Using crystallized miniemulsion nanoparticles (NPs) as synthetic templates leads to well-defined layer-by-layer (LBL) polymeric nanocapsules (NCs) under mild conditions
As a promising strategy for the treatment of various diseases, gene therapy has attracted increasing attention over the past decade. Among various gene delivery approaches, non-viral vectors made of synthetic biomaterials have shown significant potential. Due to their synthetic nature, non-viral vectors can have tunable structures and properties by using various building units. In particular, they can offer advantages over viral vectors with respect to biosafety and cytotoxicity. In this study, a well-defined poly(ethylene glycol)-block-poly(α-(propylthio-N,N-diethylethanamine hydrochloride)-ε-caprolactone) diblock polymer (PEG-b-CPCL) with one poly(ethylene glycol) (PEG) block and one tertiary amine-functionalized cationic poly(ε-caprolactone) (CPCL) block, as a novel non-viral vector in the delivery of plasmid DNA (pDNA), was synthesized and studied. Despite having a degradable polymeric structure, the polymer showed remarkable hydrolytic stability over multiple weeks. The optimal ratio of the polymer to pDNA for nanocomplex formation, pDNA release from the nanocomplex with the presence of heparin, and serum stability of the nanocomplex were probed through gel electrophoresis. Nanostructure of the nanocomplexes was characterized by DLS and TEM imaging. Relative to CPCL homopolymers, PEG-b-CPCL led to better solubility over a wide range of pH. Overall, this work demonstrates that PEG-b-CPCL possesses a range of valuable properties as a promising synthetic vector for pDNA delivery.
Nanoparticles have emerged as versatile carriers for various therapeutics and can potentially treat a wide range of diseases in an accurate and disease-specific manner. Polymeric biomaterials have gained tremendous attention over the past decades, owing to their tunable structure and properties. Aliphatic polyesters have appealing attributes, including biodegradability, non-toxicity, and the ability to incorporate functional groups within the polymer backbone. Such distinctive properties have rendered them as a class of highly promising biomaterials for various biomedical applications. In this article, well-defined alkyne-functionalized poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) diblock copolymer was synthesized and studied for pH-responsive delivery of doxorubicin (DOX). The alkyne-functionalized PEG-b-PCL diblock copolymer was prepared by the synthesis of an alkyne-functionalized ε-caprolactone (CL), followed by ring-opening polymerization (ROP) using PEG as the macroinitiator. The alkyne functionalities of PEG-b-PCL were modified through copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction to graft aldehyde (ALD) groups and obtain PEG-b-PCL-g-ALD. Subsequently, DOX was conjugated on PEG-b-PCL-g-ALD through the Schiff base reaction. The resulting PEG-b-PCL-g-DOX polymer-drug conjugate (PDC) self-assembled into a nano-sized micellar structure with facilitated DOX release in acidic pH due to the pH-responsive linkage. The nanostructures of PDC micelles were characterized using transmission electron microscopy (TEM) and dynamic light scattering (DLS). In vitro studies of the PDC micelles, revealed their improved anticancer efficiency towards MCF-7 cells as compared to free DOX.
The worldwide steady increase in the number of cancer
patients
motivates the development of innovative drug delivery systems for
combination therapy as an effective clinical modality for cancer treatment.
Here, we explored a design concept based on poly(ethylene glycol)-b-poly(2-(dimethylamino)ethyl methacrylate)-b-poly(2-hydroxyethyl methacrylate-formylbenzoic acid) [PEG-b-PDMAEMA-b-P(HEMA-FBA)] for the dual delivery
of doxorubicin (DOX) and GTI2040 (an antisense oligonucleotide for
ribonucleotide reductase inhibition) to MCF-7 breast cancer cells.
PEG-b-PDMAEMA-b-PHEMA, the precursor
copolymer, was prepared through chain extensions from a PEG-based
macroinitiator via two consecutive atom transfer radical polymerization
(ATRP) steps. Then, it was modified at the PHEMA block with 4-formylbenzoic
acid (FBA) to install reactive aldehyde moieties. A pH-responsive
polymer–drug conjugate (PDC) was obtained by conjugating DOX
to the polymer structure via acid-labile imine linkages, and subsequently
self-assembled in an aqueous solution to form DOX-loaded self-assembled
nanoparticles (DOX-SAN) with a positively charged shell. DOX-SAN condensed
readily with negatively charged GTI2040 to form GTI2040/DOX-SAN nanocomplexes.
Gel-retardation assay confirmed the affinity between GTI2040 and DOX-SAN.
The GTI2040/DOX-SAN nanocomplex at N/P ratio of 30 exhibited a volume-average
hydrodynamic size of 136.4 nm and a zeta potential of 21.0 mV. The
pH-sensitivity of DOX-SAN was confirmed by the DOX release study based
on the significant cumulative DOX release at pH 5.5 relative to pH
7.4. Cellular uptake study demonstrated favorable accumulation of
GTI2040/DOX-SAN inside MCF-7 cells compared with free GTI2040/DOX.
In vitro cytotoxicity study indicated higher therapeutic efficacy
of GTI2040/DOX-SAN relative to DOX-SAN alone because of the downregulation
of the R2 protein of ribonucleotide reductase. These outcomes suggest
that the self-assembled pH-responsive triblock copolymer is a promising
platform for combination therapy, which may be more effective in combating
cancer than individual therapies.
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