2 research outputs found
Filomicelles Deliver a Chemo-Differentiation Combination of Paclitaxel and Retinoic Acid That Durably Represses Carcinomas in Liver to Prolong Survival
Drug
resistance and relapse is common in cancer treatments with
chemotherapeutics, and while drug combinations with naturally occurring,
differentiation-inducing retinoic acid (RA) provide remission-free cures for one type of liquid tumor, solid tumors present major problems
for delivery. Here, inspired by filoviruses that can be microns in
length, flexible filomicelles that self-assemble from an amphiphilic
block copolymer (PEG–PCL) are shown to effectively deliver
RA and paclitaxel (TAX) to several solid tumor models, particularly
in the liver. These hydrophobic compounds synergistically load into
the cores of the elongated micelles, and the coloaded micelles prove
most effective at causing cell death, ploidy, and durable regression
of tumors compared to free drugs or to separately loaded drugs. RA-TAX
filomicelles also reduce mortality of human lung or liver derived
cancers engrafted at liver, intraperitoneal, and subcutaneous sites
in immunodeficient mice. In vitro studies show that the dual drug
micelles effectively suppress proliferation while upregulating a generic
differentiation marker. The results highlight the potency of dual-loaded
filomicelles in killing cancer cells or else driving their differentiation
away from growth
Progerin phosphorylation in interphase is lower and less mechanosensitive than lamin-A,C in iPS-derived mesenchymal stem cells
<p>Interphase phosphorylation of lamin-A,C depends dynamically on a cell's microenvironment, including the stiffness of extracellular matrix. However, phosphorylation dynamics is poorly understood for diseased forms such as progerin, a permanently farnesylated mutant of <i>LMNA</i> that accelerates aging of stiff and mechanically stressed tissues. Here, fine-excision alignment mass spectrometry (FEA-MS) is developed to quantify progerin and its phosphorylation levels in patient iPS cells differentiated to mesenchymal stem cells (MSCs). The stoichiometry of total A-type lamins (including progerin) versus B-type lamins measured for Progeria iPS-MSCs prove similar to that of normal MSCs, with total A-type lamins more abundant than B-type lamins. However, progerin behaves more like farnesylated B-type lamins in mechanically-induced segregation from nuclear blebs. Phosphorylation of progerin at multiple sites in iPS-MSCs cultured on rigid plastic is also lower than that of normal lamin-A and C. Reduction of nuclear tension upon i) cell rounding/detachment from plastic, ii) culture on soft gels, and iii) inhibition of actomyosin stress increases phosphorylation and degradation of lamin-C > lamin-A > progerin. Such mechano-sensitivity diminishes, however, with passage as progerin and DNA damage accumulate. Lastly, transcription-regulating retinoids exert equal effects on both diseased and normal A-type lamins, suggesting a differential mechano-responsiveness might best explain the stiff tissue defects in Progeria.</p