This document discusses ThermoDox, a liposomal formulation of doxorubicin designed for image-guided drug delivery in combination with localized hyperthermia. ThermoDox utilizes lyso-thermosensitive liposomal (LTSL) technology to encapsulate doxorubicin and selectively release it at temperatures slightly above normal body temperature. When combined with radiofrequency ablation, localized heating from RFA triggers the release of doxorubicin from ThermoDox at the tumor site, allowing for higher concentrations with less systemic toxicity compared to free doxorubicin. A phase III clinical trial evaluated ThermoDox in combination with RFA for the treatment of hepatocellular carcinoma and found improved overall survival compared to RFA alone.

1. Presented By-
Sujeet Singh
M.S.(Pharm)-Pharmaceutics
Semester-II
NK20MSPM697
Niper Kolkata
Guided By-
Dr. Victor Hmingthansanga
Dr. Pallabh Datta

2.  Introduction
 Target drug delivery
 Basic approach of ThermoDox
 Mode of action for ThermoDox
 Synergistic effects
 RFA
 USFDA status on ThermoDox
 Heat study
 Advantage
 application

3.  ThermoDox is a liposomal encapsulation of
doxorubicin .
 In 1978, Yatvin described the first temperature
sensitive formulation (thermosensitive liposome,
TSL)
 TSL was able to release a hydrophilic drug when the
temperature was increased a few degrees above
physiological temperature.
 LTSL was the first TSL formulation suitable for use in
the intravascular drug release approach.
 Thermodox based on LTSL (lyso-thermosensitive
liposomal) technology.
 Basically LTSL used to encapsulate doxorubicin, a
proven and mostly used cancer drugs.
 LTSL is designed for image guided drug delivery
tested in large multicenter phase III trial.

4. Cont.
 Lysolipid thermosensitive liposomes described by
Needham in 2000 was the breakthrough in
development of TSL formulation.
 The LTSL formulation was originally composed
of DPPC/Lyso-PC/DSPE-PEG2000 in 90:10:4
(mol/mol).
 The surfactant Lyso-PC mediates drug release.
 The release rate of doxorubicin from LTSL at
41.30C was 80% in 20 seconds.

6.  Drug targeting as the ability of the drug to
accumulate in the organ or tissue selectively
and quantitatively independent of the site and
methods of its administration.
1. Drug instability
2. Low absorption
3. Short half life
4. Large volume of distribution
5. Low specificity
6. Low therapeutic index

7. 1. Active targeting
2. Passive targeting
3. Inverse targeting
4. Dual targeting
5. Combination targeting
6. Ligand mediating targeting
 The Active targeting is achieved by
conjugating a specific ligand for the over
expressed receptor on the tumor surface or by
simple absorption process.

8.  Passive drug targeting is the spontaneous drug
accumulation in the areas with leaky
vasculature or Enhanced permeability and
retention –EPR effects.
 Liposomes can target cancer tissues by both
passive and active strategies.
 Liposomes are spherical structure made of a
hydrophilic core surrounded by phospholipid
bilayer.
 The size of liposomes can be in the range of
25nm-2.5µm.

9.  The concept of enhanced the local release of drug
by hyperthermia using thermally sensitive
liposomal carriers was introduced nearly four
decades ago.
 There are Five mechanism for enhancing drug
delivery-
a) Promotion of thermal drug release at temperature
near the lipid bilayer phase transition.
b) Increased perfusion of the target area
c) Increased capillary uptake of particles
d) Increase susceptibility of the cell to the drug
e) Increased endocytosis

10.  ThermoDox delivered by IV infusion.
 Local tissue concentration is 10 times that of
standard free doxorubicin.
 In the heat study, ThermoDox administered via IV
route in combination with RFA.
 Localized mild hyperthermia (39.5-420C) created
by RFA , releases the entrapped doxorubicin from
its liposomes.
 This technology enabling the release of high
concentration of doxorubicin to be deposited at
the targeted tumor.

12.  the FDA has granted fast track designation for the
corporation 600 patient under phase III
clinical trial (heat study) of ThermoDox
in combination with RFA.
 ThermoDox is a heat activated doxorubicin, an
anthracycline compound approved for the
treatment of wide range of cancers including
breast cancers.
 The main purpose of this study to evaluate the
efficacy of ThermoDox and RFA in comparison to
RFA alone.

13.  Cytotoxic effect enhanced by heat (doxorubicin
binding to tumor DNA)
 Reduction of ablation threshold temperature-
enhanced lesion size
 ThermoDox is designed to be used in combination
with heat-based treatments, such as
1. Radiofrequency thermal ablation (RFA),
2. Microwave hyperthermia,
3. High-intensity focused ultrasound (HIFU).

14.  RFA is a locoregional thermal therapy and is
clinically used to treat unresectable tumors of the
livers, as well as for other organs like lung,
kidney and bone
 RFA is used for the local treatment of cancer.
 RFA is effective only for small< 3cm tumors.
 Tumors >3cm, having tendency to leave viable
cells in the margins ablation zone.
 This increases the possibility of incomplete
ablation or local recurrence.

16.  USFDA confirmed that it has met the requirement
for non clinical studies for its NDA of the
ThermoDox.
 The FDA has provided written guidance that
company is not required to conduct any
additional-
Non clinical pharmacology
Safety pharmacology
General toxicological studies
 Current preclinical studies are adequate and
sufficient.

17. 1. Hyperthermia has some effects alone, with drug
and in enhancing liposomal extravasations.
2. New concept of rapid triggered release, leads to
an increased therapeutic effects.
3. Deliver 10 times more doxorubicin into tumors
4. An overall survival rate of over 50% with
primary liver cancer.
5. Well tolerated with no unexpected adverse event
6. Greatest benefits in patients with had RFA>45
minutes.

18. 7. Deliver drugs in-
High concentration
Precisely where needed
Minimizing systemic toxicity
Maximizing therapeutic effect
8. Higher cancer cytotoxicity
9. Direct toxicity to tumor vasulature

19.  A first line treatment for primary liver
cancer.
 RCW(Recurrent chest wall) breast
cancer
 Bladder Cancers

20.  TSL are a promising tool for external targeting of drugs to
solid tumors in combination with local hyperthermia.
 Several formulation have been developed, with one
currently under clinical trial.
 MRI guided drug delivery adds the possibilities of online
monitoring of heating focus, calculating locally released
drug concentration and externally controlling drug release
by steering the heating focus and power.
 The combination of external targeting with TSL and MRI
guided drug delivery will be the unique characteristics of
this nanotechnology approach in medicine.

21. References
 https://doi.org/10.1016/S0928-0987(00)00166-4
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4
172103/#!po=0.781250
 https://celsion.com/thermodox/
 https://www.proactiveinvestors.com/companies/ne
ws/74107/us-fda-confirms-celsions-preclinical-
studies-are-sufficient-to-support-nda-for-liver-
cancer-drug-8891.html.
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4
172103/.

22. End
Thermodox
-Sujeet Singh