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Confidentiality Statement This information is meant to be presented to the participating members of the 5 th Korea-US Nanoforum only. By having this information in possession, you are agreeing to keep this information non-disclosed.

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SLIDE 1

Confidentiality Statement

  • This information is meant to be presented to the

participating members of the 5th Korea-US Nanoforum

  • nly.
  • By having this information in possession, you are agreeing

to keep this information non-disclosed.

  • You may not share, use, claim or distribute the information

contained in this file/slide/handout without a written consent from NanoMedicine Research Co. (consent via email accepted.)

  • Violations of the terms above may result in legal actions.
  • Should you come in possession of this information without

the permission mentioned above, please contact j.f.chung@nmrpharma.com

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SLIDE 2

A Novel Anti-Cancer Strategy Through Biological Metal Overloading in Cancer Cells via pH-sensitive Metalo-organic Nanoparticles

Jinhyuk Fred Chung, Ph. D., CEO NanoMedicine Research Co. April 18th, 2008 The 5th Nanoforum Jeju, Korea

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SLIDE 3

Challenges & Limitations in Anti-cancer Medicines: Seesaw Dillemma

Cytotoxin Enzyme Inhibitor

Toxicity / Selectivity Efficacy Which side to leverage?

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SLIDE 4

◈ Theory – A lesson from nature

1: Mol Med. 2008 Mar-Apr;14(3-4):98-108. Links

Iron-mediated inhibition of mitochondrial manganese uptake mediates mitochondrial dysfunction in a mouse model of hemochromatosis.

Jouihan HA, Cobine PA, Cooksey RC, Hoagland EA, Boudina S, Abel ED, Winge DR, McClain DA.

Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, USA and.

Benign biological metals can KILL UPON OVERLOADING!

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SLIDE 5

“Calcium & Iron Bomb” Strategy

*Source of the depiction unknown

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SLIDE 6

◈ OFeCa-1: The Anti-Cancer Particle

  • OFeCa-1
  • pH-sensitive organo-metallic

nanoparticles with iron & calcium as the main therapeutic components.

  • Degrades near neutral pH,

releasing metals.

ICP-MS metal analysis of 11% w/w OFeCa-1 solution (same concentration solution as those used for cell & animal experiments)

Transmission Electron Microscope (TEM) Image taken near pH 2

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SLIDE 7

◈ OFeCa-1’s Degradation via pH

  • Dynamic light scattering results
  • n OFeCa-1 at varying pH,

showing pH-dependent degradation of OFeCa-1 near physiological ranges (~pH 7).

  • Horizontal axis denote

nanoparticle sizes in diameter, graphs denote mass distribution, normalized against the norm.

  • This degradation property allows

OFeCa-1 to “unload” bound metals that, in turn, kill target cancer mass

Mass Distribution at pH 6.4 20 40 60 80 100 120 0.4 0.62 0.97 1.5 2.33 3.62 5.61 8.72 13.5 21 32.7 50.7 78.8 122 190 295 459 712 1110 Diameter %Mass(Per max peak) Mass Distribution at pH 7 20 40 60 80 100 120 0.4 0.62 0.97 1.5 2.33 3.62 5.61 8.72 13.5 21 32.7 50.7 78.8 122 190 295 459 712 1110 Diameter (nm) %Mass(Per Max Peak) Mass Distribution at pH 7.4 20 40 60 80 100 120 0.4 0.62 0.97 1.5 2.33 3.62 5.61 8.72 13.5 21 32.7 50.7 78.8 122 190 295 459 712 1110 Diameter (nm) %Mass(Per Max Peak)

pH 6.4 pH 7.0 pH 7.4

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SLIDE 8

◈ Human Cancer Cell Screening

0.000 0.500 1.000 1.500 2.000 2.500 3.000 3.500 4.000 4.500 5 10 20 30 40 50 60 5 10 20 30 40 50 60 60 60 5 24hrs 48hrs 72hrs 5000 per well

Hep2 (larynx cancer)

0.000 0.500 1.000 1.500 2.000 2.500 3.000 3.500 4.000 4.500 5 10 20 30 40 50 60 5 10 20 30 40 50 60 5 10 20 30 40 50 60 24hrs 48hrs 72hrs 5000 per well

293T (kidney cancer) Cancer Survival

OFeCa-1 Added (uL/mL Media)

24hr Treated 48 72 24 48 72

Note this occurance of “critical dosage”, at which point cancer suddenly disappear altogether

*Cell counting kit-8 (Dojindo, Tokyo) was used to study cell viability.

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SLIDE 9 0.000 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 5 10 20 30 40 50 60 5 10 20 30 40 50 60 5 10 20 30 40 50 60 24hrs 48hrs 72hrs 5000 p er w ell 0.000 0.500 1.000 1.500 2.000 2.500 3.000 5 10 20 30 40 50 60 5 10 20 30 40 50 60 5 10 20 30 40 50 60 24hrs 48hrs 72hrs 5000 per well

Ramos (Burkitt's lymphoma ) T98g (brain cancer)

0.000 0.500 1.000 1.500 2.000 2.500 3.000 3.500 4.000 4.500 5.000 5 10 20 30 40 50 60 5 10 20 30 40 50 60 5 10 20 30 40 50 60

24hrs 48hrs 72hrs

H460 (lung cancer)

24hr 48hr 72hr

Continued

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SLIDE 10

◈ Toxicity Testing against HSC

  • Adult stem cells such as hair

cells & hematopoetic stem cells (HSC: blood stem cell) are easily killed by conventional anti-cancer drugs, leading to hair loss & bone marrow suppression during cancer treatment.

  • OFeCa-1, on the other hand,

displays no signs of adverse effect on mouse HSC’s survival.

HSC survival (A.U.)

0. 2 0. 4 0. 6 0. 8 1 1. 2 1. 4 1. 6 c 1 2. 5 5 10 20 40

11% OFeCa-1 in Media (uL/mL)

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SLIDE 11

Efficacy against Mouse Cancer Cell

20 40 60 80 100 120 40 20 5 1

10^ 5 2.5*10^ 4 1.25*10^ 4 0.6*10^ 4 0.3*10^ 4 0.15*10^ 4 Norm al cell

Effect of OFeCa-1 on B16F10 Melanoma & Normal Stromal Cells

  • OFeCa-1 shows

no toxicity against non- cancerous normal mouse stromal cells.

  • Within same

range, OFeCa-1 shows powerful anti-cancer activity against mouse melanoma B16F10.

% Cell Survival against Control Group 11% w/w OFeCa-1 Added (uL/mL media) # of Initial Melanoma Cells

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SLIDE 12

◈ Mouse Model Bearing Metastatic Lung Cancer

10 20 30 40 50 B16/F10 B16/F10 + P10

A B C Melanoma Colony Count Effect of sustained administration of OFeCa-1 on intravanous metastatic mouse model using B16/F10. OFeCa-1 was passively administered as water-substitute by diluting 11 % OFeCa-1 ten-fold with dietary water. Quick survey showed that the mice consumed roughly 2~3 mL of the diluted OFeCa-1 daily. (A) B16/F10

  • control. (B) B16/F10 mice fed

with 1/10 diluted OFeCa-1. (C) Quantified B16/F10 colonies found in the lungs of test

  • subjects. P10 refers to passively

fed 1/10 diluted 11% w/w OFeCa-1 against water. Experiment terminated before the extinction of melanoma colonies in the treatment group for visual confirmation of successful metastasis Control Treatment

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SLIDE 13

◈ 2W Acute Toxicity Test using SD rats

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SLIDE 14

◈ Replenishment Effect: More Effectiveness

  • The graph left shows clear

evidence of improvement in anti-cancer efficacy of OFeCa-1 upon daily replacement of the media containing OFeCa-1.

  • This data indicates that

frequent use of OFeCa-1 is likely to be recommended in the future.

  • Considering the data thus far,

greater dose and more frequent intake of OFeCa-1 is likely to be highly recommended, increasing the demand for OFeCa-1 for extra assurance in cancer treatment.

Cancer Cell Survival After 72hr Treatment 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 1 10 20 30 40 OFeCa-1 Added (uL/mL media) Abs Kept Media Fresh Media

*B16F10 mouse melanoma as model. Media of appropriate condition were replaced daily for “fresh media” group.

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SLIDE 15

OFeCa-1: Ideal Anti-Cancer Agent

  • Ultra-low toxicity*
  • Composed only of biological metals & organic nanoparticle backbone

that degrades into non-toxic biological metabolites

  • Displays effectiveness against multiple aggressive cancer cell lines

(both human & mouse origins)

  • Designed to work in multiple modes, increasing effectiveness &

reducing chances of resistance development

  • Outlook of good efficacy against Lung cancer
  • Significantly more effective upon frequent & prolonged use
  • Expected to be compatible with conventional chemotherapeutic agents.
  • And many more ideal behaviors & properties that qualify OFeCa-1 as

an ideal candidate for future broad-spectrum cancer treatments.

*Based on toxicity tests against cell-based tests & acute toxicity test using SD rats