The SH-SY5Y cell line: a valuable tool for Parkinson's disease drug discovery.

INTRODUCTION: Owing to limited efficient treatment strategies for highly prevalent and distressing Parkinson's disease (PD), an impending need emerged for deciphering new modes and mechanisms for effective management. SH-SY5Y-based in vitro neuronal models have emerged as a new possibility for the elucidation of cellular and molecular processes in the pathogenesis of PD. SH-SY5Y cells are of human origin, adhered to catecholaminergic neuronal attributes, which consequences in imparting wide acceptance and significance to this model over conventional in vitro PD models for high-throughput screening of therapeutics. AREAS COVERED: Herein, the authors review the SH-SY5Y cell line and its value to PD research. The authors also provide the reader with their expert perspectives on how these developments can lead to the development of new impactful therapeutics. EXPERT OPINION: Encouraged by recent research on SH-SY5Y cell lines, it was envisaged that this in vitro model can serve as a primary model for assessing efficacy and toxicity of new therapeutics as well as for nanocarriers' capacity in delivering therapeutic agents across BBB. Considering the proximity with human neuronal environment as in pathogenic PD conditions, SH-SY5Y cell lines vindicated consistency and reproducibility in experimental results. Accordingly, exploitation of this standardized SH-SY5Y cell line can fast-track the drug discovery and development path for novel therapeutics.

Biomacromolecule-based nanocarrier strategies to deliver plant-derived bioactive components for cancer treatment: A recent review.

The quest for safe chemotherapy has attracted researchers to explore anticancer potential of herbal medicines. Owing to upsurging evidence of herbal drug's beneficial effects, hopes are restored for augmenting survival rates in cancer patients. However, phytoconstituents confronted severe limitations in terms of poor absorption, low-stability, and low bioavailability. Along with toxicity issues associated with phytoconstituents, quality control and limited regulatory guidance also hinder the prevalence of herbal medicines for cancer therapy. Attempts are underway to exploit nanocarriers to circumvent the limitations of existing and new herbal drugs, where biological macromolecules (e.g., chitosan, hyaluronic acid, etc.) are established highly effective in fabricating nanocarriers and cancer targeting. Among the discussed nanocarriers, liposomes and micelles possess properties to cargo hydro- and lipophilic herbal constituents with surface modification for targeted delivery. Majorly, PEG, transferrin and folate are utilized for surface modification to improve bioavailability, circulation time and targetability. The dendrimer and carbon nanotubes responded in high-loading efficiency of phytoconstituent; whereas, SLN and nanoemulsions are suited carriers for lipophilic extracts. This review emphasized unveiling the latent potential of herbal drugs along with discussing on extended benefits of nanocarriers-based delivery of phytoconstituents for safe cancer therapy owing to enhanced clinical and preclinical outcomes without compromising safety.

The Female Reproductive Tract Microbiota: Friends and Foe.

We do not seem to be the only owner of our body; it houses a large population of microorganisms. Through countless years of coevolution, microbes and hosts have developed complex relationships. In the past few years, the impact of microbial communities on their host has received significant attention. Advanced molecular sequencing techniques have revealed a remarkable diversity of the organ-specific microbiota populations, including in the reproductive tract. Currently, the goal of researchers has shifted to generate and perceive the molecular data of those hidden travelers of our body and harness them for the betterment of human health. Recently, microbial communities of the lower and upper reproductive tract and their correlation with the implication in reproductive health and disease have been extensively studied. Many intrinsic and extrinsic factors influences the female reproductive tract microbiota (FRTM) that directly affects the reproductive health. It is now believed that FRTM dominated by Lactobacilli may play an essential role in obstetric health beyond the woman's intimate comfort and well-being. Women with altered microbiota may face numerous health-related issues. Altered microbiota can be manipulated and restored to their original shape to re-establish normal reproductive health. The aim of the present review is to summarize the FRTM functional aspects that influence reproductive health.

Augmented Therapeutic Efficacy of Naringenin Through Microemulsion-Loaded Sericin Gel Against UVB-Induced Photoaging.

Naringenin (NAR) is a flavonoid found in citrus fruits such as grapes and oranges. Recently, NAR has demonstrated its potential in inhibition of photoaging. The aim of the present study was to investigate the efficacy of sericin (SR) gel loaded with NAR microemulsion (ME) to inhibit UVB-induced photoaging and prevention of epidermoid carcinoma in animal model. NAR -ME was prepared and optimized through Box-Behnken design. The optimized ME was loaded into sericin (SR) gel. The formulations were subjected to various in vitro, in vivo and cytotoxicity studies over A431 cell lines. The optimized ME revealed a globule size of 249.05 ± 3.78 nm, 6.7 ± 0.5 pH and 73.1 ± 2.11% release over a period of 24 h respectively. Cytotoxicity studies revealed a depression in IC50 value in NAR -ME (65.11 ± 1.54 µg/ml) when compared with NAR (118.1 ± 2.09 µg/ml). The NAR-ME-SR gel displayed enhanced therapeutic potential when compared with plain NAR, in terms of augmented antiproliferative activity. Graphical abstract.

Magnetic Targeting and Ultrasound Activation of Liposome-Microbubble Conjugate for Enhanced Delivery of Anticancer Therapies.

Effective delivery of chemotherapeutics with minimal toxicity and maximal outcome is clinically important but technically challenging. Here, we synthesize a complex of doxorubicin (DOX)-loaded magneto-liposome (DOX-ML) microbubbles (DOX-ML-MBs) for magnetically responsive and ultrasonically sensitive delivery of anticancer therapies with enhanced efficiency. Citrate-stabilized iron oxide nanoparticles (MNs) of 6.8 ± 1.36 nm were synthesized, loaded with DOX in the core of oligolamellar vesicles of 172 ± 9.2 nm, and covalently conjugated with perfluorocarbon (PFC)-gas-loaded microbubbles to form DOX-ML-MBs of ∼4 µm. DOX-ML-MBs exhibited significant magnetism and were able to release chemotherapeutics and DOX-MLs instantly upon exposure to ultrasound (US) pulses. In vitro studies showed that DOX-ML-MBs in the presence of US pulses promoted apoptosis and were highly effective in killing both BxPc-3 and Panc02 pancreatic cancer cells even at a low dose. Significant reduction in the tumor volume was observed after intravenous administration of DOX-ML-MBs in comparison to the control group in a pancreatic cancer xenograft model of nude mice. Deeply penetrated iron oxide nanoparticles throughout the magnetically targeted tumor tissues in the presence of US stimulation were clearly observed. Our study demonstrated the potential of using DOX-ML-MBs for site-specific targeting and controlled drug release. It opens a new avenue for the treatment of pancreatic cancer and other tissue malignancies where precise delivery of therapeutics is necessary.

Uniaxial Stretching of Cell-Laden Microfibers for Promoting C2C12 Myoblasts Alignment and Myofibers Formation.

Fiber-shaped cellular constructs have attracted increasing attention in the regeneration of blood vessels, nerve networks, and skeletal myofibers. Nevertheless, the generation of functional fiber-shaped cellular constructs suffers from limited appropriate microfiber-based fabrication approaches and the maintenance of regenerated tissue functions. Herein, we demonstrate a silicone-tube-based coagulant bath free method to fabricate tens of centimeters long cell-laden microfibers using single UV exposure without pretreatment of nozzles or microchannels. By modulating the exposure time, the gelatin methacrylate microfibers with tissue-like microstructures and mechanical properties are obtained. Then, a culture system integrated with a pillar well-array based stretching device is used to apply uniaxial stretching with various strain ratios in situ to cell-laden microfibers in a 60 mm petri dish. Cells with improved spreading, elongation, and alignment are obtained under uniaxial stretching. Moreover, the promotional effects of uniaxial stretching on the differentiation of C2C12 myoblasts, the formation, and contractility of myofibers become more pronounced with increasing strain ratio and achieve saturation level as strain ratio up to ∼35%.

Synthesis of a functionalized dipeptide for targeted delivery and pH-sensitive release of chemotherapeutics.

Targeted delivery of chemotherapeutics to tumor cells is one of the biggest challenges in cancer treatment. Herein, we synthesized smart dipeptide nanoparticles for cancer-specific targeting and intracellular pH-sensitive release of chemotherapeutics. Diphenylalanine peptide was synthesized and further developed as nanoparticles (NPs), which were functionalized with folic acid utilizing the carbodiimide reaction. Doxorubicin (Dox) was loaded to self-assembled non-functionalized (FF-Dox) and folate functionalized peptides NPs (FA-FF-Dox). Moreover, the experiments revealed the pH-sensitive release of Dox for both FA-FF-Dox and FF-Dox due to the protonation of the Schiff base and the amines present in the peptides at low pH, enhancing intracellular release subsequent to receptor-mediated endocytosis. Further, biodistribution and the pharmacokinetics study revealed enhanced targeting efficiency of FA-FF-Dox with high accumulation in tumor cells.

Engineered multifunctional biodegradable hybrid microparticles for paclitaxel delivery in cancer therapy.

Ovarian cancer is one of the most lethal gynecologic malignancies due to its rapid proliferation, frequent acquisition of chemoresistance, and widespread metastasis within the peritoneal cavity. Intraperitoneal (IP) chemotherapy has demonstrated significant anti-cancer potential but its broad clinical application is hindered by several drug delivery limitations. Herein, we engineer paclitaxel (PTX) laden hybrid microparticles (PTX-Hyb-MPs) for improved delivery of chemotherapy in ovarian cancer. The PTX-Hyb-MPs are comprised of a lipid-coated shell of poly (lactic acid-co-glycolic acid) (PLGA) encapsulating hydrophobic PTX. A co-axial electrohydrodynamic (CEH) process is used for one-step and scalable production of the PTX-Hyb-MP agent with controlled particles size, uniform size distribution, tunable thickness, and high encapsulation rate (92.17 ±â€¯6.9%). The multi-layered structure of the PTX-Hyb-MPs is verified by transmission electron microscopy and confocal fluorescence microscopy. The effect of lipid coating on the enhancement of particle interactions with cancer cells is studied by flow cytometry and confocal fluorescence microscopy. The anti-cancer effect of the PTX-Hyb-MPs is evaluated in SKOV-3 ovarian cancer cells in vitro and a cancer xenograft model in vivo, in comparison with conventional drug delivery methods. Our studies reveal that the PTX-Hyb-MP agent can be potentially used for locoregional treatment of ovarian cancer and other tissue malignancies with sustained drug release, tunable release profiles, enhanced drug uptake, and reduced systemic toxicity.

Targeted co-delivery of the aldose reductase inhibitor epalrestat and chemotherapeutic doxorubicin via a redox-sensitive prodrug approach promotes synergistic tumor suppression.

Rapidly growing evidence suggests a strong dependence of a polyol pathway enzyme Aldose Reductase (AR) in cancer progression and invasion. Thus, inhibiting the AR through therapeutic inhibitors has a potential application in cancer treatment. Epalrestat (EPR) is the only marketed AR inhibitor with proven safety and efficacy in the management of complications like diabetic neuropathy. However, its short half-life and highly hydrophobic nature restrict its use as an anticancer agent. In the present study, we first developed a redox-sensitive prodrug of EPR by conjugating Tocopherol Polyethylene Glycol Succinate (TPGS) which can form a self-assembled micellar prodrug (EPR-SS-TPPGS). Subsequently, to achieve synergistic chemotherapeutic efficacy Doxorubicin (Dox) was co-loaded into the EPR-SS-TPGS micelles where the system is disrupted in a tumor redox environment and co-delivers Dox and EPR in a ratiometric manner. We then employed TPGS conjugated vitamin-B6 as a targeting moiety and prepared the mixed micelles to facilitate VTC receptor-mediated uptake. The encapsulation of Dox and EPR with the developed prodrug approach showed significant synergies with increased intracellular accumulation and redox triggered release in MDA-MB-231 and 4T1 cell lines leading to superior cell cycle arrest, mitochondrial membrane potential, and apoptosis. Prolonged circulation half-life and tumor site bioavailability were achieved for both the drugs with the developed approach. Surprisingly, EPR and Dox combination significantly down-regulated the CD44 receptor expression which is the main contributing factor of tumor metastasis. Furthermore, in vivo evaluation demonstrated a significant reduction in Dox-induced cardiotoxicity. In summary, this nanoencapsulation paradigm of AR inhibitors with chemotherapeutic agents lays the foundation of new opportunities in combination chemotherapy.

Sustained release paclitaxel-loaded core-shell-structured solid lipid microparticles for intraperitoneal chemotherapy of ovarian cancer.

The current clinical paradigm for ovarian cancer treatment has a poor prognosis, partially due to the efficacy and toxicity concerns associated with the available chemotherapeutic formulations. To overcome these limitations, we have designed core-shell-structured paclitaxel (PTX) laden solid lipid microparticles (PTX-SLMPs) for intraperitoneal treatment of ovarian cancer. A single-step coaxial electro hydrodynamic atomization (CEHDA) process has been explored to synthesize core-shell structure of PTX-SLMPs with the particle size of 1.76 ± 0.37 µm. Core-shell PTX-SLMPs have high encapsulation efficiency of 94.73% with sustained drug release profile. In vitro evaluation of PTX-SLMPs in SKOV-3 ovarian cancer cells yield significant enhancement in cytotoxicity when compared with Taxol®. In vivo pharmacokinetic study demonstrated slower absorption of PTX into the systemic circulation after intraperitoneal (i.p.) administration of PTX-SLMPs in Wistar rats implying the PTX-SLMPs remained in the peritoneal cavity and released the PTX for prolonged period of time. Through these studies, we have demonstrated the technical potential of core-shell structured PTX-SLMPs, which can enhance passive targeting of PTX to the tumor in the treatment of not only ovarian cancer but also in other peritoneal cancer.

Dextrose modified bilosomes for peroral delivery: improved therapeutic potential and stability of silymarin in diethylnitrosamine-induced hepatic carcinoma in rats.

Hepatic carcinoma (HC) is one of the most prevalent cancers, ranked as the second most common cause of cancer-related deaths worldwide. Silymarin (SYL) has been reported for its anticarcinogenic activity against various types of cancer such as prostate, breast, ovary, colon, lung, bladder and liver. Due to poor solubility and low bioavailability SYL lacks satisfactory therapeutic value thus designing a suitable and effective delivery system of SYL can led to improved therapeutic potential. The present study was aimed to develop SYL-loaded dextrose (DEX) modified bilosomes for targeted delivery to HC cells. The DEX-modified bilosomes were prepared through thin-film hydration method and optimized employing Box Behnken design. The bilosomes were evaluated for percent entrapment, drug loading, in vitro release and cytotoxicity on Hep-G2 cells. The optimized DEX-SYL-BL exhibited a particle size of 219.3 ± 2.99 nm, percent entrapment of 62.32 ± 4.23%, drug loading of 34.56 ± 1.23% and 84.96 ± 2.76% drug release respectively over a period of 24 hr. The stability of bilosomes was ascertained in simulated gastric and intestinal fluids. Cytotoxicity studies revealed greater performance of DEX-SYL-BL in terms of reduced viability in Hep-G2 cell lines when compared with pure SYL and SYL-BL. Further DEX-modified bilosomes were evaluated in vivo for their therapeutic efficacy in DEN-induced (Diethylnitrosamine) hepatic carcinoma in animal model. The DEX-SYL-BL displayed higher therapeutic potential as revealed from enhanced survival and reduced tumour burden in animals. DEX-SYL-BL also displayed significant restoration of altered oxidative markers and SGOT, SGPT levels towards normal value when compared with pure SYL.

Synchronized Ratiometric Codelivery of Metformin and Topotecan through Engineered Nanocarrier Facilitates In Vivo Synergistic Precision Levels at Tumor Site.

The combination of metabolic modulators with chemotherapy holds vast promise for effective inhibition of tumor progression and invasion. Herein, a ratiometric codelivery platform is developed for metformin (MET), a known metabolic modulator and topotecan (TPT), a chemotherapeutic drug, by engineering lipid bilayer-camouflaged mesoporous silica nanoparticles (LB-MSNs). In an attempt to deliver and maintain high tumor site concentrations of MET and TPT, a novel ion pairing-assisted loading procedure is developed using pamoic acid (PA) as an in situ trapping agent. PA, a hydrophobic counterion, increases the hydrophobicity of MET and TPT and facilitates MSNs with exceptionally high payload capacity (>40 and 32 wt%, respectively) and controlled release profile. Further, the synergy between MET and TPT determined by a modeling approach helps to afford synchronized delivery of both the drugs. Coloaded MET and TPT LB-MSNs present synergistic cytotoxicity against MDA-MB-231/4T1 cells and effectively promote apoptosis via mitochondrial membrane depolarization and cell cycle arrest. Extended pharmacokinetic profiles in preclinical models with fourfold to sevenfold longer circulation half-life and 7.5-100 times higher tumor site concentrations correspond to a significant increase in pharmacodynamic efficacy. Taken together, the developed codelivery approach effectively addresses the challenges in the chemotherapeutic efficacy of MET and TPT collectively.

Hyaluronic Acid Decorated Naringenin Nanoparticles: Appraisal of Chemopreventive and Curative Potential for Lung Cancer.

Lung carcinoma is the most common cancer in men and second in women (preceded by breast cancer) worldwide. Around 1 in 10 of all cancers diagnosed in men, lung cancer contributed to a total fraction of 20% cancer deaths. Naringenin (NAR) is well known for its chemopreventive properties since ancient times but lacks an appropriate delivery carrier. The objective of present study was to expand the functionality of naringenin loaded poly caprolactone (PCL) nanoparticles in terms of release, chemoprevention and therapeutics. Polymeric nanoparticles such as PCL lack target specificity; hence, surface modification was attempted using layer by layer technique (LBL) to achieve improved and desired delivery as well as target specificity. The designing of Hyaluronic acid (HA) decorated PCL nanoparticles were prepared by utilizing self-assembling LBL technique, where a polycationic layer of a polymer was used as a linker for modification between two polyanionic layers. Additionally, an attempt has been made to strengthen the therapeutic efficacy of PCL nanocarriers by active targeting and overcoming the extracellular matrix associated barriers of tumors using HA targeting cluster determinant 44 receptor (CD44). Cell cytotoxicity study on A549 cells and J774 macrophage cells depicted enhanced anticancer effect of NAR-HA@CH-PCL-NP with safe profile on macrophages. Uptake study on A549 cells advocated enhanced drug uptake by cancer cells. Cell cycle arrest analysis (A549 cell lines) demonstrated the superior cytotoxic effect and active targeting of NAR-HA@CH-PCL-NP. Further chemopreventive treatment with NAR-HA@CH-PCL-NP was found effective in tumor growth inhibitory effect against urethane-induced lung cancer in rat. In conclusion, developed formulation possesses a promising potential as a therapeutic and chemopreventive agent against urethane-induced lung carcinoma in albino wistar rats.

CD44 targeting hyaluronic acid coated lapatinib nanocrystals foster the efficacy against triple-negative breast cancer.

Lapatinib (LPT) is an orally administered drug for the treatment of metastatic breast cancer. For expanding its therapeutic horizon, we have prepared its nanocrystals (LPT-NCs) that were subsequently coated with hyaluronic acid (HA) to produce LPT-HA-NCs. The detailed in-vitro and in-vivo investigation of LPT-HA-NCs showed the superior anticancer activity due to active targeting to CD44 receptors than the counterparts LPT-NCs and free LPT. In the triple negative 4T1 cells induced breast tumor bearing female Balb/C mice; LPT-HA-NCs treatment caused significant retardation of tumor growth and overall increase in animal survival probability because of their higher tumor localization, increased residence time. Our findings clearly suggest that HA coated LPT-NCs formulation enhances the activity of LPT against triple negative breast cancer. It exhibited magnificent therapeutic outcome at low dose thus presenting a strategy to reduce dose administrations and minimize dose related toxicity.

PEGylated chitosan nanoparticles potentiate repurposing of ormeloxifene in breast cancer therapy.

AIM: Development and optimization of ormeloxifene-loaded PEGylated chitosan nanoparticles (CNPs) for enhancing its literature profound therapeutic activity against breast cancer. METHODS: CNPs were prepared by ionotropic gelation method and characterized. RESULTS: Optimized formulation (CNPs10) had average 304 nm particle size with 0.247 polydispersity index and spherical shape with +31 mV surface charge. CNPs10 had 88.37% entrapment efficiency and 20.93% loading efficiency. CNPs10 demonstrated dose-dependent enhancement in cytotoxicity, cellular uptake, apoptosis, disruption of mitochondrial membrane potential and activation of caspase-3 in breast cancer MDA-MB-231 and MCF-7 cells over free ormeloxifene. In vivo studies divulged improved pharmacokinetic parameters, reduced toxicity, suppressed tumor burden and increased survival in CNPs10-treated female Sprague-Dawley rats. CONCLUSION: PEGylated CNPs enhanced anticancer activity of ormeloxifene.