Page 24 - ASME_NEMB_2016_Program

Technical Program TRACK 2

provide a wealth of opportunity to provide more conformal and tumor specif- John Perry, Stowers Institute for Medical Research, Kansas City,
ic targeted approaches to therapy. MO, United States, Laura González-Fajardo, Lalit Mahajan,
Dennis Ndaya, Derek Hargrove, Rajeswari M. Kasi, University of
MRI is a unique modality for providing guidance of these rapid, high-tem- Connecticut, Storrs, CT, United States, Linheng Li, Stowers Institute
perature approaches to laser ablation owing to its inherent temperature sen- for Medical Research, Kansas City, MO, United States, Xiuling Lu,
sitivity integrated with exquisite soft tissue anatomy and functional imaging
capabilities making it useful for planning, targeting, monitoring and verifying University of Connecticut, Storrs, CT, United States
therapy delivery in a “closed-loop” fashion. MR temperature imaging data
can be integrated with physical models of bioheat transfer and biological Chemoresistance and recurrence of tumors remain among the primary
models of tissue damage so that it can play a significant role in increasing challenges in developing effective cancer treatments. While high-dose
the safety and efficacy of these rapid ablation procedures by offering a chemotherapy, which is the hallmark of current therapeutic strategies, can
mechanism monitor and control both high tissue temperatures at the probe sometimes be effective in eliminating the majority of cancer cells, it often
interface and nearby critical structures, as well as aid in prediction of lesion fails to eliminate cancer stem cells (CSCs), a subset of cells that are fre-
development, particle activation or drug delivery. quently resistant to standard chemotherapy. In addition, high-dose chemo-
therapy frequently causes severe side effects and leads to the evolution of
Here we provide an overview of MRI guidance of laser ablation procedures resistant clones with subsequent relapse and rapid disease progression. We
with examples provided in brain, prostate, liver and bone as well as a brief previously reported the development of an amphiphilic brush-like block co-
discussion of some of the current challenges associated with application of polymer composed of polynorbonene-cholesterol/polyethylene glycol that
this technique in various anatomical locations as well as the potentially com- self-assembles in aqueous media to form long circulating nanostructures
plimentary role of high performance computing and simulation may have capable of encapsulating doxorubicin (DOX-NPs). In this study, we assessed
on planning, monitoring and verification when this unique image-feedback the efficacy and toxicity of that nanoparticle formulation in tumor-bearing
modality is incorporated into treatment. mouse models and compared its effects with the non-encapsulated form
(free DOX) and the commercial liposomal doxorubicin Doxil®.

DOX-NPs at a dose of 5 mg/kg significantly reduced the growth of subcuta-
TUESDAY, FEBRUARY, 23 neous tumors after treating severe combined immunodeficiency (SCID) mice
bearing subcutaneous human lung A549 cancer once per week up to 8
weeks without any observed side effects. On the contrary, significant weight
2-3 loss, early toxic cardiomyopathy, acute toxic hepatopathy and reduced he-
CANCER NANOMEDICINE matopoiesis were prevalent in mice treated with free DOX at a dose of 1 mg/
kg, although it showed comparable tumor inhibition to DOX-NPs.
Bexar/Travis 9:30am - 11:00am In a leukemia mouse model, we developed a new treatment strategy to
combine DOX at a lower dose with a conventional chemotherapeutic drug
Nelarabine. Leukemic mice were treated with 5 daily injections of free DOX
Session Organizer: Chris Jewell, University of Maryland, College at 0.5 or 0.15 mg/kg with and without Nelarabine. Alternatively, a single in-
Park, MD, United States jection on day 1 of 0.8 or 2.5 mg/kg of DOX-NPs, or Doxil® was administered
with and without Nelarabine. At 10 days post-treatment, bone marrow was
9:30am Chemophototherapy Using Long-Circulating Lipo- analyzed by flow cytometry to determine frequency of leukemic stem cells
somes Conferred with Light-Triggered Cargo Release (LSCs) and normal hematopoietic stem and progenitor cells (HSPC). While
cytotoxic chemotherapy induced LSC expansion, low-dose doxorubicin
administered daily for five days prevented this expansion and even facili-
Keynote. NEMB2016-6155 tated recovery of HSPCs. DOX-NPs allowed for further reduction of LSCs
compared to free doxorubicin and effectively eliminated this population.
Jonathan Lovell, University at Buffalo, Buffalo, NY, United States This effect was obtained through only a single low-dose injection at 0.8 mg/
kg. Doxil® was not as effective at preventing the LSC expansion induced by
Stealth liposomes can be used to extend the blood circulation time of en- chemotherapy or at facilitating HSPC recovery as DOX-NPs.
capsulated therapeutics. Inclusion of 2 mol% porphyrin-phospholipid (PoP)
imparted optimal near infrared (NIR) light-triggered release of doxorubicin It was identified that DOX can target LSCs via inhibition of Akt and β-catenin
(Dox) from conventional sterically stabilized stealth liposomes. The type driven self-renewal. Low but effective doses of DOX offer a new opportunity
and amount of PoP affected drug loading, serum stability and drug release to target drug-resistant CSCs while reducing systemic toxicity. DOX-NPs
induced by NIR light. Cholesterol and PEGylation were required for Dox exhibited slow but steady release of DOX from NPs which provides an op-
loading, but slowed light-triggered release. Dox in stealth PoP liposomes timal sustainable drug concentration for LSC inhibition. Using precisely de-
had a long circulation half-life in mice of 21.9 h and was stable in storage for signed copolymer nanoparticles to target tumorigenic cells discretely from
months. Following intravenous injection and NIR irradiation, Dox deposition their bulk progeny and preferentially over normal stem/progenitor cells will
increased ~7 fold in treated subcutaneous human pancreatic xenografts. substantially improve patient outcomes, reduce relapse, and provide a new
Phototreatment induced mild tumor heating and complex tumor hemody- paradigm for effective and safe cancer treatment.
namics. A single chemophototherapy treatment with Dox-loaded stealth
PoP liposomes (at 5-7 mg/kg Dox) eradicated tumors while corresponding 10:20am A combined chemical and magneto-mechanical induc-
chemo- or photodynamic therapies were ineffective. A low dose 3 mg/kg tion of cancer cell death by the use of functionalized magnetic
Dox phototreatment with stealth PoP liposomes was more effective than a
maximum tolerated dose of free (7 mg/kg) or conventional long-circulating iron nanowires
liposomal Dox (21 mg/kg). To our knowledge, Dox-loaded stealth PoP lipo-
somes represent the first reported long-circulating nanoparticle capable of Technical Presentation. NEMB2016-5968
light-triggered drug release.
Aldo I. Martinez Banderas, King Abdullah University of Science
10:00am Inhibiting Chemoresistant Cancer Stem Cells and Im- and Technology, Thuwal Jeddah, Jeddah,Saudi Arabia, Antonio
proving the Safety Profile of Chemotherapy through Nanoparti- Aires, Instituto Madrileno de Estudios Avanzados Nanociencia,
24 cle-Mediated Drug Delivery Madrid, Madrid,Spain, Jose Perez, Nouf Alsharif, King Abdullah
University of Science & Technology, Thuwal, Makkah,Saudi Arabia,
Technical Presentation. NEMB2016-5975 Francisco Teran, Jael Fernandez Canderas, Instituto Madrileno