Albumin binding peptide-drug (AlBiPeD) conjugates: long circulating peptide derivatives of small molecule therapeutics
Delivery and therapeutic efficacy of small molecule imaging agents and chemotherapeutics are hampered by their short half-life, low solubility, non-selectivity to cancer cells, and toxic side effects. Small molecule chemotherapeutics, although in routine use for cancer treatment, suffer from a short circulation half-life and indiscriminate accumulation in healthy tissues that result in systemic toxicities and hence limit their maximum dose. These limitations inhibit accumulation of chemotherapeutics in tumors at therapeutic levels and limit their clinical application. Efforts in past decades have been focused on developing macromolecular and nanoparticulate drug formulations that prevent first-pass elimination in kidneys and allow for selective accumulation in tumors via the enhanced permeation and retention (EPR) effect. However, the interaction of these macromolecule and nanoparticle carriers with serum proteins and components of the immune system is not well understood and is affected by several factors such as their interfacial chemistry, size, shape and stability which makes their optimization difficult. Therefore, there remains a need for new delivery systems that can overcome these disadvantages yet provide efficacy for delivery of small molecule imaging agents and chemotherapeutics.
Duke inventors have developed a strategy, including novel materials, intended to extend the half-life and enhance the antitumor efficacy of small molecule therapeutics. The reported albumin binding peptide-drug (AlBiPeD) conjugates will have longer half-life in blood circulation than the intact because they bind to and harness the endogenous albumin that has an exceptionally long half-life in circulation. AlBiPeDs can exploit endogenous albumin in order to improve the pharmacokinetics and biodistribution profiles of small molecule chemotherapeutics and therefore enhance their antitumor activity. Binding to albumin is postulated to confer several benefits: (1) it extends the circulation half-life of drug carriers that we hypothesize sets the upper limit on their accumulation in tumors by the EPR effect. (2) It prevents premature RES uptake of micelles that is a major constraint in achieving site-specific drug targeting. (3) It actively targets tumor sites via albumin receptors overexpressed in tumors i.e. gp60 and SPARC. This technology has been demonstrated in both mouse and canine models.
Although this project focuses on doxorubicin as the anticancer drug of choice, the platforms described here can be extended to other chemotherapeutics such as paclitaxel, lapatinib, cisplatin, etc.
- Exploiting the endogenous albumin is a safer approach compared with systems that use exogenous albumin. Albumin is currently produced by fractionation of plasma obtained from blood donors and as the source of blood can vary, delivery systems based on the exogenous albumin harbor the risk the contamination with blood-borne pathogen.
- Unlike Aldoxorubicin, an albumin binding maleimide derivative of doxorubicin, that can bind to any free thiol containing protein or molecule in the body, ABDs in this platform are more specific for albumin and therefore decrease the chance of non-specific and off-target interactions.
- The improvement in pharmacokinetics afforded by albumin binding, and the lack of systemic toxicity observed in the canine model for the ABDN-CP-DOX micelles highlights its potential for translation into humans.
- Sheathing the corona of the CP-DOX micelles with an albumin corona greatly decreases their uptake by the RES organs in mice, and significantly increases their accumulation in the tumor, leading to a 3-fold increase in the therapeutic window compared to naked nanoparticles.