). As the impact of local sustained delivery on the development of multidrug resistance (MDR) is unknown, the objective of this study was to determine the impact of this drug delivery system on the in vivo expression of MDR1/P-glycoprotein (PGP) in a human ovarian xenograft tumor model. As compared to controls, intermittent i.p. dosing with PTX formulated in Cremophor EL (PTX(CrEL)) induced a two-fold increase in mRNA levels of MDR1 after a 14-day dosing period. On the other hand, sustained i.p. delivery of PTX with the implant system (PTX(film)) did not significantly affect MDR1 expression. Immunodetection of PGP in isolated xenografts supported the mRNA data. Histological analysis by H&E staining demonstrated a dose-dependent increase in tumor necrosis in the PTX(film) treated animals. Further, in vitro studies in human ovarian carcinoma cells also demonstrated a significant induction in the efflux activity of PGP with intermittent dosing schedules to PTX(CrEL) whereas this was not seen in cells dosed with PTX(film). Our findings suggest that sustained i.p. administration with PTX(film) attenuates development of MDR, suggesting that sustained, localized delivery of chemotherapeutic agents may improve current treatment strategies for ovarian cancer.

  • In vivo disposition and stability of DNA frayed wires in mice
    Maximum F. Yanze, Emmanuel A. Ho, Robert B. Macgregor, Micheline Piquette-Miller
    International Journal of Biological Macromolecules, Nov 15;39(4-5):310-6, 2006

    DNA frayed wires (DNA(FW)) are an alternate form of DNA organization formed by the self-association of several strands of guanine-rich oligonucleotides. The purpose of this study was to define for the first time the blood clearance kinetics, tissue distribution, and stability of DNA(FW) in vivo in mice. Single bolus doses (1200 pmol/mouse) of (32)P-DNA(FW) and (32)P-random DNA were administered intravenously (IV) and intraperitoneally (IP) followed by scheduled blood, urine, fecal and tissue samplings. Blood clearance kinetics was described well by a first order two-compartment open model. The overall half-lives of elimination from the central compartment (T(1/2))(K10) were 3.57+/-0.1h for IV and 2.38+/-0.11 h for IP. In contrast, random DNA was completely degraded after 15 min regardless of the route of administration. Tissue distribution results demonstrated that DNA(FW) were primarily distributed and retained in the liver, intestines, kidneys, and heart. Low levels could also be detected in brain. Autoradiographs of blood, tissues, feces and urine extracts established that DNA(FW) remained intact after administration as no measurable levels of metabolites or degradation products were found after 24h. (32)P-DNA(FW) was primarily eliminated via hepato-biliary excretion into feces after either IV or IP administration (51.8+/-4.53% and 36.2+/-3.4%, respectively). The improved stability and longer half-life of DNA(FW), previously shown in vitro, is also seen in vivo, indicating that DNA(FW) may provide a stable delivery system for DNA gene therapies. In conclusion, this is the first study demonstrating the in vivo stability, pharmacokinetics, and disposition of DNA superstructures.

  • Regulation of multidrug resistance by pro-inflammatory cytokines
    Emmanuel A. Ho and Micheline Piquette-Miller
    Current Cancer Drug Targets, Jun;6(4):295-311, 2006

    Various mechanisms have been implicated in the development of resistance of cancer cells to chemotherapy. Multidrug resistance (MDR) is a phenomenon in which cancer cells are resistant to the cytotoxic effects of various structurally and mechanistically unrelated chemotherapeutic agents. One major mechanism by which this occurs is through the over-expression of ATP-dependent drug efflux transporters such as the P-glycoprotein (PGP) and multidrug resistance-associated protein (MRP). Regulation of MDR can occur at many levels including transcriptional, mRNA, protein and post-translational. In recent years it has been demonstrated that alterations in the expression and activity of the MDR transporters are seen in numerous tissues during an inflammatory response. An acute inflammatory response is associated with many conditions including infection, injury, hypoxia and stress and is known to result in the induction of several pro-inflammatory cytokines. Whether the function of cytokines can be harnessed in overcoming drug resistance of tumors has yet to be examined and explored. In this review, we will focus on the various studies investigating the regulation of MDR during an inflammatory response, in particular by cytokines. The mediators and pathways involved as well as the possible mechanisms of MDR regulation will be discussed. It is hoped that by understanding the clinical importance of inflammatory mediators in MDR, new doors will open and future insights will lead to the development of novel immunotherapeutics for the treatment of cancer.

  • In vitro and in vivo characterization of a novel biocompatible polymer-lipid implant system for the sustained delivery of paclitaxel
    Emmanuel A. Ho, Vessela Vassileva, Christine Allen, Micheline Piquette-Miller
    Journal of Controlled Release, May 5;104(1):181-91, 2005

    Recently, a novel chitosan-based implantable formulation (chitosan-ePC) was developed to provide controlled, local release of paclitaxel (PTX) for the treatment of ovarian tumors. Hence, the objective of this study was to evaluate this delivery system in vitro in human ovarian SKOV-3 cells and in vivo in mice with intraperitoneal implants of drug-free or 14C-PTX-chitosan-ePC films. In vitro, 14C-PTX-chitosan-ePC implants (10 mg) provided zero-order constant release of 0.92+/-0.03 pg/day PTX over 5 days. Released PTX retained dose-dependent activity; effectively inhibiting SKOV-3 proliferation with an ED50 of 211 ng/ml of released PTX. Drug-free implants did not affect cell viability or cell morphology of SKOV-3 cells. A sustained, zero-order release of PTX was also seen in vivo over a 2 week period in mice implanted with 14C-PTX-chitosan-ePC films. Correlations between the in vitro and in vivo release of PTX was highly significant (R2 = 0.975). After 2-4 weeks, mice with chitosan-ePC implants did not demonstrate any signs of encapsulation, inflammation or infection. Overall, our in vitro and in vivo results demonstrated zero-order drug release and biocompatibility of the novel chitosan-ePC film. This indicates potential usefulness of chitosan-ePC implants in the sustained and local delivery of anti-neoplastic agents.