Acoustomechanically activatable liposomes for ultrasonic drug uncaging.

Ultrasound-activatable drug-loaded nanocarriers enable noninvasive and spatiotemporally-precise on-demand drug delivery throughout the body. However, most systems for ultrasonic drug uncaging utilize cavitation or heating as the drug release mechanism and often incorporate relatively exotic excipients into the formulation that together limit the drug-loading potential, stability, and clinical translatability and applicability of these systems. Here we describe an alternate strategy for the design of such systems in which the acoustic impedance and osmolarity of the internal liquid phase of a drug-loaded particle is tuned to maximize ultrasound-induced drug release. No gas phase, cavitation, or medium heating is necessary for the drug release mechanism. Instead, a non-cavitation-based mechanical response to ultrasound mediates the drug release. Importantly, this strategy can be implemented with relatively common pharmaceutical excipients, as we demonstrate here by implementing this mechanism with the inclusion of a few percent sucrose into the internal buffer of a liposome. Further, the ultrasound protocols sufficient for in vivo drug uncaging with this system are achievable with current clinical therapeutic ultrasound systems and with intensities that are within FDA and society guidelines for safe transcranial ultrasound application. Finally, this current implementation of this mechanism should be versatile and effective for the loading and uncaging of any therapeutic that may be loaded into a liposome, as we demonstrate for four different drugs in vitro, and two in vivo. These acoustomechanically activatable liposomes formulated with common pharmaceutical excipients promise a system with high clinical translational potential for ultrasonic drug uncaging of myriad drugs of clinical interest.

Heparin Biofunctionalized Selenium Nanoparticles as Potential Antiangiogenic-Chemotherapeutic Agents for Targeted Doxorubicin Delivery.

Combining antiangiogenic and chemotherapeutic agents has shown promising clinical benefits in cancer cures when the therapeutic intervention takes into account the tissue and molecular targets. Moreover, the risk of induced drug resistance is minimized when multiple pathways are involved in the treatment regimen, yielding a better therapeutic outcome. Nanodrug delivery systems have proven to be a prudent approach to treating complex disease pathologies. As such, combining antiangiogenic and chemotherapeutic drugs within multimodal nanocarriers synergistically augments the clinical efficiency of the drugs. This study reports the combinatorial efficacy of heparin (Hep), selenium NPs (SeNPs), and doxorubicin (Dox) to inhibit tumor growth and progression. Both Se@Hep-NPs and Se@Hep-Dox-NPs with excellent water dispersity having a size and charge in the range of 250 ± 5 and 253 ± 5 nm and -53 ± 0.4 and -48.4 ± 6.4 mV, respectively, showed strong anticancer potential assessed through in vitro assays like cell viability, specificity, colony formation, and wound scratch in MCF7 cells. Strong synergistic interactions among SeNPs, Hep, and Dox in Se@Hep-Dox-NPs render it to be an antiangiogenic and proapoptotic cancer cell death inducers. In vivo imaging highlights the dual-mode attributes of Se@Hep-NPs with desirable passive tumor targeting and biomedical imaging ability when tagged with Cy7.5, while Se@Hep-Dox-NPs significantly reduce the tumor burden and prolong the longevity of subcutaneous EAC-bearing mice. Histopathology studies reveal no signs of toxicity in major organs. Collectively, these results qualify Se@Hep-Dox-NPs as a plausible clinical therapeutic candidate.

Polymer-Assisted In Situ Synthesis of Silver Nanoparticles with Epigallocatechin Gallate (EGCG) Impregnated Wound Patch Potentiate Controlled Inflammatory Responses for Brisk Wound Healing.

INTRODUCTION: An ideal wound dressing material needs to be predisposed with desirable attributes like anti-infective effect, skin hydration balance, adequate porosity and elasticity, high mechanical strength, low wound surface adherence, and enhanced tissue regeneration capability. In this work, we have synthesized hydrogel-based wound patches having antibacterial silver nanoparticles and antioxidant epigallocatechin gallate (EGCG) and showed fast wound closure through their synergistic interaction without any inherent toxicity. METHODS AND RESULTS: Wound patches were synthesized from modified guar gum polymer and assessed to determine accelerated wound healing. The modified polymer beget chemical-free in-situ synthesis of monodispersed silver NPs (~12 nm), an antimicrobial agent, besides lending ionic surface charges. EGCG impregnated during ionotropic gelation process amplified the efficacy of wound patches that possess apt tensile strength, porosity, and swellability for absorbing wound exudates. Further, in vitro studies endorsed them as non-cytotoxic and the post agent effect following exposure to the patch showed an unbiased response to E coli K12 and B. subtilis. In vivo study using sub-cutaneous wounds in Wistar rats validated its accelerated healing properties when compared to a commercially available wound dressing material (skin graft; Neuskin-F®) through better wound contraction, promoted collagen deposition and enhanced vascularization of wound region by modulating growth factors and inflammatory cytokines. CONCLUSION: Synthesized wound patches showed all the desired attributes of a clinically effective dressing material and the results were validated in various in vitro and in vivo assays.

Pro-inflammatory macrophage polarization enhances the anti-cancer efficacy of self-assembled galactomannan nanoparticles entrapped with hydrazinocurcumin.

Galactomannan (GM), a natural polymer, is recognized to specifically target macrophage mannose receptors (CD206). Interestingly, some reports indicate that GM has an ability to induce pro-inflammatory (M1-like, tumericidal) polarization in macrophages, suggesting its potential use as an anti-cancer agent. Hydrazinocurcumin (HC), a pyrazole derivative of curcumin, is reported to possess increased anti-cancer efficacy over curcumin. Moreover, HC-encapsulated nanoparticles (NPs) have been reported to re-polarize tumor-associated macrophages (TAMs) from anti-inflammatory (M2-like, tumor-promoting) to pro-inflammatory phenotype. To club the therapeutic properties of both GM and HC, we synthesized self-assembled amphiphilic PEGylated GM NPs loaded with HC (PSGM-HCNPs) and evaluated their potential to re-polarize TAMs towards M1-like phenotype. PSGM-HCNPs re-polarized IL-4 polarized RAW 264.7 cells via a phenotypic switch from M2- to M1-like by elevating ROS level, decreasing CD206 and arginase-1 expressions and increasing pro-inflammatory cytokines' secretion. Conditioned medium (CM) taken from re-polarized RAW 264.7 cells containing residual PSGM-HCNPs elevated ROS, arrested cell cycle, and induced apoptosis in 4T1, breast cancer cells, and Ehrlich's ascites carcinoma (EAC) cells. Decreased levels of MMP-2, MMP-9, and Bcl-2 with increased levels of Bax in both 4T1 and EAC cells indicated anti-metastatic and apoptosis-inducing potential of the CM. Treatment of PSGM-HCNPs in EAC-bearing mice reduced tumor burden, increased their survival time, decreased CD206+F4/80+ cells, and increased TNF-α+F4/80+ cells signifying decrease in M2- and increase in M1-like skewness among ascitic TAMs.

Inhibition of Thioredoxin Reductase by Targeted Selenopolymeric Nanocarriers Synergizes the Therapeutic Efficacy of Doxorubicin in MCF7 Human Breast Cancer Cells.

Increasing evidence suggests selenium nanoparticles (Se NPs) as potential cancer therapeutic agents and emerging drug delivery carriers, yet, the molecular mechanism of their anticancer activity still remains unclear. Recent studies indicate thioredoxin reductase (TrxR), a selenoenzyme, as a promising target for anticancer therapy. The present study explored the TrxR inhibition efficacy of Se NPs as a plausible factor impeding tumor growth. Hyaluronic acid (HA)-functionalized selenopolymeric nanocarriers (Se@CMHA NPs) were designed wielding chemotherapeutic potential for target specific Doxorubicin (DOX) delivery. Se@CMHA nanocarriers are thoroughly characterized asserting their chemical and physical integrity and possess prolonged stability. DOX-loaded selenopolymeric nanocarriers (Se@CMHA-DOX NPs) exhibited enhanced cytotoxic potential toward human cancer cells compared to free DOX in an equivalent concentration eliciting its selectivity. In first-of-its-kind findings, selenium as Se NPs in these polymeric carriers progressively inhibit TrxR activity, further augmenting the anticancer efficacy of DOX through a synergistic interplay between DOX and Se NPs. Detailed molecular studies on MCF7 cells also established that upon exposure to Se@CMHA-DOX NPs, MCF7 cells endure G2/M cell cycle arrest and p53-mediated caspase-independent apoptosis. To gauge the relevance of the developed nanosystem in in vivo settings, three-dimensional tumor sphere model mimicking the overall tumor environment was also performed, and the results clearly depict the effectiveness of our nanocarriers in reducing tumor activity. These findings are reminiscent of the fact that our Se@CMHA-DOX NPs could be a viable modality for effective cancer chemotherapy.

Targeted Smart pH and Thermoresponsive N,O-Carboxymethyl Chitosan Conjugated Nanogels for Enhanced Therapeutic Efficacy of Doxorubicin in MCF-7 Breast Cancer Cells.

In cancer treatment, developing ideal anticancer drug delivery systems to target tumor microenvironment by circumventing various physiological barriers still remains a daunting challenge. Here, in our work, a series of pH- and temperature-responsive nanogels based on poly(N-isopropylacrylamide-co-1-propene-2-3-dicarboxylate-co-2-acrylamido-2-methyl-1-propanesulfonate [poly(NIPAAm-IA-AMPS)] cross-linked by ethylene glycol dimethacrylate (EGDMA) were synthesized by random copolymerization. The molar ratio between monomer-comonomers-cross-linker was varied to fine-tune the optimum responsiveness of the nanogels. These optimized nanogels were further coupled to N,O-carboxymethyl chitosan (NOCC) stoichiometrically using EDC-NHS coupling chemistry to enhance the swelling behavior at lower pH. Interestingly, these NOCC-g-nanogels, when dispersed in aqueous media under sonication, attain nanosize and retain their high water-retention capacity with conspicuous pH and temperature responsiveness (viz. nanogel shrinkage in size beyond 35 °C and swelled at acidic pH) in vitro, as reflected by dynamic light scattering data. Doxorubicin (DOX), a potent anticancer drug, was loaded into these nanogels using the physical entrapment method. These drug-loaded nanogels exhibited a slow and sustained DOX release profile at physiological temperature and cytosolic pH. Furthermore, confocal and TEM results demonstrate that these nanogels were swiftly internalized by MCF-7 cells, and cell viability data showed preferential heightened cytotoxicity toward cancer cells (MCF-7 and MDA-MB231) compared to the MCF10A cells (human breast epithelial cell). Furthermore, intracellular DNA damage and cell cycle arrest assays suggest a mitochondrial mediated apoptosis in MCF-7 cells. This study substantiates our NOCC-g-nanogel platform as an excellent modality for passive diffusive loading and targeted release of entrapped drug(s) at physiological conditions in a controlled way for the improved therapeutic efficacy of the drug in anticancer treatment.