PEG-b-poly (carbonate)-derived nanocarrier platform with pH-responsive properties for pancreatic cancer combination therapy

Autor: Sanku Mallik, Tao Wang, Pawel P. Borowicz, Matthew Confeld, Mohiuddin A. Quadir, Priyanka Ray
Rok vydání: 2018
Předmět:
Tertiary amine
Polymers
Pyridines
Nanoparticle
Mice
Nude
Apoptosis
02 engineering and technology
01 natural sciences
Deoxycytidine
Article
Polyethylene Glycols
Mice
Colloid and Surface Chemistry
Drug Delivery Systems
Pancreatic cancer
Lysosome
0103 physical sciences
PEG ratio
Antineoplastic Combined Chemotherapy Protocols
medicine
Tumor Cells
Cultured
Animals
Humans
Anilides
Physical and Theoretical Chemistry
Micelles
Cell Proliferation
Drug Carriers
Polycarboxylate Cement
010304 chemical physics
Chemistry
Surfaces and Interfaces
General Medicine
Hydrogen-Ion Concentration
021001 nanoscience & nanotechnology
medicine.disease
Xenograft Model Antitumor Assays
Gemcitabine
In vitro
Pancreatic Neoplasms
medicine.anatomical_structure
Drug delivery
Biophysics
Nanoparticles
Nanocarriers
0210 nano-technology
Biotechnology
Zdroj: Colloids and surfaces. B, Biointerfaces. 174
ISSN: 1873-4367
Popis: A pH-responsive nanoparticle platform, based on PEG-b-poly (carbonate) block copolymers have been proposed that can respond to low pH as found in many cancer micro- and intracellular environment, including that in pancreatic cancer. The hydrophobic domain, i.e., the poly (carbonate) segment has been substituted with tertiary amine side chains, such as N, Nʹ-dibutylethylenediamine (pKa = 4.0, DB) and 2-pyrrolidin-1-yl-ethyl-amine (pka = 5.4, Py) to generate two different sets of block copolymers namely PEG-DB and PEG-PY systems. These side-chain appended amines promote disassembly of nanoparticles and activation of drug release in response to pH conditions mimicking extra- (pH 6.9–6.5) and intracellular compartments (5.5–4.5, from early endosome to lysosome) of cancer tissues respectively. A frontline chemotherapy used for pancreatic cancer, i.e., gemcitabine (GEM) and a Hedgehog inhibitor (GDC 0449) has been used as the model combination to evaluate the encapsulation and pH-dependent release efficiency of these block copolymers. We found that, depending on the tertiary amine side chains appended to the polycarbonate segment, these block copolymers self-assemble to form nanoparticles with the size range of 100–150 nm (with a critical association concentration value in the order of 10−6 M). We also demonstrated an approach where GEM and GDC 0449-encapsulated PEG-DB and PEG-PY nanoparticles, responsive to two different pH conditions, when mixed at a 1:1 vol ratio, yielded a pH-dependent co-release of the encapsulated contents. We envision that such release behaviour can be exploited to gain spatiotemporal control over drug accumulation in pathological compartments with different pH status. The mixture of pH-responsive nanoparticles was found to suppress pancreatic cancer cell proliferation when loaded with anticancer agents in vitro. Cell-proliferation assay showed that both variants of PEG-b-polycarbonate block copolymers were inherently non-toxic. We have also immobilized iRGD peptide on intracellularly activable PEG-DB systems to augment cellular uptake. These targeted nanoparticles were found to promote selective internalization of particles in pancreatic cancer cells and tumor tissue.
Databáze: OpenAIRE
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