Executive Summary
Development of a drug for anticancer chemotherapy:
Smart nano-capsules for drug delivery, targeting & controlled release in the tumor.

The Need:
Current anticancer chemotherapy treatments have limited efficacy and cause severe side effects. The needs are:
  • To improve the therapeutic effect of anti-cancer drugs while minimizing side effects.
  • New applications (and patents) for drugs whose patents have expired.
Approach & solution:
FULCRUM SP PHARMA develops smart nano-capsules for existing anti-cancer drugs (Doxorubicin or taxanes) for tumor targeting & controlled release in the tumor, in order to improve the therapeutic effect of anti-cancer drugs while minimizing side effects.

Technology:
The technology is based on a newly discovered protein - SP1, which is exceptionally stable under extreme conditions. The homo-dodecamer self-assembles to a ring-shaped complex, where the 12 N-termini (six on each face of the ring) project into the central cavity.

The SP1 complex was engineered for nano-encapsulation of both water soluble drugs (such as doxorubicin) and water-insoluble anti-cancer drugs, such as taxanes. Using genetic engineering, a cysteine residue was inserted in the N-terminal region, which results in formation of disulfide bonds between neighboring subunits. The disulfide bonds form a molecular lid over the central cavity, "locking" into place the encapsulated drug.

Water-based formulation of taxane: Encapsulation of taxane anticancer agents paclitaxel and docetaxel by SP1 in water avoid the use of formulation vehicles Cremophor EL and polysorbate 80 (Tween 80). Both solubilizers are biologically and pharmacologically active compounds, and their use as drug formulation vehicles has been implicated in clinically important adverse effects, including acute hypersensitivity reactions and peripheral neuropathy.

Passive tumor targeting: The SP1/drug complex accumulates in the tumor as a result of the Enhanced Permeability and Retention (EPR) effect. SP1 slow clearance rate from the blood stream and its ability to accumulate in the tumor was demonstrated using C57B1/6 mice transplanted subcutaneously with B16F10 murine melanoma.

Tumor specific drug release: SP1 was genetically engineered to release the drug specifically to the tumor. •The tumor specific drug release mechanism is based on the observation enzyme (such as thioredoxin, glutathione-S-transferase, and peroxiredoxin) expression is increased in a variety of human malignancies. Moreover; their expression is associated with aggressive tumor growth and drug resistance. The reducing conditions in the tumor reduce the disulfide bonds of the SP1 encapsulating lid, unlocking the lid and inducing drug release. Moreover, under oxidizing conditions, in the blood stream, heart, and other healthy organs, the drug is kept encapsulated in the protein cavity and does not produce harmful side-effects.

Intellectual Property:
The SP1-based technology is protected by a patent held by the Hebrew University and Fulcrum SP Ltd. The Hebrew University and Fulcrum SP Ltd. have granted FULCRUM SP PHARMA an exclusive worldwide license to commercialize SPs to their full potential for anti-cancer applications. The patent application includes claims for composition of matter, methods of production and applications for the entire family of SP chaperones, as well as the use of SP1 for drug delivery.

The business advantage:
  • The SP1/drug complex will increase the drug efficacy of the encapsulated drugs and will dramatically minimize side effects.
  • New highly toxic drugs, that are too toxic to be used by current technologies, can be encapsulated by SP1.
  • Extension of patent lifetime of existing drugs by optimizing products through drug delivery.


    • Competition:
    Several other nano-scale drug delivery systems have been tested. Liposomes and albumin-based nano-particles are already on the market. SP1's advantages include its exceptional stability, its uniform small size (11nm), and the fact that it is a protein, which is a biocompatible molecule. Animal studies indicate that SP1 is safe, SP1 limits antigenic response (no antibodies were detected in preliminary toxicity experiments), and that it is easy to manipulate its physical properties by genetic engineering - advantages over the competition.