8/20/2020

1

Nanotechnology

for Radiation Oncology

Tatiana BronichCollege of Pharmacy

Center for Drug Delivery and NanomedicineUniversity of Nebraska Medical Center

2020 Midwest Radiation Oncology SymposiumAugust 22-23, UNMC, Omaha

NANOMEDICINE

Nanotechnology:Nanomaterials

Nanofabrication

Molecular basis of diseaseGenomics, Proteomics

Chemistry, Material Science, Physics, Biology, Pharmaceutical Sciences, Engineering

Integration of nanoscale technologies and medicine can transform how disease is understood, attacked, and possibly prevented.

Therapeutics

Medical Imaging

Biosensors

Vaccines

Regenerative Medicine

Nanomedicine refers to the the use of nanoscale or nanostructured materials in medicine that according to their structure have unique medical effects

8/20/2020

2

Nanotechnology applied to Cancer

deliver versatile payloads with favorable pharmacokinetics

target-specific

trigger-based drug delivery

multiple targeting strategies

passive targeting, active targeting

enhanced specificity and efficacy

enable the use of lower doses

side effects may be minimized, reduced need for toxic drug

solvents and prolonged intravenous infusions

advance early detection and diagnostics

Arsenal of nanomedicine platforms

Adapted from http://www.britishsocietynanomedicine.org/what-is-nanomedicine.html

VirusProteinsDNA

8/20/2020

3

Tunable properties of nanocarriers

metalliclipidic

inorganicpolymeric

size shape

stiffness/elasticityporosity

roughness

small moleculespeptidesantibodyaptamers

chargehydrophobicityfunctionality

Protein corona

Plasma concentration

Biodistribution

Tissue penetration

Cellular internalization

Rational design of nanocarriers for cancer therapy

● be made from a material that is biocompatible, well characterized, and easily functionalized;

● exhibit high differential uptake efficiency in the target cells over normal cells (or tissue);

● be either soluble or colloidal under aqueous conditions for increased effectiveness;

● have an extended circulating half-life, a low rate of aggregation, and a long shelf life.

For effective clinical translation, a nanocarrier should:

8/20/2020

4

Cancer Nanomedicines

16 approved 75 in clinical trials

Data from Acc. Chem. Res. 2019, 52, 2445−2461

PEGylated liposomal doxorubicin

liposomal daunorubicin

liposomal doxorubicin

liposomal paclitaxel

liposomal mifamurtide

liposomal mifamurtide

liposomal vincristine liposomal vincristine sulfate

liposomal cytarabine

liposomal irinotecan

liposomal daunorubicin and

cytarabine

L asparaginase L-asparaginase conjugate

micellar paclitaxel

iron oxide nanoparticles

albumin-bound paclitaxel

micellar paclitaxel

paclitaxel lipid nanoparticles

hafnium oxide nanoparticles

(US 1995)MM, Kaposi”s sarcoma, BC, OC

(Europe 2009)osteogenic sarcoma

(Europe/Canada (2000)BC

(China 2006)BC, NSCLC

(US 1999)solid tumors or leukemia

(US 1996)Kaposi’s sarcoma

(US 2015)advanced pancreatic cancer

(US 2012)leukemia

(US 2017)leukemia

(US 2006)leukemia

(US 2005)BC, NSCLC, pancreatic cancer

(Korea 2016)BC, NSCLC, pancreatic cancer

(Europe 2018)ovarian cancer, peritoneal cancer,

fallopian tube cancer

(Korea 2007)BC, , NSCLC, OC, gastric cancer

(Europe 2011)brain tumors

(Europe 2019)locally-advanced soft tissue sarcoma

Opportunities to improve radiotherapy

• Nanotherapeutics for radiosensitization

• Nanotherapeutics for combined chemoradiotherapy

• Nanoparticles can help tumor delineation for image-guided RT

8/20/2020

5

Improving radiosensitizer delivery through nanomedicine

Wortmanin (Wtmn) effective radiosensitizer

poor solubilitylow stabilityhigh toxicity

PLGA/Wtmn core

Lecithin/PEG-DSPE lipid coating

D ≃ 40 nm

inhibits radiation-induced autophosphorylation of DNA-dependent protein kinase

Karve S., et.al. Proc Natl Acad Sci USA. 2012, 109(21), 8230

s.c. KB cell xenograftsi.v. 0.07 mg/kg Wtmn eq.RT – 6Gy, 3h post injection

pDNA-PKcs immunohistochemistry (24 h post treatment)

HT- 29 xenograftsi.v. 0.07 mg/kg Wtmn eq.25 mg/kg 5-flurouracil (5-FU)RT – 6Gy, 3h post injection

8/20/2020

6

Nanoparticles as radiosensitizers

• crystalline hafnium oxide NPs, NBTXR3 (HfO2, ∼ 50 nm, negative surface charge, aqueous suspension )

• inert by nature and activated by radiation

nanoparticles containing high Z material (where Z is atomic number) with a high electron density (transition metals and their compounds, e.g gold, platinum, hafnium oxide)

• maximizes X-ray absorption in the tumor• non-specific physical cellular destruction and enhancing the intratumoral

immune profile

Clinical trials are ongoing across the EU, USA and Asia for various other indications such as head and neck cancers (NCT01946867, NCT02901483), liver cancer (NCT02721056), rectal cancer (NCT02465593) and prostate cancer (NCT02805894).

NCT03589339 - NBTXR3 activated by radiotherapy in combination with an anti-PD-1 therapy in patients with advanced cancers.

Phase II/III Act.In.Sarc trial in patients with locally advanced soft tissue sarcoma.

A single intratumoral administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery.

The addition of NBTXR3 resulted in a higher pathologic complete response rate.

No additional or new radiation-related adverse events were observed in the NBTXR3 group.

NBTXR3 received European market approval (2019) for STS treatment.

8/20/2020

7

Nanotherapeutics to improve chemoradiation

Nano-camptothecin, an investigational nanoparticle–drug conjugate CRLX101

Cyclodextrin - camptothecin conjugate

Eliasof S, et.al. Proc Natl Acad Sci U S A 2013;110:15127–32.

• Camptothecin is a topo I inhibitors and is a known radiosensitizer

• CRLX101 can also inhibit hypoxia-inducible factor-1 alpha (HIF1α), a signaling molecule that promotes radioresistance in cancer cells

• CRLX101 has not demonstrated any significant GI toxicity to date

Svenson S, et.al. J Control Release. 2011,153, 49–55.

CRLX101 improves rectal cancer chemoradiotherapy

Tian X., et. al. Cancer Res. 2017, 77(1), 112–122.

• the addition of CRLX101 to standard chemoradiotherapy significantly increased therapeutic efficacy

• CRLX101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy

• Phase I/II clinical trial, LCCC1315 “Neoadjuvant Chemoradiotherapy with CRLX101 and Capecitabine for Rectal Cancer” (NCT02010567)

• The weekly MTD was identified as 15 mg/m2 .• Pathologic complete response (pCR) was achieved in 6/32 (19%) patients overall and

2/6 (33%) patients at the weekly MTD. • CRLX101 with neoadjuvant CRT is a feasible combination strategy with an excellent

toxicity profile.Sanoff H., et. al. Nanomedicine 2019, 18, 189–195

8/20/2020

8

Radiation potentiates tumoral nanoparticle accumulation

Artwork adapted from Stapleton S., et al. Adv Drug Del Rev 2017, 109, 119–130

Tumor accumulation of different NPs administered 72 h after a single dose of 5 Gy in 4 T1 bearing mice

Miller et al., Sci. Transl. Med. 2017, 9, eaal0225

Cellular distribution of liposomal doxorubicin (LDX) in orthotopic tumors treated with LDX alone or a single 8 Gy dose of RT followed 14 h later by LDX. Images: 2 days after RT; doxorubicin (green), capillaries (red)

Davies et. al. Cancer Res. 2004, 64, 547-553

Applications of nanoparticles to radioimmunology

Artwork from Min et.al. Nat Nanotechnol. 2017, 12(9), 877–882

antigen-capturing PLGA nanoparticles (AC-NP)

diversity and composition of captured neoantigens is dependent upon NPs surface chemistries

8/20/2020

9

• AC-NPs deliver tumor specific proteins to antigen-presenting cells

• improve the local immune response and stimulate the abscopal effect

• significantly improve the efficacy of αPD-1 treatment (up to 20% cure rate)

• induce an expansion of CD8+ cytotoxic T cells, increase CD4+/Treg and CD8+/Tregratios

Min et.al. Nat Nanotechnol. 2017, 12(9), 877–882

s.c. B16F10 melanoma model;αPD-1 Abs (i.p., 10 mg/kg); RT: 8 GyAC-NPs: 2 mg, intratumorally

Path for successful translation of nanomedicines to radiotherapy

Biology principles

- disease-driven rational development of nanomedicines

- dynamic aspects of tumor spatial and temporal heterogeneity, complexities of diffusional barriers in solid tumors

- understanding of the interactive, RT dose- and time-dependent effects on the tumor microenvironmental in the context of specific nanomedicine

- simple but robust processes for nanoparticle assembly

- the ability to optimize in parallel multiple biophysicochemical parameters of nanoparticles important for pharmacokinetic properties and possible cell uptake

- the development of scalable procedures for manufacturing large quantities of nanoparticles needed for clinical translation

Engineering principles

Regulatory considerations

Cost/Commercial potential