March 26, 2022

Vidhi M. Shah 1,2,3, Craig Dorrell 2, Adel Al-Fatease 1,3, Brittany L. Allen-Petersen 4, Yeonhee Woo 1, Yuliya Bortnyak 1, Rohi Gheewala 5, Brett C. Sheppard 2,6,7, Rosalie C. Sears 2,4,7, and Adam WG. Alani 1,7,8

Abstract: Pancreatic ductal adenocarcinoma (PDAC) presents as an unmet clinical challenge for drug delivery due to its unique hypoxic biology. Vinblastine-N-Oxide (CPD100) is a hypoxia-activated prodrug (HAP) that selectively converts to its parent compound, vinblastine, a potent cytotoxic agent, under oxygen gradient. The study evaluates the efficacy of microfluidics formulated liposomal CPD100 (CPD100Li) in PDAC. CPD100Li were formulated with a size of 95 nm and a polydispersity index of 0.2. CPD100Li was stable for a period of 18 months when freeze-dried at a concentration of 3.55 mg/mL. CPD100 and CPD100Li confirmed selective activation at low oxygen levels in pancreatic cancer cell lines. Moreover, in 3D spheroids, CPD100Li displayed higher penetration and disruption compared to CPD100. In patient-derived 3D organoids, CPD100Li exhibited higher cell inhibition in the organoids that displayed higher expression of hypoxia-inducible factor 1 alpha (HIF1A) compared to CPD100. In the orthotopic model, the combination of CPD100Li with gemcitabine (GEM) (standard of care for PDAC) showed higher efficacy than CPD100Li alone for a period of 90 days. In summary, the evaluation of CPD100Li in multiple cellular models provides a strong foundation for its clinical application in PDAC.
  1. Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 South Moody Avenue, Portland, OR 97201, USA; shahv@ohsu.edu (V.M.S.); afatease@kku.edu.sa (A.A.-F.); rosalynn.woo@gmail.com (Y.W.); bortnyak.yuliya@gmail.com (Y.B.)
  2. Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA; dorrellc@ohsu.edu (C.D.); sheppard@ohsu.edu (B.C.S.); searsr@ohsu.edu (R.C.S.)
  3. Department of Pharmaceutics, College of Pharmacy, King Khalid University, Guraiger, Abha 62529, Saudi Arabia
  4. Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA; ballenpe@purdue.edu
  5. School of Medicine, Oregon Health & Science University, 3181 Southwest Sam Jackson Road, Portland, OR 97239, USA; gheewala@ohsu.edu
  6. Department of Surgery, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
  7. Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97120, USA
  8. Department of Biomedical Engineering, School of Medicine at Oregon Health & Science University, Portland, OR 97239, USA

* Correspondence: Adam.Alani@oregonstate.edu

May 10, 2017

Shah VM, Nguyen DX, Alfatease A, Bracha S, Alani AW.

Solid tumors often contain hypoxic regions which are resistant to standard chemotherapy and radiotherapy. We have developed a liposomal delivery system for a prodrug of vinblastine (CPD100) which converts to the parent compound only in the presence of lower oxygen levels. As a part of this work we have developed and optimized two formulations of CPD100: one composed of sphingomyelin/cholesterol (55/45; mol/mol) (CPD100Li) and the other composed of sphingomyelin/cholesterol/PEG (55/40/5; mol/mol) (CPD100 PEGLi). We evaluated the antiproliferative effect of CPD100 and the two formulations against A549 non-small lung cancer cell. A549 cell line showed to be sensitive to CPD100 and the two formulations displayed a higher hypoxic: air cytotoxicity ratio compared to the pro-drug. CPD100 elimination from the circulation after injection in mouse was characterized by a very short circulation time (~0.44h), lower area under the curve (AUC) (33μgh/mL) and high clearance (916mL/h/kg) and lower volume of distribution (17.4mL/kg).Total drug elimination from the circulation after the administration of liposomal formulation was characterized by prolonged circulation time (5.5h) along with increase in the AUC (56μgh/mL) for CPD100 Li and (9.5h) with AUC (170μgh/mL) for CPD100PEGLi. This was observed along with increase in volume of distribution and decrease in clearance for the liposomes. The systemic exposure of the free drug was much lower than that achieved with the liposomes. When evaluated for the efficacy in A549 xenograft model in mice, both the liposomes demonstrated excellent tumor suppression and reduction for 3months. The blood chemistry panel and the comprehensive blood analysis showed no increase or decrease in the markers and blood count. In summary, the pharmacokinetic analysis along with the efficacy data emphasis on how the delivery vehicle modifies and enhances the accumulation of the drug and at the same time the increased systemic exposure is not related to toxicity…

Dec. 15, 2005

Primeau AJ, Rendon A, Hedley D, Lilge L, Tannock IF.

PURPOSE: Anticancer drugs gain access to solid tumors via the circulatory system and must penetrate the tissue to kill cancer cells. Here, we study the distribution of doxorubicin in relation to blood vessels and regions of hypoxia in solid tumors of mice.

EXPERIMENTAL DESIGN: The distribution of doxorubicin was quantified by immunofluorescence in relation to blood vessels (recognized by CD31) of murine 16C and EMT6 tumors and human prostate cancer PC-3 xenografts. Hypoxic regions were identified by injection of EF5.

RESULTS: The concentration of doxorubicin decreases exponentially with distance from tumor blood vessels, decreasing to half its perivascular concentration at a distance of about 40 to 50 mum, The mean distance from blood vessels to regions of hypoxia is 90 to 140 microm in these tumors. Many viable tumor cells are not exposed to detectable concentrations of drug following a single injection.

CONCLUSIONS: Limited distribution of doxorubicin in solid tumors is an important and neglected cause of clinical resistance that is amenable to modification. The technique described here can be adapted to studying the distribution of other drugs within solid tumors and the effect of strategies to modify their distribution…