10 research outputs found
Anticancer Therapeutic Alginate-Based Tissue Sealants for Lung Repair
Injury
to the connective tissue that lines the lung, the pleura,
or the lung itself can occur from many causes including trauma or
surgery, as well as lung diseases or cancers. To address current limitations
for patching lung injuries, to stop air or fluid leaks, an adherent
hydrogel sealant patch system was developed, based on methacrylated
alginate (AMA) and AMA dialdehyde (AMA-DA) blends, which is capable
of sealing damaged tissues and sustaining physiological pressures.
Methacrylation of alginate hydroxyl groups rendered the polysaccharide
capable of photo-cross-linking when mixed with an eosin Y-based photoinitiator
system and exposed to visible green light. Oxidation of alginate yields
functional aldehyde groups capable of imine bond formation with proteins
found in many tissues. The alginate-based patch system was rigorously
tested on a custom burst pressure testing device. Blending of nonoxidized
material with oxidized (aldehyde modified) alginates yielded patches
with improved burst pressure performance and decreased delamination
as compared with pure AMA. Human mesothelial cell (MeT-5A) viability
and cytotoxicity were retained when cultured with the hydrogel patches.
The release and bioactivity of doxorubicin-encapsulated submicrospheres
enabled the fabrication of drug-eluting adhesive patches and were
effective in decreasing human lung cancer cell (A549) viability
Dual-Cross-Linked Methacrylated Alginate Sub-Microspheres for Intracellular Chemotherapeutic Delivery
Intracellular delivery vehicles comprised
of methacrylated alginate
(Alg-MA) were developed for the internalization and release of doxorubicin
hydrochloride (DOX). Alg-MA was synthesized via an anhydrous reaction,
and a mixture of Alg-MA and DOX was formed into sub-microspheres using
a water/oil emulsion. Covalently cross-linked sub-microspheres were
formed via exposure to green light, in order to investigate effects
of cross-linking on drug release and cell internalization, compared
to traditional techniques, such as ultraviolet (UV) light irradiation.
Cross-linking was performed using light exposure alone or in combination
with ionic cross-linking using calcium chloride (CaCl<sub>2</sub>).
Alg-MA sub-microsphere diameters were between 88 and 617 nm, and ζ-potentials
were between −20 and −37 mV. Using human lung epithelial
carcinoma cells (A549) as a model, cellular internalization was confirmed
using flow cytometry; different sub-microsphere formulations varied
the efficiency of internalization, with UV-cross-linked sub-microspheres
achieving the highest internalization percentages. While blank (nonloaded)
Alg-MA submicrospheres were noncytotoxic to A549 cells, DOX-loaded
sub-microspheres significantly reduced mitochondrial activity after
5 days of culture. Photo-cross-linked Alg-MA sub-microspheres may
be a potential chemotherapeutic delivery system for cancer treatment
Self-Healing and Thermoresponsive Dual-Cross-Linked Alginate Hydrogels Based on Supramolecular Inclusion Complexes
β-Cyclodextrin
(β-CD), with a lipophilic inner cavity
and hydrophilic outer surface, interacts with a large variety of nonpolar
guest molecules to form noncovalent inclusion complexes. Conjugation
of β-CD onto biomacromolecules can form physically cross-linked
hydrogel networks upon mixing with a guest molecule. Herein, the development
and characterization of self-healing, thermoresponsive hydrogels,
based on host–guest inclusion complexes between alginate-<i>graft</i>-β-CD and Pluronic F108 (polyÂ(ethylene glycol)-<i>b</i>-polyÂ(propylene glycol)-<i>b</i>-polyÂ(ethylene
glycol)), are described. The mechanics, flow characteristics, and
thermal response were contingent on the polymer concentration and
the host–guest molar ratio. Transient and reversible physical
cross-linking between host and guest polymers governed self-assembly,
allowing flow to occur under shear stress and facilitating complete
recovery of the material’s properties within a few seconds
of unloading. The mechanical properties of the dual-cross-linked,
multi-stimuli-responsive hydrogels were tuned as high as 30 kPa at
body temperature and are advantageous for biomedical applications
such as drug delivery and cell transplantation
Internalized FGF-2-Loaded Nanoparticles Increase Nuclear ERK1/2 Content and Result in Lung Cancer Cell Death
Innovative cancer treatments, which improve adjuvant therapy and reduce adverse events, are desperately needed. Nanoparticles provide controlled intracellular biomolecule delivery in the absence of activating external cell surface receptors. Prior reports suggest that intracrine signaling, following overexpression of basic fibroblast growth factor (FGF-2) after viral transduction, has a toxic effect on diseased cells. Herein, the research goals were to (1) encapsulate recombinant FGF-2 within stable, alginate-based nanoparticles (ABNs) for non-specific cellular uptake, and (2) determine the effects of ABN-mediated intracellular delivery of FGF-2 on cancer cell proliferation/survival. In culture, human alveolar adenocarcinoma basal epithelial cell line (A549s) and immortalized human bronchial epithelial cell line (HBE1s) internalized ABNs through non-selective endocytosis. Compared to A549s exposed to empty (i.e., blank) ABNs, the intracellular delivery of FGF-2 via ABNs significantly increased the levels of lactate dehydrogenase, indicating that FGF-2-ABN treatment decreased the transformed cell integrity. Noticeably, the nontransformed cells were not significantly affected by FGF-2-loaded ABN treatment. Furthermore, FGF-2-loaded ABNs significantly increased nuclear levels of activated-extracellular signal-regulated kinase ½ (ERK1/2) in A549s but had no significant effect on HBE1 nuclear ERK1/2 expression. Our novel intracellular delivery method of FGF-2 via nanoparticles resulted in increased cancer cell death via increased nuclear ERK1/2 activation