Thermosensitive and biodegradable hydrogel encapsulating targeted nanoparticles for the sustained co-delivery of gemcitabine and paclitaxel to pancreatic cancer cells

Ahmed M Shabana; Siva P Kambhampati; Ru-Ching Hsia; Rangaramanujam M Kannan; Efrosini Kokkoli

doi:10.1016/j.ijpharm.2020.120139

Thermosensitive and biodegradable hydrogel encapsulating targeted nanoparticles for the sustained co-delivery of gemcitabine and paclitaxel to pancreatic cancer cells

Int J Pharm. 2021 Jan 25:593:120139. doi: 10.1016/j.ijpharm.2020.120139. Epub 2020 Dec 3.

Authors

Ahmed M Shabana¹, Siva P Kambhampati², Ru-Ching Hsia³, Rangaramanujam M Kannan⁴, Efrosini Kokkoli⁵

Affiliations

¹ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, United States; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
² Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
³ Department of Neural and Pain Sciences, Electron Microscopy Core Imaging Facility, University of Maryland Baltimore Dental School, Baltimore, MD 21201, United States.
⁴ Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, United States.
⁵ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, United States; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, United States. Electronic address: kokkoli@jhu.edu.

PMID: 33278494
DOI: 10.1016/j.ijpharm.2020.120139

Abstract

Pancreatic cancer represents a life threatening disease with rising mortality. Although the synergistic combination of gemcitabine and albumin-bound paclitaxel has proven to enhance the median survival rates as compared to gemcitabine alone, their systemic and repeated co-administration has been associated with serious toxic side effects and poor patient compliance. For this purpose, we designed a thermosensitive and biodegradable hydrogel encapsulating targeted nanoparticles for the local and sustained delivery of gemcitabine (GEM) and paclitaxel (PTX) to pancreatic cancer. GEM and PTX were loaded into PR_b-functionalized liposomes targeting integrin α₅β₁, which was shown to be overexpressed in pancreatic cancer. PR_b is a fibronectin-mimetic peptide that binds to α₅β₁ with high affinity and specificity. The PR_b liposomes were encapsulated into a poly(δ-valerolactone-co-D,L-lactide)-b-poly(ethylene glycol)-b-poly(δ-valerolactone-co-D,L-lactide) (PVLA-PEG-PVLA) hydrogel and demonstrated sustained release of both drugs compared to PR_b-functionalized liposomes free in solution or free drugs in the hydrogel. Moreover, the hydrogel-nanoparticle system was proven to be very efficient towards killing monolayers of human pancreatic cancer cells (PANC-1), and showed a significant reduction in the growth pattern of PANC-1 tumor spheroids as compared to hydrogels encapsulating non-targeted liposomes with GEM/PTX or free drugs, after a one week treatment period. Our hybrid hydrogel-nanoparticle system is a promising platform for the local and sustained delivery of GEM/PTX to pancreatic cancer, with the goal of maximizing the therapeutic efficacy of this synergistic drug cocktail while potentially minimizing toxic side effects and eliminating the need for repeated co-administration.

Keywords: Liposomes; PR_b fibronectin-mimetic peptide; Sustained release; Targeted drug delivery; Targeting integrin α(5)β(1).

MeSH terms

Cell Line, Tumor
Deoxycytidine / analogs & derivatives
Drug Delivery Systems
Gemcitabine
Humans
Hydrogels / therapeutic use
Nanoparticles*
Paclitaxel / therapeutic use
Pancreatic Neoplasms* / drug therapy
Polyethylene Glycols / therapeutic use

Substances

Hydrogels
Deoxycytidine
Polyethylene Glycols
Paclitaxel
Gemcitabine