Modified Cytotoxins and their Therapeutic Use

NU 2022-111

INVENTORS

• Cassandra Callmann
• Matthew Thompson
• Clare LeGuyader
• Paul Bertin
• Nathan Gianneschi*

SHORT DESCRIPTION

This invention is for chemically modified small-molecule cytotoxic drugs conjugated to long-chain fatty acid-like hydrophobic moieties that bind non-covalently to albumin, creating improved cancer therapeutics with enhanced tumor delivery and reduced systemic toxicity.

BACKGROUND

Cytotoxic chemotherapy agents are a primary treatment modality for cancer, but these agents also harm normal cells, causing severe side-effects that limit therapeutic dosing. While some cytotoxins like gemcitabine incorporate targeting moieties to preferentially accumulate in cancer cells, and others like pemetrexed actively target receptors overexpressed on tumor cells, there remains a critical need for delivery systems that can safely deliver higher doses of potent cytotoxins specifically to solid tumors while minimizing damage to healthy tissues. The challenge is compounded by the fact that many highly toxic agents cannot be administered at therapeutically effective concentrations due to unacceptable systemic toxicity, creating a therapeutic window problem that limits treatment efficacy.

ABSTRACT

Small molecule cytotoxins were developed such that a cytotoxic drug moiety is chemically modified with a fatty acid-containing moiety. These modified cytotoxins bind non-covalently to serum albumin proteins, forming stable aqueous pharmaceutical compositions where the drug-albumin complexes remain solvated without forming nanoparticle aggregates. The hydrophobic fatty acid-like chain serves as a "protein binding moiety" that anchors the cytotoxic payload to albumin, creating a prodrug system that exploits albumin's natural tumor-homing properties via enhanced permeability and retention effects to deliver cytotoxins preferentially to solid tumors while keeping them sequestered in the bloodstream away from normal tissues.

APPLICATIONS

• Intravenous chemotherapy formulations for treating solid tumors, enabling parenteral administration of highly toxic agents that would otherwise be unsuitable for systemic delivery.
• Albumin-hitchhiking drug delivery exploiting the SPARC (secreted protein acidic and rich in cysteine) receptor and gp60-caveolin pathway that tumors use to accumulate albumin.
• Prodrug cancer therapy where esterases or other enzymes present in the tumor microenvironment cleave the fatty acid linker to release active cytotoxin locally at the tumor site.
• Combination chemotherapy regimens allowing rational design of multi-drug protocols with improved therapeutic indices and potentially synergistic anticancer effects.

ADVANTAGES

• Improved therapeutic index and reduced side effects as demonstrated by in vivo mouse xenograft studies.
• Simple aqueous formulation without nanoparticles or aggregates, eliminating manufacturing complexity, avoiding regulatory challenges of nanomedicines, and providing improved stability.
• Modular chemical platform enabling rational drug design where the linker length, linker chemistry, and terminal functional group can be systematically varied to tune albumin binding affinity, plasma half-life, tumor accumulation kinetics, and enzymatic release rates.
• Broad applicability across diverse cytotoxin classes, including paclitaxel, anthracyclines, camptothecin, antifolates, and other major chemotherapy drug families.

PUBLICATION

Callmann et al. Antitumor Activity of 1,18-Octadecanedioic Acid-Paclitaxel Complexed with Human Serum Albumin. J Am Chem Soc. 141 (30): 11765-11769 (2019).

IP STATUS

• Issued US patents 10,023,581, 10,286,079, and 10,654,864