Formulation and Delivery
Diana Chow, PhD
Professor and Director
University of Houston
Houston, Texas
Jaymin Shah, PhD
Research Fellow and Head of Topical and Advanced Drug Delivery
Pfizer Worldwide Research and Development
Groton, Connecticut
Unmet medical needs: Little progress has been made in treating pancreatic ductal adenocarcinoma (PDAC) with 5-year survival rate of 11.5%. PDAC is expected to be the 2nd leading cause of cancer-related death by 2030. Hepatocellular carcinoma (HCC) is the most common form of liver cancer, which is often treated with chemotherapy. However, long-term survival of HCC patients is hindered by high recurrence and drug resistance.
To address the needs, an innovative polymeric micellar platform has been developed in our research team with Dr. Chun Li and his team at M.D. Anderson Cancer Center and my team at University of Houston College of Pharmacy. The platform is uniquely designed with a novel block copolymer that can encapsulate multi-drugs for co-delivery. The block copolymer has a dense, brush-like PEG block that, compared to linear PEG, can better prevent the adsorption of complement proteins on the surface and is less likely to induce anti-PEG immune reactions. Drugs are encapsulated via 1) a hydrophobic interaction between the poly(ε-caprolactone) block and the more lipophilic payload, and 2) an ionic interaction between the carboxylate pendant groups of the polymer and the amine groups of the other amine-containing payload. Since many drugs are amine-containing weak bases, we anticipate that a large number of potential drugs may be similarly encapsulated into the block copolymer with excellent stability. Thus far, we have successfully encapsulated paclitaxel (PTX), cyclopamine (CPA), dactolisib, triptolide, calcipotriol (a synthetic derivative of vitamin D used in the treatment of psoriasis), and other drugs, underscoring the suitability of our approach for a wide variety of drugs that will be evaluated in future studies. A patent has been granted on the polymeric micellar carrier as a platform technology (US patent No. 11,026,889, issued Jun 8, 2021; International Application No. PCT/US16/65763).
To demonstrate the benefits of this platform, we have developed a lead candidate, M-CPA/PTX, consisting of our novel block copolymer encapsulating CPA and PTX. PTX in the form of albumin complex is a chemotherapeutic commonly used in combination with gemcitabine for the treatment of PDAC, while CPA is a natural product that could deplete cancer stem cells (CSCs) and overcome drug resistance, and is known to enhance the cytotoxic effect of PTX. Thus, co-delivery of these drugs via M-CPA/PTX enables simultaneous targeting of the tumor and stromal compartments. Based on promising results in animal models, M-CPA/PTX successfully delivers both CPA and PTX to tumors above therapeutic concentration and is more efficacious than any other existing therapeutics at much reduced drug dose, including the current standard of care abraxane (albumin-bound PTX). Co-delivery of CPA and PTX via M-CPA/PTX results in exceptionally high antitumor efficacy while enabling significantly reduced doses for both CPA and PTX. M-CPA/PTX alone significantly extends the median survival of PDAC-bearing KPC-Luc mice from 4 weeks to 14 weeks and provides superior benefit compared to gemcitabine and abraxane. M-CPA/PTX was also demonstrated a robust antitumor activity in a transgenic liver cancer model and improved liver function.