Berberine encapsulated phenylboronic acid-conjugated pullulan nanoparticles: Synthesis, characterization and anticancer activity validated in A431 skin cancer cells and 3D spheroids.

Polysaccharide-based drug delivery systems are in high demand due to their biocompatibility, non-toxicity, and low-cost. In this study, sialic acid receptor targeted 4-carboxy phenylboronic acid modified pullulan-stearic acid conjugate (4-cPBA-PUL-SA) was synthesized and characterized for the delivery of Berberine (BBR). BBR-loaded 4-cPBA-PUL-SA nanoparticles (BPPNPs) were monodispersed (PDI: 0.238 ± 0.07), with an average hydrodynamic particle size of 191.6 nm and 73.6 % encapsulation efficiency. BPPNPs showed controlled BBR release and excellent colloidal stability, indicating their potential for drug delivery application. The cytotoxicity results indicated that BPPNPs exhibited dose and time-dependent cytotoxicity against human epidermoid carcinoma cells (A431) as well as 3D spheroids. Targeted BPPNPs demonstrated significantly higher anticancer activity compared to BBR and non-targeted BPNPs. The IC50 values for BPPNPs (2.29 µg/ml) were significantly lower than BPNPs (4.13 µg/ml) and BBR (19.61 µg/ml), indicating its potential for skin cancer treatment. Furthermore, CSLM images of A431 cells and 3D spheroids demonstrated that BPPNPs have higher cellular uptake and induced apoptosis compared to free BBR and BPNPs. In conclusion, BPPNPs demonstrate promising potential as an effective drug delivery system for skin cancer therapy.

Synthesis, characterization, and application of honey stabilized inulin nanoparticles as colon targeting drug delivery carrier.

Inulin (INU) is a versatile natural polysaccharide primarily derived from chicory roots. INU possesses the unique quality of evading digestion or fermentation in the early stages of the human digestive tract, instead reaching the lower colon directly. Exploiting on this distinctive attribute, INU finds application in the creation of targeted carrier systems for delivering drugs tailored to colon-related diseases. This study presents a novel method for synthesizing highly stable and non-aggregatory inulin nanoparticles (INU NPs) by ionotropic gelation method, using calcium chloride as crosslinker and natural honey as a stabilizing agent. Different formulation and process parameters were optimized for the synthesis of monodispersed INU NPs. These INU NPs efficiently encapsulated a hydrophilic drug irinotecan hydrochloride trihydrate (IHT) and drug loaded formulation (IINPs) demonstrated excellent colloidal and storage stabilities. Notably, these IINPs exhibited pH-dependent drug release, suggesting potential for colon-specific drug delivery. Anticancer activity of the NPs was found significantly higher in comparison to IHT through cytotoxicity and apoptosis studies against human colorectal carcinoma cells. Overall, this study revealed that the INU NPs synthesized by ionotropic gelation will be an efficient nanocarrier system for colon-targeted drug delivery due to their exceptional biocompatibility and stability in stomach and upper intestinal conditions.

Development of thiolated xanthan gum-stearylamine conjugate based mucoadhesive system for the delivery of biochanin-A to melanoma cells.

Recently, instead of creating new active compounds, scientists have been working to increase the bioavailability and residence time of existing drugs by modifying the characteristics of the delivery systems. In the present study, a novel mucoadhesive bioconjugate (SN-XG-SH) was synthesized by functionalizing a polysaccharide xanthan gum (XG) with cysteamine hydrochloride (CYS) and a lipid stearylamine (SN). FTIR, CHNS and 1H NMR studies confirmed the successful synthesis of SN-XG-SH. Mucoadhesion of the thiolated XG was enhanced and evaluated by different methods. Disulfide bond formation between thiolated XG and skin mucus enhances mucoadhesive behavior. The mucoadhesive bioconjugate was used to prepare nanoparticles for the delivery of hydrophobic biochanin-A (Bio-A) for the treatment of melanoma. The thiolated xanthan gum nanoparticles also demonstrated high drug entrapment efficiency, sustained drug release, and high storage stability. The drug loaded nanoparticles (Bio-A@TXNPs) significantly improved the cytotoxicity of Bio-A against human epidermoid cancer cells (A431 cells) by inducing apoptosis and changing mitochondrial membrane potential. In conclusion, thiolation of XG improves its mucoadhesive properties and prolongs the release of Bio-A. Thus, thiolated XG conjugate has a high potential for use as a bioadhesive agent in controlled and localised delivery of drugs in different skin diseases including melanoma.

Exploration of sialic acid receptors as a potential target for cancer treatment: A comprehensive review.

The potential to target anticancer drugs directly to cancer cells is the most difficult challenge in the current scenario. Progressive works are being done on multifarious receptors and are on the horizon, expected to facilitate tailored treatment for cancer. Among several receptors, one is the sialic acid (SA) receptor by which cancer cells can be targeted directly as hyper sialylation is one of the most distinguishing characteristics of cancer cells. SA receptors have shown tremendous potential for tumor targeting because of their elevated expression in a range of human malignancies including prostate, breast, gastric cells, myeloid leukemia, liver, etc. This article reviews the overexpression of SA receptors in various tumors and diverse strategies for targeting these receptors to deliver drugs, enzymes, and genes for therapeutic applications. It also summarizes the diagnostic applications of SA-grafted nanoparticles for imaging various SA-overexpressing cancer cells and technological advances that are propelling sialic acid to the forefront of cancer therapy.

Design of manganese-based nanomaterials for pharmaceutical and biomedical applications.

In the past few years, manganese-based nanostructures have been extensively investigated in the biomedical field particularly to design highly biocompatible theranostics, which can not only act as efficient diagnostic imaging contrast agents but also deliver the drugs to the target sites. The nanoscale size, large surface area-to-volume ratio, availability of cheap precursors, flexibility to synthesize nanostructures with reproducible properties and high yield, and easy scale up are the major reasons for the attraction towards manganese nanostructures. Along with these properties, the nontoxic nature, pH-sensitive degradation, and easy surface functionalization are additional benefits for the use of manganese nanostructures in biomedical and pharmaceutical sciences. Therefore, in this review, we discuss the recent progress made in the synthesis of manganese nanostructures, describe the attempts made to modify their surfaces to impart biocompatibility and stability in biological fluids, and critically discuss their use in magnetic resonance imaging, drug and gene delivery, hyperthermia, photothermal/photodynamic, immunotherapy, biosensing and tumor diagnosis.

Dendrimer-Mediated Delivery of Anticancer Drugs for Colon Cancer Treatment.

The third most common cancer worldwide is colon cancer (CC). Every year, there more cases are reported, yet there are not enough effective treatments. This emphasizes the need for new drug delivery strategies to increase the success rate and reduce side effects. Recently, a lot of trials have been done for developing natural and synthetic medicines for CC, among which the nanoparticle-based approach is the most trending. Dendrimers are one of the most utilized nanomaterials that are accessible and offer several benefits in the chemotherapy-based treatment of CC by improving the stability, solubility, and bioavailability of drugs. They are highly branched polymers, making it simple to conjugate and encapsulate medicines. Dendrimers have nanoscale features that enable the differentiation of inherent metabolic disparities between cancer cells and healthy cells, enabling the passive targeting of CC. Moreover, dendrimer surfaces can be easily functionalized to improve the specificity and enable active targeting of colon cancer. Therefore, dendrimers can be explored as smart nanocarriers for CC chemotherapy.

Advances in Xanthan Gum-Based Systems for the Delivery of Therapeutic Agents.

In the last three decades, polymers have contributed significantly to the improvement of drug delivery technologies by enabling the controlled and sustained release of therapeutic agents, versatility in designing different delivery systems, and feasibility of encapsulation of both hydrophobic and hydrophilic molecules. Both natural and synthetic polymers have been explored for the delivery of various therapeutic agents. However, due to the disadvantages of synthetic polymers, such as lack of intrinsic biocompatibility and bioactivity, hydrophobicity, and expensive and complex procedure of synthesis, there is a move toward the use of naturally occurring polymers. The biopolymers are generally derived from either plants or microorganisms and have shown a wide range of applications in drug administration due to their hydrophilic nature, biodegradability, biocompatibility, no or low toxicity, abundance, and readily available, ease of chemical modification, etc. This review describes the applications of a biopolymer, xanthan gum (XG), in the delivery of various therapeutic agents such as drugs, genetic materials, proteins, and peptides. XG is a high molecular weight, microbial heteropolysaccharide and is produced as a fermented product of Gram-negative bacteria, Xanthomonas campestris. Traditionally, it has been used as a thickener in liquid formulations and an emulsion stabiliser. XG has several favourable properties for designing various forms of drug delivery systems. Furthermore, the structure of XG can be easily modified using different temperature and pH conditions. Therefore, XG and its derivatives have been explored for various applications in the food, pharmaceutical, and cosmetic industries.

A Clinical Insight on New Discovered Molecules and Repurposed Drugs for the Treatment of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began churning out incredulous terror in December 2019. Within several months from its first detection in Wuhan, SARS-CoV-2 spread to the rest of the world through droplet infection, making it a pandemic situation and a healthcare emergency across the globe. The available treatment of COVID-19 was only symptomatic as the disease was new and no approved drug or vaccine was available. Another challenge with COVID-19 was the continuous mutation of the SARS-CoV-2 virus. Some repurposed drugs, such as hydroxychloroquine, chloroquine, and remdesivir, received emergency use authorization in various countries, but their clinical use is compromised with either severe and fatal adverse effects or nonavailability of sufficient clinical data. Molnupiravir was the first molecule approved for the treatment of COVID-19, followed by Paxlovid™, monoclonal antibodies (MAbs), and others. New molecules have variable therapeutic efficacy against different variants or strains of SARS-CoV-2, which require further investigations. The aim of this review is to provide in-depth information on new molecules and repurposed drugs with emphasis on their general description, mechanism of action (MOA), correlates of protection, dose and dosage form, route of administration, clinical trials, regulatory approval, and marketing authorizations.

Ameliorating the antitumor activity of gemcitabine against breast tumor using αvß3 integrin-targeting lipid nanoparticles.

OBJECTIVE: The main objective is to formulate solid lipid nanoparticles conjugated with cyclic RGDfk peptide encapsulated with gemcitabine hydrochloride drug for targeting breast cancer. SIGNIFICANCE: The hydrophilic nature of gemcitabine hampers passive transport by cell membrane permeation that may lead to drug resistance as it has to enter the cells via nucleoside transporters. The art of encapsulating the drug in a nanovesicle and then anchoring it with a targeting ligand is one of the present areas of research in cancer chemotherapy. METHODS: In this study, solid lipid nanoparticles were prepared by double emulsification and solvent evaporation method. Cyclic RGDfk and gemcitabine hydrochloride were used as targeting ligands and chemotherapeutic drugs, respectively, for targeting breast cancer. The prepared nanoparticles were evaluated for in vitro and in vivo performance to showcase the targeting efficiency and therapeutic benefits of the gemcitabine-loaded ligand conjugated nanoparticles. RESULTS: When compared with gemcitabine (GEM) and GEM loaded nanoparticles (GSLN), the ligand conjugated GEM nanoparticles (cGSLN) showed superior cytotoxicity, apoptosis, and inhibition of 3D multicellular spheroids in human breast cancer cells (MDA MB 231). The in vivo tumor regression studies in orthotopic breast cancer induced Balb/C mice showed that cGSLN displayed superior tumor suppression and also the targeting potential of the cGSLN toward induced breast cancer. CONCLUSION: Prepared nanoformulations showed enhanced anticancer activity in both 2D and 3D cell culture models along with antitumor efficacy in orthotopic breast cancer mouse models.

Improving Anticancer Activity of Chrysin using Tumor Microenvironment pH-Responsive and Self-Assembled Nanoparticles.

Chrysin is a natural bioactive compound with potential biological activities. However, unfavorable physicochemical properties of native chrysin make it difficult to achieve good therapeutic efficacies. In this study, poly(ethylene) glycol (PEG4000)-conjugated chrysin nanoparticles were prepared. The PEG4000 was conjugated to chrysin through cis-aconityl and succinoyl linkers to achieve tumor microenvironment-specific drug release from PEGylated nanoparticles. The conjugation of PEG and chrysin via succinoyl (PCNP-1) and cis-aconityl (PCNP-2) linkers was confirmed by the 1H NMR and FTIR analysis. The nanoparticles were characterized by DLS, TEM, XRD, and DSC analysis. Comparatively, PCNP-2 showed a better drug release profile and higher anticancer activity against human breast cancer cells than chrysin or PCNP-1. The apoptosis studies and colony formation inhibition assay revealed that the PCNP-2 induced more apoptosis and more greatly controlled the growth of human breast cancer cells than pure chrysin. Thus, the use of PCNPs may help to overcome the issues of chrysin and could be a better therapeutic approach.

Genistein encapsulated inulin-stearic acid bioconjugate nanoparticles: Formulation development, characterization and anticancer activity.

Achieving controlled and site-specific delivery of hydrophobic drugs in the colon environment is a major challenge. The primary goal of this research was to synthesize inulin-stearic acid (INU-SA) conjugate and to evaluate its potential in the site-specific delivery of genistein (GEN) for the treatment of colon cancer. INU is a hydrophilic polysaccharide biological macromolecule was modified with hydrophobic SA to form amphiphilic conjugate (INU-SA) which can self-assemble into spherical nanoparticles with interesting drug release properties. The hydrophobic GEN was encapsulated into the INU-SA conjugate to prepare GEN loaded nanoparticles (GNP). The prepared GNP possessed nano size (115 nm), good colloidal dispersibility (0.066 PDI), and high drug encapsulation efficiency (92.2%). The release behaviour of GNP indicated the site-specific release of GEN, only 3.4% at gastric pH while 94% at intestinal pH. The prepared GNP showed potential cytotoxicity against HCT 116 human colorectal cancer cells, as demonstrated by antiproliferation and apoptosis assays. The observed half maximum inhibitory concentration (IC50) value of GNP (5.5 µg/mL) was significantly lower than pure GEN (28.2 µg/mL) due to higher cellular internalization of GNP than free GEN. Therefore, this research suggests a way to improve the therapeutic effectiveness of natural biomolecules using modified and biocompatible polysaccharide INU.

Inulin coated Mn3O4 nanocuboids coupled with RNA interference reverse intestinal tumorigenesis in Apc knockout murine colon cancer models.

This study reports the development and pre-clinical evaluation of biodrug using RNA interference and nanotechnology. The major challenges in achieving targeted gene silencing in vivo include the stability of RNA molecules, accumulation into pharmacological levels, and site-specific targeting of the tumor. We report the use of Inulin for coating the arginine stabilized manganese oxide nanocuboids (MNCs) for oral delivery of shRNA to the gut. Furthermore, bio-distribution analysis exhibited site-specific targeting in the intestines, improved pharmacokinetic properties, and faster elimination from the system without cytotoxicity. To evaluate the therapeutic possibility and effectiveness of this multimodal bio-drug, it was orally delivered to Apc knockout colon cancer mice models. Persistent and efficient delivery of bio-drug was demonstrated by the knockdown of target genes and increased median survival in the treated cohorts. This promising utility of RNAi-Nanotechnology approach advocates the use of bio-drug in an effort to replace chemo-drugs as the future of cancer therapeutics.

Biotinylated Mn3O4 nanocuboids for targeted delivery of gemcitabine hydrochloride to breast cancer and MRI applications.

Multifunctional nanocarriers have been found as potential candidate for the targeted drug delivery and imaging applications. Herein, we have developed a biocompatible and pH-responsive manganese oxide nanocuboid system, surface modified with poly (ethylene glycol) bis(amine) and functionalized with biotin (Biotin-PEG-MNCs), for an efficient and targeted delivery of an anticancer drug (gemcitabine, GEM) to the human breast cancer cells. GEM-loaded Biotin-PEG@MNCs showed high drug loading efficiency, controlled release of GEM and excellent storage stability in the physiological buffers and different temperature conditions. GEM-loaded Biotin-PEG@MNCs showed dose- and time-dependent decrease in the viability of human breast cancer cells. Further, it exhibited significantly higher cell growth inhibition than pure GEM which suggested that Biotin-PEG@MNCs has efficiently delivered the GEM into cancerous cells. The role of biotin in the uptake was proved by the competitive binding-based cellular uptake study. A significant decrease in the amount of manganese was observed in biotin pre-treated cancer cells as compared to biotin untreated cancer cells. In MRI studies, Biotin-PEG-MNCs showed both longitudinal and transverse relaxivity about 0.091 and 7.66 mM-1 s-1 at 3.0 T MRI scanner, respectively. Overall, the developed Biotin-PEG-MNCs presents a significant potential in formulation development for cancer treatment via targeted drug delivery and enhanced MRI contrast imaging properties.

Self-assembled and pH-responsive polymeric nanomicelles impart effective delivery of paclitaxel to cancer cells.

Chemotherapy is an essential component of breast cancer therapy, but it is associated with serious side effects. Herein, a pluronic F68-based pH-responsive, and self-assembled nanomicelle system was designed to improve the delivery of paclitaxel (PTX) to breast cancer cells. Two pH-responsive pluronic F68-PTX conjugates i.e. succinoyl-linked conjugate (F68-SA-PTX) and cis-aconityl-linked conjugate (F68-CAA-PTX) were designed to respond the varying pH-environment in tumour tissue. Although both the linkers showed pH-sensitivity, the F68-CAA-PTX exhibited superior pH-sensitivity over the F68-SA-PTX and achieved a more selective release of PTX from the self-assembled nanomicelles. The prepared nanomicelles were characterized by dynamic light scattering, transmittance electron microscopy, differential scanning calorimetry and powder X-ray diffraction techniques. The anticancer activity of prepared nanomicelles and pure PTX were evaluated by 2D cytotoxicity assay against breast cancer cell line MDA-MB-231 and in the real tumour environments i.e. 3D tumor spheroids of MDA-MB-231 cells. The highest cytotoxicity effect of PTX was observed with F68-CAA-PTX nanomicelles followed by F68-SA-PTX and free PTX. Further, the F68-CAA-PTX nanomicelles also induced significant apoptosis with a combination of increase in ROS generation, decrease in the depolarisation of MMP and G2/M cell cycle arrest. These observed results provide a new insight for breast cancer treatment using pluronic nanomicelles.

Morin hydrate loaded solid lipid nanoparticles: Characterization, stability, anticancer activity, and bioavailability.

Nanotechnology has come up as a protean field integrating concepts of alternate drug delivery systems using nanocarriers. The idea of encapsulating a drug molecule into a colloidal carrier like solid lipid nanoparticle has been a promising approach for development of nanomedicines. In this research work, a hydrophobic, natural, and an anticancer bioflavonoid, morin hydrate (MH) was encapsulated into solid lipid nanoparticles to overcome the issues of its poor aqueous solubility and low oral bioavailability. The prepared morin hydrate loaded solid lipid nanoparticles (MSN) were characterized by DLS, FTIR, and DSC analysis. The MSN showed nanoscale size, good steric stability, and release in simulated intestinal fluid. The in-vitro anticancer studies against human cervical cancer cells revealed the higher cytotoxicity of encapsulated MH than free or pure MH. MSN also demonstrated a significant improvement in pharmacokinetics of encapsulated MH.

Baicalin encapsulating lipid-surfactant conjugate based nanomicelles: Preparation, characterization and anticancer activity.

Lung cancer is one of the most common malignant tumors and emerged as one of the leading causes of cancer-related death worldwide. Surgical resection can be a curative treatment for early stage but the most of lung cancer patients are diagnosed at an advanced stage when the pulmonary tumor has been invaded beyond the respiratory system. Therefore, chemotherapy is suitable for curing metastasized tumor. Baicalin (BL) is a flavonoid which has been studied in the treatment of several types of cancer including lung cancer. However, its low solubility in water and non-specificity impede its practical utilization. Hence, we have reported a stearic acid and pluronic F68 conjugated nanomicelles (PF68-SA) system to improve therapeutic efficacy of BL. Solvent evaporation method was used to prepare the BL-loaded PF68-SA nanomicelles (BLNM). The designed BLNM were characterized for the particle size, surface charge, critical micelle concentration, colloidal stability, morphology, and total drug content. BLNM formulation showed improved toxicity of BL against A549 human lung cancer cells in cytotoxicity assay. Further, apoptosis study also depicted BLNM-induced cell death in A549 cells. Therefore, the synthesized fatty acid-modified polymeric nanomicellar system could be useful in overcoming the stability and low therapeutic efficacy issues of hydrophobic anticancer drugs like BL and delivering them to the cancer cells.

Inulin-pluronic-stearic acid based double folded nanomicelles for pH-responsive delivery of resveratrol.

Herein, we introduce a novel amphiphilic bioconjugate (INU-F68-SA), synthesized by functionalization of pluronic F68 with a polysaccharide inulin (INU) and a lipid stearic acid (SA). The synthesis of INU-F68-SA was confirmed by FTIR and 1H-NMR analysis. INU-F68-SA can self-assemble into nanomicelles and therefore, its application in delivering of hydrophobic resveratrol (RSV) was investigated. The RSV-loaded INU-F68-SA nanomicelles (RSNM) had about 172 nm size, spherical shape, 0.237 polydispersity index, and -18 mV zeta potential. More importantly, the RSNM showed high drug entrapment efficiency, controlled drug release and protection of drug during storage. The RSNM significantly enhanced the cytotoxicity of RSV against colorectal cancer cells by inducing apoptosis and changing mitochondrial membrane potential. Further, in-vivo pharmacokinetic experiment indicated an improvement in pharmacokinetics of RSV after administering as RSNM. Thus, the use of self-assembled nanomicelles of amphiphilic INU-F68-SA bioconjugate could be a better alternative to overcome the poor in-vitro and in-vivo performance of RSV.

N-acetyl-d-glucosamine-conjugated PAMAM dendrimers as dual receptor-targeting nanocarriers for anticancer drug delivery.

N-acetyl-d-glucosamine-labelled dendrimers (NAG-Dend) were synthesized for the targeted delivery of camptothecin (CPT) to A549 human lung adenocarcinoma cells, which overexpress glucose transporters and lectin receptors. CPT loaded, NAG-Dend (NAG-Dend-CPT) exhibited more rapid and higher cellular uptake than the unlabelled dendrimer formulation (Dend-CPT), leading to enhanced cytotoxicity. Compared with native CPT, NAG-Dend-CPT was 4.5 times more toxic to A549 cells. The anticancer activity of the different CPT formulations was dose and time dependent. NAG-Dend-CPT also increased reactive oxygen species generation, induced higher apoptosis and showed greater inhibition of A549 cell migration than Dend-CPT. The selective accumulation of NAG-Dend in the lungs of tumour-bearing mice confirmed that the NAG-based dendrimer system can target lung metastasis tumours in a biological system. Overall, our results show that NAG-conjugated dendrimers could be a promising nanocarrier system for the delivery of anticancer drugs, including CPT, to human lung cancer cells.

Site-specific delivery of a natural chemotherapeutic agent to human lung cancer cells using biotinylated 2D rGO nanocarriers.

Chemotherapy has remained one of the most commonly employed treatment modalities for cancer. Despite the clinical availability of a large number of chemotherapeutic agents, the uncontrolled systemic distribution and the associated harmful side effects of chemotherapeutic agents pose major challenges demanding concerted efforts to enhance their cancer targetability. The layered structure of two-dimensional (2D) materials offers new opportunities by increasing the drug pay-load influencing the drug-release kinetics in a cancer micro-environment and facilitating targetability through the large accessible surface area. To investigate such potential benefits of 2D materials, we have developed a biocompatible targeted 2D drug delivery system using graphene oxide (GO) as a model nanocarrier (NC) that could hold a high concentration of gallic acid (GA), a natural chemotherapeutic agent found in green tea. Interestingly, the antioxidant nature of GA also reduced GO to a high-quality few-layered thin reduced-graphene oxide (rGO) during drug loading while forming rGO nanocarrier (rGONC). The biotinylated rGONC further improved their targetability to A549 human lung carcinoma cells and they enhanced cellular internalization efficiency. From these targeted 2D NCs, the drug could release only slowly at the physiological pH but liberated rapidly at lower pH encountered by the tumor microenvironment resulting in significant toxicity toward the lung carcinoma cells. As such, this work opens up new possibilities for employing 2D materials for targeted chemotherapeutic applications.