noel treatment strategies for cancer treatment.

1. Novel formulations in the
treatment of Breast Cancer
DR.DAMODARA KUMARAN.P

2. Breast Cancer: Global incidence & mortality
• 2nd most common
cancer
• 5th leading cancer
contributing cancer
deaths
Globocan 2018

3. Treatment modalities
• Surgery
• Radiation therapy
• Chemotherapy
• Hormone therapy
• Targeted therapy
• Supportive therapy
Chemotherapy
• Taxanes Eg: Paclitaxel, docetaxel
• Anthracyclines Eg: Doxorubicin, Epirubicin
• Vinca alkaloid Eg: Vinorelbine
• Fluorouracil Eg: 5-flourouracil, gemcitabine
Hormone therapy:
• Estrogen receptors blockers: Tamoxifen, Raloxifen
• Estrogen receptor destructors (ERDs) Eg:
fulvestrant
• Aromatase inhibitors Eg: Anastrozole, letrozole
and exemestane
Targeted therapy
• Trastuzumab
• Pertuzumab
• Ado-trastuzumab emtansine (T-DM1)
• Everolimus
• Lapatinib

4. Breast Cancer: General Treatment Choice

5. Breast Cancer: General Treatment Choice

6. Breast Cancer: General Treatment Choice
Preferred Breast Cancer Adjuvant Systemic Therapy

7. Molecular subtypes of breast cancer and their current
standard drug therapy
Wu D et al. Int J Nanomedicine. 2017;12:5879-5892.

8. Challenges limiting drug therapy
Category 1:
Related to suboptimal biodistribution of the drug in body, that is, too little drug in
tumor tissues (so, suboptimal efficacy) and too much in healthy tissues (so, high
toxicity).
Category 2:
Related to the poor response to the drug even though it reaches the tumor
Category 3:
Related to the inherent properties of the drug or drug combination itself
Wu D et al. Int J Nanomedicine. 2017;12:5879-5892.

9. Key Challenges and solutions provided by
nanomedicines
Category 1
Sr. No Challenges to breast cancer drug therapy How nanomedicine can help
1 Insufficient specificity for breast cancer Passive targeting and active targeting by
nanomedicine to increase tumor drug level
and decrease noncancer drug levels
2 Inefficient access of drugs to metastatic sites
such as brain and bone
Many nanomedicine formulations inherently
may improve brain and bone penetration
3 Undesirable pharmacokinetics such as quick
clearance and short half-life
Use of strategies such as PEGlyation to
extend the circulation time
4 Dose-limiting toxicity of the anticancer drugs
or the excipients, for
example, surfactants and organic co-solvents
Increased tumor specificity as above;
controlled drug release from nanocarrier;
solvent-, surfactant-free nanoformulation
Wu D et al. Int J Nanomedicine. 2017;12:5879-5892.

10. Key Challenges and solutions provided by
nanomedicines
Category 2
Sr. No Challenges to breast cancer drug therapy How nanomedicine can help
1 Drug resistance at cellular level, for example,
increased drug efflux transport
Passive and active targeting both may enhance
endocytosis; some nanoformulations may
inhibit drug efflux mechanisms; co-delivery of
agents that target drug resistance mechanism.
2 Drug resistance at tumor microenvironment
level, for example, lower pH, hypoxia, cancer
microenvironment crosstalk and so on
Targeting tumor microenvironment; use of
stimulus-responsive nanoformulations such as
pH-responsive devices
3 Difficulty in eradicating cancer stem cells Targeting cancer stem cells
Wu D et al. Int J Nanomedicine. 2017;12:5879-5892.

11. Key Challenges and solutions provided by
nanomedicines
Category 3
Sr. No Challenges to breast cancer drug therapy How nanomedicine can help
1 Undesirable pharmaceutical properties of the
drugs, for example, low aqueous solubility,
poor in vivo stability
Many nanocarriers can achieve drug
solubilization and can protect unstable drugs
2 Suboptimal dosing schedule and sequence,
especially when combinations of multiple
drugs are involved
Careful optimization of dosing schedule and
sequence; use of nanocarrier to co-deliver
multiple drugs
Wu D et al. Int J Nanomedicine. 2017;12:5879-5892.

12. Nanomedicine: novel formulations
• Nanomedicine is one of these promising new therapeutic options
• Refers to biomedical application of materials with at least one dimension below
100 nm, although devices of 100–200 nm are often considered nanomedicine in
practice
• Examples: liposomes, nanoparticles, micelles, dendrimers, nanotubes etc.
• Made up of diverse materials including lipids, phospholipids, polymers, proteins,
inorganic materials and a combination of them.
Wu D et al. Int J Nanomedicine. 2017;12:5879-5892.

13. Novel formulation with nanomedicine
• Extremely large surface area-to-volume ratio of nanocarriers provides an
opportunity to manipulate their surface properties for improved treatment, for
example, cancer targeting, extended circulation, increased endocytosis and
transcytosis, in order to gain more efficient access into tumor sites, metastatic
sites and cancer cells.
• Moreover, by entrapping in or binding onto nanocarriers, the therapeutic agents
can also gain better stability, increased solubility and controlled release kinetics.
• Widely use for breast cancer: Liposomal Doxorubicin and Nanoparticle paclitaxel
Wu D et al. Int J Nanomedicine. 2017;12:5879-5892.

14. Paclitaxel
• Paclitaxel which is a member of the taxane family is one of the most useful and
effective antineoplastic agents.
• Paclitaxel : Broad spectrum of anti-tumour activity, effectiveness on both solid
and disseminated tumours, unique mechanism of action
• Crucial role in treatment of ovarian cancer, breast cancer, NSCLC
Bernabeu E et al. Int J Pharm. 2017;526(1–2):474–495

15. Limitations of Conventional, Solvent-based Taxane
Therapy
• Paclitaxel has poor aqueous solubility
• Paclitaxel in clinical use is formulated vehicle composed of polyoxyethylated
castor oil (Cremophor) and dehydrated alcohol to enhance drug solubility
• Cremophor is not inert and adds to the toxic effects of paclitaxel
Ranade AA et al. Asia Pac J Clin Oncol. 2013 Jun; 9(2):176-81.

16. Problems with Cremophor based Formulations
• Hypersensitivity reactions – Occur in some patients despite use of pre-
medications (1)
• Cremophor associated with hyperlipidemia, abnormal lipoprotein patterns and
aggregation of erthrocytes (1)
• Requires special non-di-2 ethylhexyl phthalate (DEHP) tubing and in line filters for
infusion (1)
• Cremophor can cause neurotoxixity, respiratory difficulties and vasodilatation (2)
• Alters the pharmacokinetic profile of the drug which results in reduction in
plasma clearance of paclitaxel (2)
1 Ranade AA et al. Asia Pac J Clin Oncol. 2013 Jun; 9(2):176-81.
2 Bernabeu E et al. Int J Pharm. 2017;526(1–2):474–495

17. Cremophor Entraps Paclitaxel in Micelles
in the Plasma Compartment
Sparreboom A et al. Cancer Research, 1999;59:1454–1457.
van Tellingen O et al: British Journal of Cancer, 1999; 81:330-35.
Control plasma Plasma + Taxol
Cremophor
Micelle
 Paclitaxel is entrapped in hydrophobic interior of Cremophor micelles
 This diminishes free fraction of paclitaxel and makes less drug available for distribution to tumor

18. Nanotechnological Platforms for Paclitaxel Delivery
• Liposomes
• Albumin Bound Paclitaxel
• Polymer –drug-conjugates
• Polymeric Micelles – Nanoparticle Paclitaxel

19. Enhanced Permeability and Retention (EPR) Effect
AM Jhaveri and VP Torchlin . Front. Pharmacol., 25 April 2014

20. Nanoparticle Paclitaxel
• Cremophor free formulation of paclitaxel
• Average size of nanoparticles less than 100 nm
• Approved for treatment of metastatic breast cancer, ovarian cancer, NSLC and AIDS related
Kaposi’s sarcoma.
Carrying
Vehicle
• Consists of hydrophobic and hydrophilic regions
• Forms nano-sized micelles when exposed to an
aqueous environment.
• Hydrophobic region serves as reservoir of paclitaxel.

21. Mechanism of drug delivery
Drug delivered in the form of nanomicelles
(average size < 100 nm)
Easily passed through endothelial cells
Reaches tumor surface
The nanomicelles gets endocytosed by tumor cells.
pH dependent release of paclitaxel
(acidic endo-lysosomal compartment)
Increased tubulin stabilization and induction of apoptosis
Death of cancer cells

22. Uptake of Paclitaxel
Madan A et al. Clon. Transl. Oncol. 15, 26–32. doi:http://dx.doi.org/10.1007/ s12094-012-0883-2.
Intaxel: Paclitaxel
Abraxane: Nanoparticle Albumin bound Paclitaxel
Nanoxel: Nanoparticle (Polymeric micelle) Paclitaxel

23. Nanoxel Vs Albumin bound paclitaxel
ABRAXANE NANOXEL
Albumin bound Nanoparticles Nanomicelles using a Polymeric carrier
Nanoparticles size: 130 nm Nanomicelles size: < 100 nm
Approved dosage: 260 mg/m2 over 30
mins infusion q 3 wks
Approved dosage: 220 mg/m2 over 1
hr infusion q 3 wks
Response Rate: 33 % Response Rate: 40 %
Neutropenia (All Grades): 80 % Neutropenia (All Grades): 39.4 %
Neuropathy (Any Symptoms): 71% Neuropathy (Any Symptoms):51.5%
Anemia (All Grades): 33% Anemia (All Grades): 13.6 %
Diarrhea (All Grades): 26 % Diarrhea (All Grades): 12.1%

25. Ranade AA et al. Asia Pac J Clin Oncol. 2013 Jun;9(2):176-81.

26. Cremophor-free polymeric nanoparticle formulation of paclitaxel in
women with locally advanced and/or metastatic breast cancer after
failure of anthracycline
N=195 Metastatic Breast Cancer patients randomized to 3 arms
Treatment in each arm was administered once every 3 weeks (1 cycle) for 6 cycles
Design:
Multicenter, Open label, randomized
study
Inclusion criteria:
Anthracycline –failed advanced
recurrent/metastatic breast cancer
patients
ER/PR –ve or ER/PR status unknown
ECOG PS of 1 or 2
Adequate hematologic, renal and
hepatic function
Arm A: Cremophor-paclitaxel 175 mg/m2 as 3
hr infusion with standard medication
Arm B: Nano paclitaxel 300 mg/m2 as 1 hr
infusion without any premedication
Arm C: Nano Paclitaxel 220 mg/m2 as 1 hr
infusion without any premedication
R
A
N
D
O
M
I
Z
E
D
Ranade AA et al. Asia Pac J Clin Oncol. 2013 Jun;9(2):176-81.

27. Cremophor-free polymeric nanoparticle formulation of paclitaxel in
women with locally advanced and/or metastatic breast cancer after
failure of anthracycline
Ranade AA et al. Asia Pac J Clin Oncol. 2013 Jun;9(2):176-81.
Efficacy assessment
Greater response rate and lower progressive disease seen with nano-paclitaxel compared to
conventional paclitaxel.

28. Cremophor-free polymeric nanoparticle formulation of paclitaxel in
women with locally advanced and/or metastatic breast cancer after
failure of anthracycline
Ranade AA et al. Asia Pac J Clin Oncol. 2013 Jun;9(2):176-81.
Safety data:
• Lower incidence of neutropenia (all
grades in the NP 220 arm despite
increased dose compared to CP
• Lower incidence of grade 3
neuropathy in NP 220 arm
• Neuropathy-related discontinuation
was lowest in NP 220 arm

29. Cremophor-free polymeric nanoparticle formulation of paclitaxel in
women with locally advanced and/or metastatic breast cancer after
failure of anthracycline
Ranade AA et al. Asia Pac J Clin Oncol. 2013 Jun;9(2):176-81.
Conclusion:
• Nano-paclitaxel at a dose of 220 mg/m2 is comparable in efficacy and has a
better safety profile than conventional paclitaxel (175 mg/m2)
• It can be safely administered without any pre-medication.

30. Clinical and economic implications of the use of
nanoparticle paclitaxel (Nanoxel) in India
Ranade AA et al. Ann Oncol. 2013 Sep;24 Suppl 5:v6-12.
Using 3-weekly doses: CrEL paclitaxel at 175 mg/m2 and Nanoxel at
300 mg/m2: Cost savings of 9767 Indian rupees

31. • ADR profiles of Nanoxel and conventional paclitaxel appear to be similar from a
statistical viewpoint and events such as myalgia, paresthesia, anorexia, nausea,
vomiting, diarrhea, stomatitis, alopecia, and myelosuppression occur with either
formulation.
• Despite a significantly higher dose, the incidence and severity of many of these
events are comparatively less with Nanoxel, suggesting that Nanoxel may actually
be better tolerated, even in higher doses.
• Myalgia and arthralgia, however, tend to occur more frequently with Nanoxel.
• Lack of hypersensitivity reactions despite skipping prophylactic premedication
suggests that the nanoparticle formulation is probably less allergic.
Brahmachari B, Hazra A, Majumdar A. Indian J Pharmacol. 2011;43(2):126-130.

32. ONCOLOGY LETTERS 16: 3757-3769, 2018

33. Other novel approaches
• Antibody-drug conjugates (ADC) –TDM1
• Aptamers These macromolecules are single stranded DNA or RNA that binds to
proteins and peptides with higher specificity and affinity.
• Intracellular targeted drug delivery – targets DNA
• Its barriers – plasma membrane and nuclear transport

35. GENE THERAPY
• Gene therapy involves the delivery of genetic materials into cancer cells
• A vector is employed as a carrier -VIRAL AND NO VIRAL MODES

37. • Ritonavir and reversal of chemo-resistance

38. Current non-invasive strategies for cancer
treatment
• Ultrasound-mediated treatment :
• potential mechanisms of ultrasound for drug delivery involves three strategies
including thermal effects, cavitation and radiation forces.

39. Magnetic nanoparticles (MNP)
• MNP’s are typically 10 to 100 nm in size
• Chemotherapeutic agents can be incorporated in the polymeric film of MNP or
chemically conjugated to polymer chains via suitable linker.

40. HYPERTHERMIA
• Hyperthermia is another application of superparamagnetic iron oxide
nanoparticles (SPIONs) [263]. MNP can raise local temperature to ~ 41–46 °C
under alternating magnetic field

41. Take home message….
• Breast cancer is most deadly and toughest to treat when metastasis occurs, many
sites are not even easily accessible.
• Designing nano-formulations that can adequately penetrate all of these sites
without causing excessive adverse effects is of critical importance.
• Paclitaxel is a preferred single chemotherapeutic agent for recurrent or MBC
according to NCCN guidelines 2017
• Novel formulations of paclitaxel were developed to eliminate CrEL from the
conventional paclitaxel, and thus reduce the toxicities associated with it.
• Nanoparticle paclitaxel: well tolerated and can safely administered without any
premedication