Hydrogen Sulfide-Induced Activatable Photodynamic Therapy Adjunct to Disruption of Subcellular Glycolysis in Cancer Cells by a Fluorescence-SERS Bimodal Iridium Metal-Organic Hybrid.

The practical application of photodynamic therapy (PDT) demands targeted and activatable photosensitizers to mitigate off-target phototoxicity common in "always on" photosensitizers during light exposure. Herein, a cyclometalated iridium complex-based activatable photodynamic molecular hybrid, Cy-Ir-7-nitrobenzofurazan (NBD), is demonstrated as a biomedicine for molecular precision. This design integrates a hydrogen sulfide (H2S)-responsive NBD unit with a hydroxy-appended iridium complex, Cy-Ir-OH. In normal physiological conditions, the electron-rich Ir metal center exerts electron transfer to the NBD unit, quenches the excited state dynamics, and establishes a PDT-off state. Upon exposure to H2S, Cy-Ir-NBD activates into the potent photosensitizer Cy-Ir-OH through nucleophilic substitution. This mechanism ensures exceptional specificity, enabling targeted phototherapy in H2S-rich cancer cells. Additionally, we observed that Cy-Ir-NBD-induced H2S depletion disrupts S-sulfhydration of the glyceraldehyde-3-phosphate dehydrogenase enzyme, impairing glycolysis and ATP production in the cellular milieu. This sequential therapeutic process of Cy-Ir-NBD is governed by the positively charged central iridium ion that ensures mitochondria-mediated apoptosis in cancer cells. Dual-modality SERS and fluorescence imaging validate apoptotic events, highlighting Cy-Ir-NBD as an advanced theranostic molecular entity for activatable PDT. Finally, as a proof of concept, clinical assessment is evaluated with the blood samples of breast cancer patients and healthy volunteers, based on their H2S overexpression capability through SERS and fluorescence, revealing Cy-Ir-NBD to be a promising predictor for PDT activation in advanced cancer phototherapy.

Cyclometalated Ir(III) theranostic molecular probe enabled mitochondria targeted fluorescence-SERS-guided phototherapy in breast cancer cells.

The increased energy demands inherent in cancer cells necessitate a dependence on mitochondrial assistance for their proliferation and metastatic activity. Herein, an innovative photo-medical approach has been attempted, specifically targeting mitochondria, the cellular powerhouses, to attain therapeutic benefit. This strategy facilitates the rapid and precise initiation of apoptosis, the programmed cell death process. In this goal, we have synthesized cyclometalated Iridium (III) molecular probes, denoted as Ir-CN and Ir-H, with a nitrile (CN) and a hydrogen-functionalized bipyridine as ancillary ligands, respectively. Ir-CN has shown superior photosensitizing properties and lower dark cytotoxicity compared to Ir-H in the breast cancer cell line MCF-7, positioning it as the preferred probe for photodynamic therapy (PDT). The synthesized Ir-CN induces alterations in mitochondrial membrane potential, disrupting the respiratory chain function, and generating reactive oxygen species that activate signaling pathways leading to cell death. The CN-conjugated bipyridine ligand in Ir-CN contributes to the intense red fluorescence and the positive charge on the central metal atom facilitates specific mitochondrial colocalization (colocalization coefficient of 0.90). Together with this, the Iridium metal, with strong spin-orbit coupling, efficiently generates singlet oxygen with a quantum yield of 0.79. Consequently, the cytotoxic singlet oxygen produced by Ir-CN upon laser exposure disrupts mitochondrial processes, arresting the electron transport chain and energy production, ultimately leading to programmed cell death. This mitochondrial imbalance and apoptotic induction were dually confirmed through various apoptotic assays including Annexin V staining and by mapping the molecular level changes through surface-enhanced Raman spectroscopy (SERS). Therefore, cyclometalated Ir-CN emerges as a promising molecular probe for cancer theranostics, inducing laser-assisted mitochondrial damage, as tracked through bimodal fluorescence and SERS.

Exploring a Mitochondria Targeting, Dinuclear Cyclometalated Iridium (III) Complex for Image-Guided Photodynamic Therapy in Triple-Negative Breast Cancer Cells.

Photodynamic therapy (PDT) has emerged as an efficient and noninvasive treatment approach utilizing laser-triggered photosensitizers for combating cancer. Within this rapidly advancing field, iridium-based photosensitizers with their dual functionality as both imaging probes and PDT agents exhibit a potential for precise and targeted therapeutic interventions. However, most reported classes of Ir(III)-based photosensitizers comprise mononuclear iridium(III), with very few examples of dinuclear systems. Exploring the full potential of iridium-based dinuclear systems for PDT applications remains a challenge. Herein, we report a dinuclear Ir(III) complex (IRDI) along with a structurally similar monomer complex (IRMO) having 2-(2,4-difluorophenyl)pyridine and 4'-methyl-2,2'-bipyridine ligands. The comparative investigation of the mononuclear and dinuclear Ir(III) complexes showed similar absorption profiles, but the dinuclear derivative IRDI exhibited a higher photoluminescence quantum yield (Φp) of 0.70 compared to that of IRMO (Φp = 0.47). Further, IRDI showed a higher singlet oxygen generation quantum yield (Φs) of 0.49 compared to IRMO (Φs = 0.28), signifying the enhanced potential of the dinuclear derivative for image-guided photodynamic therapy. In vitro assessments indicate that IRDI shows efficient cellular uptake and significant photocytotoxicity in the triple-negative breast cancer cell line MDA-MB-231. In addition, the presence of a dual positive charge on the dinuclear system facilitates the inherent mitochondria-targeting ability without the need for a specific targeting group. Subcellular singlet oxygen generation by IRDI was confirmed using Si-DMA, and light-activated cellular apoptosis via ROS-mediated PDT was verified through various live-dead assays performed in the presence and absence of the singlet oxygen scavenger NaN3. Further, the mechanism of cell death was elucidated by an annexin V-FITC/PI flow cytometric assay and by investigating the cytochrome c release from mitochondria using Western blot analysis. Thus, the dinuclear complex designed to enhance spin-orbit coupling with minimal excitonic coupling represents a promising strategy for efficient image-guided PDT using iridium complexes.

Exploration of Phaeanthine: A Bisbenzylisoquinoline Alkaloid Induces Anticancer Effect in Cervical Cancer Cells Involving Mitochondria-Mediated Apoptosis.

Natural-product-based pharmacophores possess considerably more structural diversity, attractive physicochemical features, and relatively less toxicity than synthesized drug entities. In this context, our studies on phaeanthine, a bisbenzylisoquinoline alkaloid isolated from the rhizomes of Cyclea peltata (Lam) Hook.f & Thoms., showed selective cytotoxicity toward cervical cancer cells (HeLa) with an IC50 of 8.11 ± 0.04 µM. Subsequent investigation with in silico molecular docking of phaeanthine displayed preferential binding to the antiapoptotic protein Akt as reflected by a docking score of -5.023. Interestingly, the follow-up in vitro assessment of the compound correlated with mitochondria-mediated apoptosis specifically by downregulating the expression of Akt and p-Akt, including other antiapoptotic proteins MCl-1, IGF-2, and XIAP. In the complementary in vitro assessment, mitochondrial membrane polarization and dynamics of intercellular cytochrome c validated the intrinsic mechanism of the apoptotic phenomenon. To the best of our knowledge, this is the first comprehensive anticancer profiling study of phaeanthine against HeLa cells.

A clinically feasible diagnostic spectro-histology built on SERS-nanotags for multiplex detection and grading of breast cancer biomarkers.

Simultaneous detection of multiple biomarkers is always an obstacle in immunohistochemical (IHC) analysis. Herein, a straightforward spectroscopy-driven histopathologic approach has emerged as a paradigm of Raman-label (RL) nanoparticle probes for multiplex recognition of pertinent biomarkers in heterogeneous breast cancer. The nanoprobes are constructed by sequential incorporation of signature RL and target specific antibodies on gold nanoparticles, which are coined as Raman-Label surface enhanced Raman scattering (RL-SERS)-nanotags to evaluate simultaneous recognition of clinically relevant breast cancer biomarkers i.e., estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor2 (HER2). As a foot-step assessment, breast cancer cell lines having varied expression levels of the triple biomarkers are investigated. Subsequently, the optimized detection strategy using RL-SERS-nanotags is subjected to clinically confirmed, retrospective formalin-fixed paraffin embedded (FFPE) breast cancer tissue samples to fish out the quick response of singleplex, duplex as well as triplex biomarkers in a single tissue specimen by adopting a ratiometric signature RL-SERS analysis which enabled to minimize the false negative and positive results. Significantly, sensitivity and specificity of 95% and 92% for singleplex, 88% and 85% for duplex, and 75% and 67% for triplex biomarker has been achieved by assessing specific Raman fingerprints of the respective SERS-tags. Furthermore, a semi-quantitative evaluation of HER2 grading between 4+/2+/1+ tissue samples was also achieved by the Raman intensity profiling of the SERS-tag, which is fully in agreement with the expensive fluorescent in situ hybridization analysis. Additionally, the practical diagnostic applicability of RL-SERS-tags has been achieved by large area SERS imaging of areas covering 0.5-5 mm2 within 45 min. These findings unveil an accurate, inexpensive and multiplex diagnostic modality envisaging large-scale multi-centric clinical validation.

Monitoring glutathione dynamics in DNA replication (S-phase) using a two-photon reversible ratiometric fluorescent probe.

The redox regulator glutathione (GSH) migrates to the nucleus to give a safeguard to DNA replication in the S-phase. The fluctuation of GSH dynamics in the cell cycle process may help to understand cancerogenesis or other abnormalities in DNA replication. For the first time, we attempted to track the time-dependent S-phase change using the newly developed ratiometric fluorescent probe Nu-GSH. This probe is highly chemoselective towards glutathione and shows an emission intensity shift from 515 nm to 455 nm. It has shown fluorescence reversibility from blue to green channels while scavenging reactive oxygen species H2O2. Both ratiometric fluorescence images and FACS analysis have provided quantitative information on the GSH levels in the nucleoli during DNA replication in the S-phase. Furthermore, GSH fluctuation reciprocated the decay of the S-phase on a time scale. Additionally, its two-photon ability guaranteed its capability to study GSH dynamics in live cells/tissues noninvasively. We envision that the probe Nu-GSH can be used to get high-throughput quantitative information on glutathione dynamics and give an opportunity to monitor its perturbation during the course of cell division.

Spatial and seasonal trends of trace metals in the surficial sediments from off Kochi - Geochemistry and environmental implications.

Fifty four sediment samples representing pre and post-monsoon seasons were collected along a transect from off Kochi, lying between the latitudes 9°57'59.5″-9°54'30.4″ and longitudes 76°11'7.04″-75°38'50.3″ of the South eastern Arabian Sea. The present study investigates the levels of trace metals (Zn, Cd, Pb, Cu, Fe, Ni, Mn, Co and Cr), total organic carbon (TOC), total inorganic carbon (TIC), elemental composition and grain size to assess the extent of environmental pollution and to discuss the distribution of these trace metals in the surficial sediments. Sediment pollution assessment was done using the Contamination factor (C.F), Geoaccumulation Index (Igeo), Enrichment Factor (EF), and Pollution Load Index (PLI). The majority of trace metals analysed in this study exhibited the highest concentrations at stations 1, 2 and 3 where the land-based anthropogenic input was found to be maximum.

Elucidating cell surface glycan imbalance through SERS guided metabolic glycan labelling: An appraisal of metastatic potential in cancer cells.

The intrinsic complexities of cell-surface glycans impede tracking the metabolic changes in cells. By coupling metabolic glycan labelling (MGL) and surface-enhanced Raman scattering (SERS), we employed the MGL-SERS strategy to elucidate the differential glycosylation pattern in cancer cell lines. Herein, for the first time, we are reporting an N-alkyl derivative of glucosamine (GlcNPhAlk) as a glycan labelling precursor. The extent of labelling was assessed by utilizing Raman imaging and verified by complementary fluorescence and Western blot analysis. MGL-SERS technique was implemented for a comparative evaluation of cell surface glycan imbalance in different cancer cells wherein a linear relationship between glycan expression and metastatic potential was established. Further, the effect of sialyltransferase inhibitor, P-3Fax-Neu5Ac, on metabolic labelling of GlcNPhAlk proved the incorporation of GlcNPhAlk to the terminal glycans through the sialic acid biosynthetic pathway. Hence, this methodology unveils the phenomenon of metastatic progression in cancer cells with inherent glycosylation-related dysplasia.

NADH-depletion triggered energy shutting with cyclometalated iridium (III) complex enabled bimodal Luminescence-SERS sensing and photodynamic therapy.

The nicotinamide adenine dinucleotide-reduced (NADH) function as a hydride (H) carrier to maintain cellular homeostasis. Herein, we report a quinoline appended iridium complex (QAIC) as a molecular probe in fluorescence and surface-enhanced Raman spectroscopy (SERS) modalities to evaluate the endogenous NADH status. NADH-triggered activation of QAIC enabled luminescence (turn-ON) and SERS (turn-OFF) switching phenomenon with a detection limit of 25.6 nM and 15 pM for NADH in luminescence and SERS respectively. Transition state modelling using density functional theory calculations proved that a facile migration of H from NADH to QAIC transformed the activated QAIC (N-QAIC) with an energy span of 19.7 kcal/mol. Furthermore, N-QAIC is probed as a photosensitizer to source singlet oxygen by blocking the photo induced electron transfer (PeT) and generate NAD radicals. Therefore, an efficient light triggered cyclometalated iridium-based molecular probe has been divulged to promote bimodal NADH sensing and multiphase photodynamic therapy.

Dynamic self-assembly of mannosylated-calix[4]arene into micelles for the delivery of hydrophobic drugs.

Carbohydrate-lectin interactions and glycol-molecule-driven self-assembly are powerful yet challenging strategies to create supramolecular nanostructures for biomedical applications. Herein, we develop a modular approach of micellization with a small molecular mannosylated-calix[4]arene synthetic core, CA4-Man3, to generate nano-micelles, CA4-Man3-NPs, which can target cancer cell surface receptors and facilitate the delivery of hydrophobic cargo. The oligomeric nature of the calix[4]arene enables the dynamic self-assembly of calix[4]arene (CA4), where an amphiphile, functionalized with mannose units (CA-glycoconjugates) in the upper rim and alkylated lower rim, afforded the CA4-Man3-NPs in a controllable manner. The presence of thiourea units between calixarene and tri-mannose moiety facilitated the formation of a stable core with bidentate hydrogen bonds, which in turn promoted mannose receptor targeted uptake and helped in the intracellular pH-responsive release of antineoplastic doxorubicin (Dox). Physiochemical features including the stability of the nanomicelle could circumvent the undesirable leakage of the cargoes, ensuring maximum therapeutic output with minimum off-targeted toxicity. Most importantly, surface-enhanced Raman scattering (SERS) was utilized for the first time to evaluate the critical micelle concentration during the formation, cellular uptake and intracellular drug release. The present study not only provides an architectural design of a new class of organic small molecular nanomicelles but also unveils a robust self-assembly approach that paves the way for the delivery of a wide range of hydrophobic chemotherapeutic drugs.

Elucidating Raman Image-Guided Differential Recognition of Clinically Confirmed Grades of Cervical Exfoliated Cells by Dual Biomarker-Appended SERS-Tag.

Ultrasensitive detection of cancer biomarkers via single-cell analysis through Raman imaging is an impending approach that modulates the possibility of early diagnosis. Cervical cancer is one such type that can be monitored for a sufficiently long period toward invasive cancer phenotype. Herein, we report a surface-enhanced Raman scattering (SERS) nanotag (SERS-tag) for the simultaneous detection of p16/K-i67, a dual biomarker persisting in the progression of squamous cell carcinoma of human cervix. A nanoflower-shaped SERS-tag, constituted of hybrid gold nanostar with silver tips to achieve maximum fingerprint enhancement from the incorporated reporter molecule, was further functionalized with the cocktail monoclonal antibodies against p16/K-i67. The recognition by the SERS-tag was first validated in cervical squamous cell carcinoma cell line SiHa as a foot-step study and subsequently implemented to different grades of clinically confirmed exfoliated cells including normal cell (NC), high-grade intra-epithelial lesion (HC), and squamous cell carcinoma (CC) samples of the cervix. Precise Raman mapped images were constituted based on the average intensity gradient of the signature Raman peaks arising from different grades of exfoliated cells. We observed a distinct intensity hike of around 10-fold in the single dysplastic HC and CC samples in comparison to NC specimen, which clearly justify the prevalence of p16/Ki-67. The synthesized probe is able to map the abnormal cells within 20 min with high reproducibility and stability for 1 mm × 1 mm mapping area with good contrast. Amidst the challenges in Raman image-guided modality, the technique was further complemented with the gold standard immunocytochemistry (ICC) dual staining analysis. Even though both are time-consuming techniques, tedious steps can be avoided and real-time readout can be achieved using the SERS mapping unlike immunocytochemistry technique. Therefore, the newly developed Raman image-guided SERS imaging emphasizes the approach of uplifting of SERS in practical utility with further improvement for clinical applications for cervical cancer detection in future.

Mesenchymal stromal cell-derived extracellular vesicles for bone regeneration therapy.

PURPOSE: To analyze preclinical bone regeneration studies employing mesenchymal stromal cell (MSC)- derived extracellular vesicles (EVs) and highlight any commonalities in EV biomarker expression, miRNA cargo(s) or pathway activation that will aid in understanding the underlying therapeutic mechanisms. METHODS: Articles employing EVs derived from either MSCs or MSC-like osteogenic stromal cells in preclinical bone regeneration studies are included in this review. RESULTS: EVs derived from a variety of MSC types were able to successfully induce bone formation in preclinical models. Many studies failed to perform in-depth EV characterization. The studies with detailed EV characterization data report very different miRNA cargos, even in EVs isolated from the same species and cell types. Few preclinical studies have analyzed the underlying mechanisms of MSC-EV therapeutic action. CONCLUSION: There is a critical need for mechanistic preclinical studies with thorough EV characterization to determine the best therapeutic MSC-EV source for bone regeneration therapies. Issues including controlled EV delivery, large scale production, and proper storage also need to be addressed before EV-based bone regeneration therapies can be translated for clinical bone repair.

Simvastatin loaded chitosan guided bone regeneration membranes stimulate bone healing.

BACKGROUND AND OBJECTIVE: Electrospun chitosan membranes (ESCM) modified with short-chain fatty acids have the ability to control the release of simvastatin (SMV), an anti-cholesterol drug with osteogenic potential, for guided bone regeneration (GBR) applications. This study evaluated in vivo osteogenic effects of rapid short release of SMV (4 weeks) vs long sustained release (8 weeks) from acetic anhydride (AA)-and hexanoic anhydride (HA)-modified ESCMs, respectively. METHODS: AA ESCMs loaded with 10 or 50 µg SMV and HA ESCMs loaded with 50 µg SMV were evaluated for biocompatibility and bone formation at 4 and 8 weeks, in 5 mm critical size rat calvarial defects, using histological evaluation and micro-CT analysis. RESULTS: No severe inflammatory response was noticed around the ESCMs. Less hydrophobic AA membranes showed signs of resorption by week 4 and were almost completely resorbed by week 8 whereas the more hydrophobic HA membranes resorbed slowly, remaining intact over 8 weeks. In micro-CT analysis, 10 µg SMV-loaded AA membranes did not show significant bone formation as compared to non-loaded AA membranes at either evaluation time points. 50 µg SMV-loaded AA membranes stimulated significantly more bone formation than non-loaded AA membranes by week 4 (%bone = 31.0 ± 5.9% (AA50) vs 18.5 ± 13.7% (AA0)) but showed no difference at week 8. HA membranes with 50 µg SMV showed significantly more bone formation as compared to corresponding non-loaded membranes by week 8 (%bone = 61.7 ± 8.9% (HA50) vs 33.9 ± 29.7% (HA0)), though such an effect was not significant at week 4. CONCLUSION: These results indicate that modified ESCMs may be used to control the release of SMV and promote bone healing in GBR applications.

Biomaterial-based extracellular vesicle delivery for therapeutic applications.

Extracellular vesicle (EV)- based therapies have been successfully tested in preclinical models for several biomedical applications, including tissue engineering, drug delivery and cancer therapy. However, EVs are most commonly delivered via local or systemic injection, which results in rapid clearance. In order to prolong the retention of EVs at target site and improve their therapeutic efficacy, biomaterial-based delivery systems are being investigated. This review discusses the various biomaterial-based systems that have been used to deliver EVs for therapeutic applications, specifically highlighting any strategies for controlled release. Further, challenges to clinical translation of biomaterial-based EV delivery systems are also discussed.

Phthalimide conjugation turns the AIE-active tetraphenylethylene unit non-emissive: its use in turn-on sensing of hydrazine in solution and the solid- and vapour-phase.

Hydrazine is a vital precursor used in several pharmaceuticals and pesticide industries and upon exposure can cause severe health hazards. Herein, a new AIEgen, tetraphenylethylene phthalimide (TPE-PMI), is synthesized in a one-step solvent-free mechanochemical approach exploiting the simple condensation between TPE-NH2 and phthalic anhydride and used for the selective and sensitive detection of hydrazine. TPE-PMI with an AIE-active TPE-moiety is non-emissive in the solid phase by design. Hydrazine performs the cleavage of TPE-PMI in a typical "Gabriel synthesis" pathway to release AIE-active TPE-NH2 in an aqueous solution to emit blue fluorescence. A gradual rise in fluorescence intensity at 462 nm was due to the increasing hydrazine concentration and TPE-PMI showed a linear relationship with hydrazine in the concentration range from 0.2 to 3 µM. The selectivity study confirmed that the probe is inert to amines, amino acids, metal anions, anions and even common oxidants and reductants. The detection limit is 6.4 ppb which is lower than the US Environmental Protection Agency standard (10 ppb). The practical utilities of TPE-PMI were successfully demonstrated through quantitative detection of hydrazine vapour on solid platforms like paper strips and TLC plates. Furthermore, on-site detection of hydrazine in the solid phase was demonstrated by spiking the soil samples with measured quantities of hydrazine and quantitation through image analysis. This cost-effective sensing tool was successfully utilized in in vitro detection of hydrazine in live HeLa cells.

NADH-Activated Dual-Channel Fluorescent Probes for Multicolor Labeling of Live Cells and Tumor Mimic Spheroids.

The 1,4-dihydronicotinamide adenine dinucleotide (NADH) is one of the key coenzymes that participates in various metabolic processes including maintaining the redox balance. Early information on the imbalance of NADH is crucial in the context of diagnosing the pathogenic conditions. Thus, a dual-channel fluorescent probe (MQN) is developed for tracking of NADH/NAD(P)H in live cells. In the presence of NADH, only it showed emission signals at 460 and 550 nm upon excitation at 390 and 450 nm, respectively. The probe could provide accurate information on NADH levels in cancer cells (HeLa) and normal cells (WI-38). We observed that the NADH level in cancer cells (HeLa) is relatively higher than that in normal WI-38 cells. We received similar information on NADH upon calibrating with a commercial NADH kit. Moreover, we evaluated substrate-specific NADH expression in the glycolysis pathway and oxidative phosphorylation process. Also, the dual-channel probe MQN has visualized NADH manipulation in the course of depletion of GSH to maintain cellular redox balance. This dual-channel molecular probe MQN comes out as a new detection tool for NADH levels in live cells and tumor mimic spheroids.

Modified electrospun chitosan membranes for controlled release of simvastatin.

Chitosan nanofibrous membranes have immense potential in tissue engineering and drug delivery applications because of their increased surface area, high degree of biocompatibility, and their ability to mimic the extracellular matrix. However, their use is often limited due to their extreme hydrophilic nature causing them to lose their nanofibrous structure in vivo. In the present study, chitosan membranes were modified either by acylation reactions using fatty acids of different chain lengths or tert-butyloxycarbonyl (tBOC) protecting groups to increase the hydrophobicity of the membranes and protect the nanofibrous structure. The modified membranes were characterized using scanning electron microscopy, attenuated total reflectance Fourier transform infrared spectroscopy, water contact angle and elemental analysis to confirm the addition of the modification groups. These membranes were then evaluated to control the release of a hydrophobic osteogenic drug-simvastatin (SMV). The interaction between SMV and the polymer was determined using molecular modeling. Pure SMV and SMV loaded membranes were examined for their in vitro cytotoxicity and osteogenic potential using preosteoblast mouse bone marrow stromal cells. From results, it was evident that as the fatty acid chain length increased from two to six methylene groups, the hydrophobicity of the membranes increased (59.2 ± 8.2° to 94.3 ± 8.5° water contact angle). The amount of drug released from the membranes could be controlled by changing the amount of initial drug loaded and/or the type of modifications. After 4 weeks, for a 500 µg loading, the short chain fatty acid modified membranes released 17.8 ± 3.2% of the drug whereas a long chain fatty acid released only 4.8 ± 0.8%. Similarly, for a 50 µg loading, short chain modified membranes released more (73.3 ± 33.3%) of the loaded drug as compared to the long chain membranes (43.0 ± 3.5%). The long chain fatty acid membranes released SMV for extended time periods of up to 90 days. This data was further supported by molecular modeling, which revealed that SMV was more compatible with more hydrophobic membranes. Cell studies showed that pure SMV from 75 to 600 ng/ml range possessed osteogenic potential in a dose dependent manner and the amount of SMV released from the most hydrophobic FA treated membranes was not cytotoxic and supported osteogenic differentiation. Therefore, this study demonstrates our ability to control the release of a hydrophobic drug from modified chitosan membranes as per the clinical need.

Surface charge modulates the internalization vs. penetration of gold nanoparticles: comprehensive scrutiny on monolayer cancer cells, multicellular spheroids and solid tumors by SERS modality.

Precise control over the dynamics of nanoparticles (NPs) in a tumor microenvironment is highly warranted for the development of an efficient nanotheranostic agent. Even though inductively coupled plasma mass spectrometry can provide a quantitative assessment regarding the uptake efficiency of metal NPs, enumeration of deep tissue penetration capacity remains as a challenge. Herein, we have demonstrated an accurate tracking of the uptake efficiency and penetration phenomenon of gold nanoparticles (AuNPs: 40-50 nm) with respect to three different surface charges in monolayer (2D) cells, multicellular spheroids (3D) and in vivo tumors by surface-enhanced Raman spectroscopy (SERS). While positively charged AuNPs showed around two-fold increased internalization in monolayer cells, SERS-tag-based line scanning on multi-layered tumor spheroids illustrated almost nine-fold superior penetration capability with negatively charged AuNPs. Further, the enhanced solid tumor distribution contributed by the negatively charged AuNPs could appreciably escalate its clinical utility in cancer management.

Stimuli-Responsive Drug Release from Smart Polymers.

Over the past 10 years, stimuli-responsive polymeric biomaterials have emerged as effective systems for the delivery of therapeutics. Persistent with ongoing efforts to minimize adverse effects, stimuli-responsive biomaterials are designed to release in response to either chemical, physical, or biological triggers. The stimuli-responsiveness of smart biomaterials may improve spatiotemporal specificity of release. The material design may be used to tailor smart polymers to release a drug when particular stimuli are present. Smart biomaterials may use internal or external stimuli as triggering mechanisms. Internal stimuli-responsive smart biomaterials include those that respond to specific enzymes or changes in microenvironment pH; external stimuli can consist of electromagnetic, light, or acoustic energy; with some smart biomaterials responding to multiple stimuli. This review looks at current and evolving stimuli-responsive polymeric biomaterials in their proposed applications.

Curculigoside augments cell-mediated immune responses in metastatic tumor-bearing animals.

A positive modulation of immune system is necessary for preparing the body to fight against malignant tumor cells. In the present study, the stimulatory effect of Curculigoside on cell-mediated immune response against the metastasis of B16F10 melanoma cells was analyzed in C57BL/6 mice. Curculigoside is a phenolic glucoside present in the plant Curculigo orchioides Gaertn. (Family - Amaryllidaceae). Administration of Curculigoside enhanced the natural killer (NK) cell activity, antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity in metastatic tumor-bearing animals, when compared to the untreated control animals. The compound was also found to be effective in reducing the levels of proinflammatory cytokines such as TNF-α, IL-1ß, IL-6 and GM-CSF during metastasis. Besides these, levels of TH1 cytokines, such as IL-2 and IFN-γ, were significantly enhanced (p < 0.001) by Curculigoside administration and thereby reduces the metastatic lung colony formation along with an increased lifespan of the experimental animals. These studies provide an evidence for the stimulation of cell-mediated immune responses by Curculigoside against B16F10-induced metastatic tumor progression in experimental animals.