Nano Delivery of Cancer Therapeutics &

siRNA

A smart delivery system – small, safe, simple, and

versatile.

Improved Efficacy Lower Dosing Fewer Side Effects

The Opportunity

Employ NanoJackets to create more effective cancer and potentially gene

therapeutics at lower dosing

with fewer side-effects

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NanoJackets Are Distinct

• Small & do not agglomerate (20 – 50nm)• Protect Active Pharmaceutical Ingredient• Calcium Phosphate based• Increased time in circulation• Dissolve in the cell• Scalable and low-cost manufacturing

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NanoJacket Structure

Active Pharmaceutical Ingredient

Calcium Phosphate NanoJacket

Surface Treatment (Carboxylic Acid, Amine, or PEG)

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Keystone Nano Overview

• Licensed and internally developed IP• In-Vivo Data and Characterization of nanoparticles• Focused and expedited path to Market• Effective Partnerships with Nalco driving toward

product revenues• Ability to “package” compounds and siRNA in nano

scale Calcium Phosphate

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KN Lead Compound

Doxorubicin

Application Area

Breast, Bladder, Stomach, Ovaries, Thyroid

Label Objective

Similar efficacy with decreased nausea, vomiting, decrease in white blood cells, hair loss, congestive heart failure, cardiomyopathy

Comparative Drugs

Doxorubicin

KN Additional Compounds

Docetaxel, siRNA, Etc.

Keystone Nano Summary

NanoJackets are Molecular Smart Bombs; Encapsulated components are released as a function of pH

NanoJackets

NJs

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1. This is the 1st trial of NanoJacketed Doxorubicin in a Doxorubicin Resistant breast cancer model and dose level or schedule has not yet been optimized.

2. NanoJacketed Doxorubicin is at 10% of concentration of free doxorubicin.

3. Dosing was 3 times weekly, which has not been optimized.8

Doxorubicin NanoJackets Treating Dox Resistant Cancer

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Near-Infrared Emitting Fluorophore-Doped Calcium Phosphate Nanoparticles for In Vivo Imaging of

Human Breast CancerACS NANO

Erhan I˙. Altınoglu, Timothy J. Russin, James M. Kaiser, Brian M. Barth, Peter C. Eklund, Mark Kester, and James H. Adair

PEG Coated NJs

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Intellectual Property

A. Patent Application – Kester / Adair use of NanoJackets in cancer product applications

B. Patent Application – Adair / Kester on process to make and “NanoJacket” drugs

C. Patent Applications (KN and Nalco) on methods and applications relating to industrial uses

D. Patent Application (KN) on alternative methods of manufacturing

E. Know-how in creating NanoJackets

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Development Path

Testing NanoJackets inAnimal Models

Testing NanoJackets inAnimal Models

Co-DevelopmentAgreements

Co-DevelopmentAgreements

New DrugApplication

New DrugApplication

Studies asAdvised by

Regulatory Team & FDA

Studies asAdvised by

Regulatory Team & FDA

505 (b) (2)Trial

505 (b) (2)Trial

Partnering Discussions

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Partnership with Nalco• Joint venture is - NanoSpecialties LLC

• Focus on industrial applications - non-pharmaceutical, non-biotechnology, and non-imaging applications

• Nalco provides up front research investment, milestone payments, and profit sharing

• First Industrial Product Launch 2009

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Investment Opportunity• KN is finalizing a multi-million investment in

development with Nalco around our joint venture• KN is seeking to complete a $7 million pre-A

convertible debt round for the Cancer / siRNA applications of the technology

• KN will test its first product in a comparison trial within 18 months of financing

• KN will file an NDA within 24 months of financing

Thank You!

For More Information Contact:Jeff Davidson

Keystone Nano, Inc.1981 Pine Hall Road

State College, PA 16801jdavidson@keystonenano.com

(814) 466-5080

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505 (b) (2)

• Shorter, less expensive regulatory path

• Testing CHANGE from approved therapeutic, no need to repeat Phase 1, 2, 3 trials

• More than 100 therapeutics approved

• Often used for alternative delivery systems

• Examples – Abraxane, Doxil, ANX-514

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siRNA is Captured and Protectedby NanoJackets

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Free siRNA

BoundsiRNA

No

Ca

Ca binding

siR

NA

co

ntr

ol

RN

A-N

Js

RN

A-N

Js +

ED

TA

NanoJacket payloads are delivered intracellularly

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Cy3

-Nan

oJac

kets

Fre

e cy

3

+ cytochalasin D•Cy3 is a fluorescent, organic molecule which has been encapsulated in NanoJackets

•Similar staining pattern in endothelial cells treated with free Cy3 and Cy3-NJs suggests NJs have dissolved

•Punctuate staining seen when Cy3-NJs are treated with cytochalasin D suggests that late endocytosis is involved in NJ dissolution

Competitive Approaches

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Company (Product) Technology Key Difference

J & J (Doxil) Liposome NJ likely to provide improved delivery and fewer lipid associated side effects

Abraxis Oncology (Abraxane)

Albumin Coupled Taxol NJ should not cause pains in joints and muscles

pSividia Silica NJs are soluble and less toxic

Tempo Pharmaceuticals

Combined Delivery of APIs NJ are simpler to produce and validate with clinical trials

Insert Therapeutics Polymeric particles NJ offer pH dependent dissolution and have better biological compatibility

Bind Biosciences Polymeric particles NJ pH dependent dissolution and have better biological compatibility

NanoJackets (NJs)• 40 nm, non-toxic, stable, calcium phosphate

• Targetable, pH dependent dissolution

• Provides intracellular release of drugs

• Lessens systemic exposure and toxicity

• Shown to allow use of potent/insoluble drugs

• Simple surface chemistry for targeting moieties

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Key Team Members• Jeff Davidson, CEO, BS Chemical Engineering, MBA

– Developed Partnerships with Nalco & Ben Franklin raising $1.5 million to support KN

– Founded PA BIO, Co-Founder of KN• Mark Kester, Chief Medical Officer, Ph.D.

– G. Thomas Passananti Professor of Pharmacology Hershey Medical– Scientific Advisor to Several Companies

• Jim Adair, Chief Science Officer, Ph.D.– Developed NanoJacket Technology – Professor of Materials Science and Engineering

– Robert Cornwall, VP Operations, MS– Mylisa Paretter, Technical Lead, Ph.D.• Penn State University / Hershey Medical • Nalco, Inc.• Sage Advisors, Inc.• Axiom Capital, Inc.• Mostafa Analoui

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KN Lead Compound DoxorubicinApplication Area Breast, Bladder, Stomach, Ovaries, ThyroidLabel Objective Similar efficacy with decreased nausea, vomiting, decrease in

white blood cells, hair loss, congestive heart failure, cardiomyopathy

Comparative Drugs Doxorubicin (Likely Doxil after NDA)Nano - Differentiation Calcium Phosphate 20 to 40 nm particle with good safety

profile – small, simple, non-exoticEvidence of Efficacy Cellular and animal experiments have demonstrated efficacy.

Additional animal experiments are plannedTargeting We have early supporting evidence supporting longer

circulatory residence time and Enhanced Permeability and Retention effects.

Targeting Moieties KN views additional targeting moieties on the surface as being opportunities for 2nd generation nanoparticles rather than 1st generation.

Keystone Nano Summary

Summary of NanoJacket Experimentation• Lack of calcium-induced toxicology for amine functionalized NanoJackets in vitro

(normal calcium currents in imaged neural stellate ganglia) as well as in vivo (ApoE knock out model of atherosclerosis);

• In-vitro efficacy against drug sensitive and drug resistant breast cancer cells with Ceramide NanoJackets;

• In-vitro efficacy against melanoma cells with Ceramide NanoJackets;

• In-vivo (mice) biodistribution data shows effect of surface functionalization

• In-vivo (mice) safety / efficacy for delivery of NanoJacketed Doxorubicin

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NanoJackets are non-toxic In-Vivo

1. NanoJackets do not affect weight gain of ApoE knockout mice, a model of atherosclerosis

1. Dose of 1015 NanoJackets three times per week25

NanoJacketed Ceramide (as API) kills drug sensitive and drug resistant breast cancer cells

1. At 1/5 of the dosing NanoJackets are approximately 7 times as effective2. NanoJackets are effective against drug resistant cells (Panel B)

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Untreated Melanoma Cells

Melanoma Imaged with

NanoJackets

NanoJacketed Ceramide Eliminates

Melanoma Cells

Ceramide NanoJackets Image & Treat Melanoma Cells

Panel 1 – DAPI Stained Melanoma CellsPanel 2 – Demonstrating NanoJackets Image (Target) Melanoma CellsPanel 3 – When treated with NanoJacketed Ceramide the cells quickly die

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Ceramide NanoJackets reduce melanoma growth In Vivo without toxicology

1. Mice treated with NanoJackets were not harmed.

2. Mice treated had a 40% smaller tumor at the conclusion

of the study with suboptimal dose of Ceramide28

PEG Coated NanoJackets

• Image of Mouse with NJ at right showing recirculation of NJs for extended circulation

• NJs provide sustained distribution as shown in the photo of the NJs at right

• Free ICG entirely susceptible to hepatic clearance (Secretion in bile through gastrointestinal track)

• Localization in tumors evident with PEGylated NJs after 24 hours

Stomach

Duodenum

Pancreas

Small Intestine

Excised GI Track after 4-hourICG-doped NJ injection

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Work Underway DEVELOPMENT EXPERIMENTS PLANNED

• Dose Response versus free Dox (7 groups of 6 animals)• Surface Treatment Effects (4 groups of 6 animals with dosing) • CRO Toxicology and biodistribution / PK Study (designs being

planned) REGULATORY INITIATIVES

• Prepare for Pre-IND discussions with FDA (planning underway)

Small, simple, safe, versatile delivery technology

Large cancer therapy opportunitiesExpedited / Advantaged Pathway to MarketProtected IPStrong in-vivo data

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Summary