Download Localized Tumor Delivery of Radiosensitizers and Chemotherapeutics Using ‘INCeRT’ Implants

Graduate
Interdisciplinary Topics
PhD in Bioengineering
Abstract ID# 230
Localized Tumor Delivery of Radiosensitizers and Chemotherapeutics Using ‘INCeRT’ Implants
Jodi Belz1, Stacey Markovic2, Rajiv Kumar1,3, Mark Neidre2, Robert Cormack3, Mike Makrigiorgos3, Srinivas Sridhar1,3
of Radiation Oncology, Dana Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
IN VIVO THERAPEUTIC EFFICACY OF DTX SPACERS
INNOVATION AND ADVANTAGES
CHARACTERIZATION OF INCeRT SPACERS
1
3
Harvested Tumors
Comparison of systemic IV injected DTX verses localized release of DTX INCeRT
Spacer injected Intraturmorally (IT) in PC3 Subcutaneous Tumors grown on hind leg
of Male Nude Mice.
Tumor Volume (mm^3)
1200
Fluorescence Intensity(CPS)
ORM E1
Gauss Fit
Intensity (a.u.)
60
40
20
0
100
150
200
250
300
350
400
ORM
ORM
ORM
ORM
ORM
1.0
TEM of Silica NPs
09
08
07
06
05
0.0
750
800
850

900
Wavelength (nm)
DLS Of Silica NPs
Optical signature of Si NPs
IN VIVO DIFFUSION STUDIES BY OPTICAL IMAGING
IN VIVO DIFFUSION STUDY DESIGN
(Fluorescent Image-Dark Count)/Exposure Time

(Intrinsic Image-Dark Count)/Exposure Time
1800
1600
8000
1400
7000
1200
6000
1000
5000
800
4000
600
400
200
Normalized Image
3000
2000

1000
0
0.35
0.3
Fluorescence image
Spacer Area Comparisons

0.2
0.15
0.1
0.05
10
Normalized Image Overlaid on White Light Image
9
8
Area (mm2)
7
A DUAL RELEASE PLATFORM
6
200
5
10
Time (Days)
Control 2
Control 4
15
R²= 0.3879
0
Free DTX 1
Free DTX 3
10
Time (Days)
Free DTX 2
Free DTX: IV injection
1000
800
R²= 0.951
600
400
R²= 0.9069
200
0
0
2
4
6
8
10 12 14 16
Time (Days)
DTX Spacer 1
DTX Spacer 3
DTX Spacer 2
DTX spacers

CONCLUSIONS
Developed a nanoparticle-based platform for combined local chemo-radiation
therapy.
Fabricated INCeRT spacers with biocompatible and biodegradable polymer, PLGA
impregnated with varying sized nanoparticles encapsulating imaging probe (Cy 7.5)
and chemotherapeutic drug, docetaxel. We have also fabricated PLGA spacers
impregnated with high Z (atomic number) gold nanoparticles (Hi-Z-CuRE) for
effectively boosting the radiation dose locally.
In-vivo optical imaging demonstrates that the INCeRT spacer has a size dependent
release profile of Silica NPs.
In-vivo measurements demonstrate that NP remain resident in the vicinity of the
implanted eluting spacers with accumulation over times appropriate to improve
brachytherapy’s therapeutic ratio.
In-vivo DTX spacers were shown to inhibit growth and shrink the tumor for a
number of days as the drug was released intratumorally with minimal visible
adverse effects to the mice. The spacers were most effective in smaller tumors,
where the size of the tumor shrank at the time of sacrifice.
4
REFERENCES
3
Free Dye Spacers
30 nm NP Spacers
200 nm NP Spacers
1
0
0
Commercial Spacers
R²= 0.9297
R²= 0.5076
R²= 0.8078
1200
5
2
PLGA Spacer with Encapsulated Silica
nanoparticles with drug/dye
R²= 0.8424
R²= 0.8152
1400
DTX Dose: single intravenous injection of ~12mg/kg body weight
DTX spacer: 2 spacers 3mm long with total DTX ~12mg/kg body weight
11
Release of Silica NPs
from spacer
400
800
700
600
500
400
300
200
100
0
0.5
Size (nm)
Transmission image
INCeRT-2
Conjugated
system
600
Control : No spacers
0.25
INCeRT-1
Encapsulated
system
R²= 0.6832
Control 1
Control 3
NPs impression in flash frozen
fractured sample
80
Release of drug/dye
from NPs
800
0
100
INCeRT SPACERS DESIGN
R²= 0.9628
1000
0
SEM images of the Spacers
BIOLOGICAL IN SITU IMAGE GUIDED RADIOTHERAPY
 Biologic in-situ image guided radiation therapy (BISIGRT)1,2,3,4 offers the potential to deliver planned,
localized and sustained delivery of chemotherapy
agent, without systemic toxicities, as part of routine
minimally invasive image guided radiation therapy
procedures
 This new approach for localized chemoradiation
therapy, involves fabrication of spacers routinely
used during prostate brachytherapy with
radiosensitizing drugs/dyes. Cormack, et. al.,
IJROBP, v.76, 615 (2010 )
 These Implantable Nanoplatforms for
Chemoradiation Therapy (INCeRT) utilizes the
nanoparticles properties of sustained drug release
along with one or more imaging modality.
1. IT DTX Spacer Injection
2. IV DTX Injection
3. No treatment
2
Tumor Volume (mm^3)
 Localized sustained delivery of chemotherapeutic drug vs. intermittent systemic administration
 INCeRT provides means of image guided chemoradiation therapy by estimating the drug distribution
produced by optical imaging.
 Tailored release profiles of the encapsulated drug to achieve radiosensitization synchronized with the
radioactive decay rate for different sources such as Cs-131, Pd-103 and I-125.
 Minimal additional inconvenience to the patient (uses current implant needles and procedures).
 The synergistic effect of radiosensitization and radiation therapy could lead to reduced radiation doses
and improved survival.
Top view
ABSTRACT
Systemic chemotherapy is often used with radiation therapy in the management of
prostate cancer, but leads to severe systemic toxicities. We have introduced the
fabrication of an Implantable Nanoplatform for Chemo-radiation Therapy (INCeRT)
spacer that offers the potential to deliver planned, localized and sustained delivery of
chemotherapy and imaging agent. This new modality of chemotherapy would be
delivered as part of a routine minimally invasive image guided radiation therapy
procedure in brachytherapy. Such image guided chemoradiation therapy replaces
currently used inert spacers with no therapeutic impact, with drug eluting spacers that
provide the same spatial benefit with the added localized chemotherapeutic. This new
therapeutic modality requires characterization of the drug distribution produced by
implantable drug eluters. This work presents imaging based means to measure and
compare temporal and spatial properties of diffusion distributions around spacers loaded
with multi-sized dye-doped nanoparticles or spacers loaded with free dye. The optimized
spacer was loaded with chemotherapeutics and inserted intratumorally for efficacy of the
localized chemotherapy versus the standard systemic dosing. The in vivo chemotherapy
measurements demonstrate that local chemotherapy is not only feasible, but as effective
as current treatment options. This new localized chemo-treatment shows great potential
in increased tumor reduction with overall decreased systemic toxicity.
3Department
Tumor Volume (mm^3)
Nanomedicine Science and Technology Center,2 ECE Department, Northeastern University, Boston, MA 02115
Lateral view
1
2
4
6
8
Time (days)
10
12
14
Size dependent diffusion profile
16
Comparison between dye doped (left) and NPs
doped spacers (right)
1.
2.
3.
4.
Cormack, R.A., Sridhar, S., Suh, W.W., et al Int J Radiat Oncol Biol Phys 76:615-23, 2010.;
Nagesha, D.K., Tada, D.B., Stambaugh, C.K., et al Phys Med Biol, 55:6039-52, 2010.
Tada, D.B., Singh, S., Nagesha, D., et al Pharm Res, 27:1738-45, 2010.
Cormack, RA, Nguyen P, D’Amico AV, et al Proc. SPIE, V.7964, P.79640A Orlando 2011.
Supported by IGERT grant NSF-DGE- 0965843 and ARMY/ W81XWH-12-1-0154. and by Brigham and Women’s Hospital.