Hybrid PEGylated chitosan/PLGA nanoparticles designed as pH-responsive vehicles to promote intracellular drug delivery and cancer chemotherapy.

To achieve effective intracellular anticancer drug release for boosted antitumor efficacy, the acidity-responsive nanovehicles for doxorubicin (DOX) delivery were fabricated by tailor-made co-assembly of amphiphilic PEGylated chitosan20k and hydrophobic poly(lactic-co-glycolic acid) (PLGA) segments at pH 8.5. The attained DOX-loaded PEGylated chitosan20k/PLGA nanoparticles (DOX-PC20kPNs) were characterized to have a spherical shape composed of drug-encapsulated chitosan20k/PLGA-constituted solid core surrounded by hydrophilic PEG shells. Compared to non-pH-sensitive DOX-loaded PLGA nanoparticles (DOX-PNs), the DOX-PC20kPNs displayed outstanding colloidal stability under serum-containing condition and tended to swell in weak acidic milieu upon increased protonation of chitosan20k within hybrid cores, thus accelerating drug release. The in vitro cellular uptake and cytotoxicity studies revealed that the DOX-PC20kPNs after being endocytosed by prostate TRAMP-C1 cancer cells rapidly liberated drug, thus promoting drug accumulation in nuclei to enhance anticancer potency. Moreover, the hydrated PEG shells of DOX-PC20kPNs remarkably reduced their uptake by macrophage-like RAW264.7 cells. Importantly, in vivo animal findings showed that the DOX-PC20kPNs exhibited the capability of inhibiting TRAMP-C1 tumor growth superior to free hydrophobic DOX molecules and DOX-PNs, demonstrating the great potential in cancer chemotherapy.

Tumor acidity-responsive polymeric nanoparticles to promote intracellular delivery of zoledronic acid by PEG detachment and positive charge exposure for enhanced antitumor potency.

Zoledronic acid (ZA), a third-generation bisphosphonate, has been extensively used to treat osteoporosis and cancer bone metastasis and demonstrated to suppress proliferation of varied cancer cells and selectively kill tumor-associated microphages (TAMs). However, the clinical applications of ZA in extraskeletal tumor treatment are largely restricted due to its rapid renal clearance and binding to bones. In this study, to promote intracellular delivery of ZA for amplified antitumor efficacy, tumor acidity-responsive polymeric nanoparticles with high ZA payload (ca. 12.3 wt%) and low premature ZA leakage were designed. As a pivotal material for surface coating, the acidity-sensitive and amphiphilic methoxy poly(ethylene glycol) (mPEG)-benzoic imine-octadecane (C18) (mPEG-b-C18) was synthesized by conjugation of mPEG-CHO with 1-octadecylamine upon Schiff base reaction. Through tailor-made co-assembly of the hydrophobic poly(lactic-co-glycolic acid) (PLGA), amphiphilic tocopheryl polyethylene glycol succinate (TPGS) and mPEG-b-C18 to encapsulate ionic complexes composed of ZA molecules and branched poly(ethylenimine) (PEI) segments, the attained therapeutic polymeric nanoparticles, characterized to have a hydrophobic PLGA/ZA/PEI-constituted core covered with mPEG-b-C18 and TPGS, were able to not only detach mPEG shielding upon acidity-triggered hydrolysis of benzoic imine bonds but also expose surface positive charges of protonated PEI segments. The in vitro cellular uptake and cytotoxicity studies demonstrated that the internalization of acidity-sensitive ZA-encapsulated nanoparticles by TRAMP-C1 mouse prostate cancer cells and murine macrophages RAW 264.7 was considerably promoted upon acidity-elicited PEG detachment and surface charge conversion, thus remarkably boosting intracellular ZA delivery and anticancer potency. Compared to PEG non-detachable ZA-loaded nanoparticles with poor tumor deposition and antitumor effect, the PEG-detachable ZA-carrying nanoparticles markedly accumulated in TRAMP-C1 solid tumors in vivo and inhibited tumor growth, thereby increasing the survival rate of the treated mice. The collective data suggest the great promise of tumor acidity-sensitive ZA-carrying hybrid nanoparticles in the treatment of extraskeletal solid tumors.

Government-sponsored disinformation and the severity of respiratory infection epidemics including COVID-19: A global analysis, 2001-2020.

Internet misinformation and government-sponsored disinformation campaigns have been criticized for their presumed/hypothesized role in worsening the coronavirus disease 2019 (COVID-19) pandemic. We hypothesize that these government-sponsored disinformation campaigns have been positively associated with infectious disease epidemics, including COVID-19, over the last two decades. By integrating global surveys from the Digital Society Project, Global Burden of Disease, and other data sources across 149 countries for the period 2001-2019, we examined the association between government-sponsored disinformation and the spread of respiratory infections before the COVID-19 outbreak. Then, building on those results, we applied a negative binomial regression model to estimate the associations between government-sponsored disinformation and the confirmed cases and deaths related to COVID-19 during the first 300 days of the outbreak in each country and before vaccination began. After controlling for climatic, public health, socioeconomic, and political factors, we found that government-sponsored disinformation was significantly associated with the incidence and prevalence percentages of respiratory infections in susceptible populations during the period 2001-2019. The results also show that disinformation is significantly associated with the incidence rate ratio (IRR) of cases of COVID-19. The findings imply that governments may contain the damage associated with pandemics by ending their sponsorship of disinformation campaigns.

Indocyanine green-carrying polymeric nanoparticles with acid-triggered detachable PEG coating and drug release for boosting cancer photothermal therapy.

In order to boost anticancer efficacy of indocyanine green (ICG)-mediated photothermal therapy (PTT) by promoting intracellular ICG delivery, the ICG-carrying hybrid polymeric nanoparticles were fabricated in this study by co-assembly of hydrophobic poly(lactic-co-glycolic acid) (PLGA) segments, ICG molecules, amphiphilic tocopheryl polyethylene glycol succinate (TPGS) and pH-responsive methoxy poly(ethylene glycol)-benzoic imine-1-octadecanamine (mPEG-b-C18) segments in aqueous solution. The ICG-loaded nanoparticles were characterized to have ICG-containing PLGA core stabilized by hydrophilic PEG-rich surface coating and a well-dispersed spherical shape. Moreover, the ICG-loaded nanoparticles in pH 7.4 aqueous solution sufficiently inhibited ICG self-aggregation and leakage, thereby increasing aqueous photostability of ICG molecules. Notably, when the solution pH was reduced from pH 7.4-5.5, the acid-triggered hydrolysis of benzoic-imine linkers within mPEG-b-C18 remarkably facilitated the detachment of mPEG segments from ICG-loaded nanoparticles, thus accelerating ICG release. The findings of in vitro cellular uptake and cytotoxicity studies further demonstrated that the PEGylated ICG-carrying hybrid nanoparticles were efficiently internalized by MCF-7 cells compared to free ICG and realized intracellular acid-triggered rapid ICG liberation, thus enhancing anticancer effect of ICG-mediated PTT to potently kill cancer cells.

Hybrid polymeric nanoparticles with high zoledronic acid payload and proton sponge-triggered rapid drug release for anticancer applications.

Zoledronic acid (ZA), a third-generation nitrogen-heterocycle-containing bisphosphonate, has been frequently used as an anti-resorptive agent to treat cancer-involved hypercalcemia and painful bone metastases. In order to expand the clinical applications of ZA toward the extraskeletal tumor treatment, it is essential to develop the functionalized nanocarriers capable of carrying high ZA payload and achieving intracellular triggered ZA release. In this end, the ZA-encapsulated hybrid polymeric nanoparticles were fabricated in this work by co-association of the amphiphilic diblock copolymer poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG), tocopheryl polyethylene glycol succinate (TPGS) segments and ionic complexes composed of ZA molecules and branched poly(ethylenimine) (PEI) segments. Notably, the ionic pairings of PEI segments with ZA molecules not only assisted encapsulation of ZA into the PLGA-rich core of hybrid nanoparticles but also reduced adhesion of ZA on the surfaces of hydrophobic cores, thus largely increasing ZA loading capacity. The dynamic light scattering (DLS) and transmission electron microscopy (TEM) characterization revealed that the ZA/PEI-loaded nanoparticles had a well-dispersed spherical shape. Moreover, compared to short PEI1.8k (1.8 kDa) segments, the longer PEI10k (10 kDa) segments formed more robust complexes with ZA molecules, thus prominently promoting ZA loading content of hybrid nanoparticles and their colloidal stability. Interestingly, with the suspension pH being reduced from 7.4 to 5.0, the considerable disruption of ZA/PEI ionic complexes owing to the acid-activated protonation of ZA molecules and the developed proton sponge-like effect inside the nanoparticle matrix upon the protonated PEI segments facilitated the rapid release of ZA molecules from drug-loaded hybrid nanoparticles. The results of in vitro cellular uptake and cytotoxicity studies showed that the ZA/PEI-loaded hybrid nanoparticles were internalized by MCF-7 cells upon energy-dependent endocytosis and displayed a superior cytotoxic effect to free ZA. This work demonstrates that the unique ZA/PEI-loaded hybrid polymeric nanoparticles display great promise for anticancer applications.

pH-responsive polymeric micelles self-assembled from benzoic-imine-containing alkyl-modified PEGylated chitosan for delivery of amphiphilic drugs.

In order to efficiently promote loading efficiency and aqueous photostability of indocyanine green (ICG), an amphiphilic tricarbocyanine dye, the polysaccharide-based nanomicelles utilized as a vehicle for ICG were fabricated by self-assembly of the amphiphilic benzoic-imine-containing PEGylated chitosan/4-(dodecyloxy)benzaldehyde (DBA) conjugates in aqueous solution of pH 7.4. The resulting polymeric micelles were characterized to have a hydrophobic hybrid chitosan/DBA core surrounded by hydrophilic PEG shells. Importantly, the encapsulation of ICG into the hybrid chitosan/DBA core of polymeric micelles by the combined hydrophobic and electrostatic interactions not only promoted the ICG loading but also enhanced its aqueous photostability. With the pH of micelle suspension being reduced from 7.4 to 5.0, upon acid-triggered cleavage of benzoic-imine bonds between chitosan and DBA as well as the extending of the protonated chitosan segments from hybrid cores toward aqueous phase, the rather hydrophobic DBA-rich core was formed within micelles, thereby leading to shrinking of the polymeric micelles. The robust ICG-loaded polymeric micelles showed several superior properties including the inhibition of ICG leakage under the mimic physiological and acidic conditions, favorable biocompatibility and photo-activated hyperthermia effect. This work suggests that the pH-responsive ICG-carrying chitosan-based micelles display great potential in cancer theranostic.