3 research outputs found
Drug Combination Synergy in Worm-like Polymeric Micelles Improves Treatment Outcome for Small Cell and Non-Small Cell Lung Cancer
Nanoparticle-based
systems for concurrent delivery of multiple
drugs can improve outcomes of cancer treatments, but face challenges
because of differential solubility and fairly low threshold for incorporation
of many drugs. Here we demonstrate that this approach can be used
to greatly improve the treatment outcomes of etoposide (ETO) and platinum
drug combination (“EP/PE”) therapy that is the backbone
for treatment of prevalent and deadly small cell lung cancer (SCLC).
A polymeric micelle system based on amphiphilic block copolymer polyÂ(2-oxazoline)Âs
(POx) polyÂ(2-methyl-2-oxazoline-<i>block</i>-2-butyl-2-oxazoline-<i>block</i>-2-methyl-2-oxazoline) (PÂ(MeOx-<i>b</i>-BuOx-<i>b</i>-MeOx) is used along with an alkylated cisplatin prodrug
to enable co-formulation of EP/PE in a single high-capacity vehicle.
A broad range of drug mixing ratios and exceptionally high two-drug
loading of over 50% wt. drug in dispersed phase is demonstrated.
The highly loaded POx micelles have worm-like morphology, unprecedented
for drug loaded polymeric micelles reported so far, which usually
form spheres upon drug loading. The drugs co-loading in the micelles
result in a slowed-down release, improved pharmacokinetics, and increased
tumor distribution of both drugs. A superior antitumor activity of
co-loaded EP/PE drug micelles compared to single drug micelles or
their combination as well as free drug combination was demonstrated
using several animal models of SCLC and non-small cell lung cancer
<i>In Situ</i> Observation of Chymotrypsin Catalytic Activity Change Actuated by Nonheating Low-Frequency Magnetic Field
Magnetomechanical
modulation of biochemical processes is a promising
instrument for bioengineering and nanomedicine. This work demonstrates
two approaches to control activity of an enzyme, α-chymotrypsin
immobilized on the surface of gold-coated magnetite magnetic nanoparticles
(GM-MNPs) using a nonheating low-frequency magnetic field (LF MF).
The measurement of the enzyme reaction rate was carried out <i>in situ</i> during exposure to the magnetic field. The first
approach involves α-chymotrypsin-GM-MNPs conjugates, in which
the enzyme undergoes mechanical deformations with the reorientation
of the MNPs under LF MF (16–410 Hz frequency, 88 mT flux density).
Such mechanical deformations result in conformational changes in α-chymotrypsin
structure, as confirmed by infrared spectroscopy and molecular modeling,
and lead to a 63% decrease of enzyme initial activity. The second
approach involves an α-chymotrypsin–GM-MNPs/trypsin inhibitor–GM-MNPs
complex, in which the activity of the enzyme is partially inhibited.
In this case the reorientation of MNPs in the field leads to disruption
of the enzyme–inhibitor complex and an almost 2-fold increase
of enzyme activity. The results further demonstrate the utility of
magnetomechanical actuation at the nanoscale for the remote modulation
of biochemical reactions
Luteinizing Hormone Releasing Hormone-Targeted Cisplatin-Loaded Magnetite Nanoclusters for Simultaneous MR Imaging and Chemotherapy of Ovarian Cancer
Given the superior
soft tissue contrasts obtained by MRI and the
long residence times of magnetic nanoparticles (MNPs) in soft tissues,
MNP-based theranostic systems are being developed for simultaneous
imaging and treatment. However, development of such theranostic nanoformulations
presents significant challenges of balancing the therapeutic and diagnostic
functionalities in order to achieve optimum effect from both. Here
we developed a simple theranostic nanoformulation based on magnetic
nanoclusters (MNCs) stabilized by a bisphosphonate-modified polyÂ(glutamic
acid)-<i>b</i>-(ethylene glycol) block copolymer and complexed
with cisplatin. The MNCs were decorated with luteinizing hormone releasing
hormone (LHRH) to target LHRH receptors (LHRHr) overexpressed in ovarian
cancer cells. The targeted MNCs significantly improved the uptake
of the drug in cancer cells and decreased its IC<sub>50</sub> compared
to the nontargeted formulations. Also, the enhanced LHRHr-mediated
uptake of the targeted MNCs resulted in enhancement in the T<sub>2</sub>-weighted negative contrast in cellular phantom gels. Taken together,
the LHRH-conjugated MNCs show good potential as ovarian cancer theranostics