Smart Magnetic Nanocarriers for Codelivery of Nitric Oxide and Doxorubicin for Enhanced Apoptosis in Cancer Cells.

Extremely short half-life therapeutic molecule nitric oxide (NO) plays significant roles in the functioning of various physiological and pathological processes in the human body, whereas doxorubicin hydrochloride (DOX) is a clinically important anticancer drug widely used in cancer chemotherapy. Thus, the intracellular delivery of these therapeutic molecules is tremendously important to achieve their full potential. Herein, we report a novel approach for the development of highly water-dispersible magnetic nanocarriers for codelivery of NO and DOX. Primarily, bifunctional magnetic nanoparticles enriched with carboxyl and thiol groups were prepared by introducing cysteine onto the surface of citrate-functionalized Fe3O4 nanoparticles. DOX was electrostatically conjugated onto the surface of bifunctional nanoparticles via carboxyl moieties, whereas the thiol group was further nitrosated to provide NO-releasing molecules. The developed magnetic nanocarrier exhibited good aqueous colloidal stability, protein resistance behavior, and high encapsulation efficacy for NO (65.5%) and DOX (85%), as well as sustained release characteristics. Moreover, they showed superior cytotoxicity toward cancer (A549 and MCF-7) cells via apoptosis induction over normal (WI26VA4) cells. Specifically, we have developed magnetic nanocarriers having the capability of dual delivery of NO and DOX, which holds great potential for combinatorial cancer treatment.

Radiolabelled folate micellar carriers as proposed diagnostic aid for CNS tumors by nasal route.

Glioma refers to the most atypical variant of the malignant central nervous system tumors posturing massive challenge to the research fraternity owing to the flimsy improvement in the patient survival rate over the past years. The aim of the proposed work was developing a diagnostic aid for brain tumors, which could be administered via the non-invasive intranasal route. Since overexpression of folate receptors in the central nervous system tumors is 500 times more than the normal healthy cells, we aimed at fabricating a radiolabeled folate encapsulated micellar delivery system to be given via the nasal route. Folate conjugated bifunctional chelating agent was synthesized, radiolabeled with 99mTc, and encapsulated in a micellar carrier. The fabricated micelles were further evaluated for in vivo nasal toxicity in rats and the same were found safe for intranasal administration. The fabricated micelles owing to their nano size, mucoadhesive nature, and enhanced permeation were observed to have a higher uptake into the brain (around 16% in 4 h) than as compared to the radiolabeled conjugated folate solution when studied for in vivo biodistribution in mice. Single-photon emission computerized tomography imaging performed in higher animals upon intranasal administration of the micellar formulation revealed enhanced uptake of the micelles into the animal brain. It is believed that the aforementioned formulation can be of a great diagnostic value in the detection of not only brain tumors but also other folate expressing cancers such as cervical, breast, and lungs as the system is fast, non-toxic, accurate, non-invasive, and simple.

Carbon nano-dot for cancer studies as dual nano-sensor for imaging intracellular temperature or pH variation.

Cellular temperature and pH govern many cellular physiologies, especially of cancer cells. Besides, attaining higher cellular temperature plays key role in therapeutic efficacy of hyperthermia treatment of cancer. This requires bio-compatible, non-toxic and sensitive probe with dual sensing ability to detect temperature and pH variations. In this regard, fluorescence based nano-sensors for cancer studies play an important role. Therefore, a facile green synthesis of orange carbon nano-dots (CND) with high quantum yield of 90% was achieved and its application as dual nano-sensor for imaging intracellular temperature and pH was explored. CND was synthesized from readily available, bio-compatible citric acid and rhodamine 6G hydrazide using solvent-free and simple heating technique requiring purification by dialysis. Although the particle size of 19 nm (which is quite large for CND) was observed yet CND exhibits no surface defects leading to decrease in photoluminescence (PL). On the contrary, very high fluorescence was observed along with good photo-stability. Temperature and pH dependent fluorescence studies show linearity in fluorescence intensity which was replicated in breast cancer cells. In addition, molecular nature of PL of CND was established using pH dependent fluorescence study. Together, the current investigation showed synthesis of highly fluorescent orange CND, which acts as a sensitive bio-imaging probe: an optical nano-thermal or nano-pH sensor for cancer-related studies.

Recent advances in active targeting of nanomaterials for anticancer drug delivery.

One of the challenges in cancer chemotherapy is the low target to non-target ratio of therapeutic agents which incur severe adverse effect on the healthy tissues. In this regard, nanomaterials have tremendous potential for impacting cancer therapy by altering the toxicity profile of the drug. Some of the striking advantages provided by the nanocarriers mediated targeted drug delivery are relatively high build-up of drug concentration at the tumor site, improved drug content in the formulation and enhanced colloidal stability. Further, nanocarriers with tumor-specific moieties can be targeted to the cancer cell through cell surface receptors, tumor antigens and tumor vasculatures with high affinity and accuracy. Moreover, it overcomes the bottleneck of aimless drug biodistribution, undesired toxicity and heavy dosage of administration. This review discusses the recent developments in active targeting of nanomaterials for anticancer drug delivery through cancer cell surface targeting, organelle specific targeting and tumor microenvironment targeting strategies. Special emphasis has been given towards cancer cell surface and organelle specific targeting as delivery of anticancer drugs through these routes have made paradigm change in cancer management. Further, the current challenges and future prospects of nanocarriers mediated active drug targeting are also demonstrated.

Curcumin Encapsulated Casein Nanoparticles: Enhanced Bioavailability and Anticancer Efficacy.

The poor water solubility and bioactivity of drugs can be potentially improved by using suitable nanocarriers. Herein, an economically viable methodology is developed for encapsulation of hydrophobic anticancer agent, curcumin in casein nanoparticles (CasNPs). The successful encapsulation of curcumin was evident from the structural, thermal and spectroscopic analysis of curcumin encapsulated CasNPs (Cur-CasNPs). The CasNPs and Cur-CasNPs samples were lyophilized for their long-term stability and lyophilized powders are found to be stable for more than 6 months at 4-8 °C. From DLS studies, it has been observed that the variation in average size of drug formulations before and after reconstitution were less than 5%. Further, it shows good water-dispersibility, enhanced bioavailability and pH dependent charge conversal feature. Cur-CasNPs showed pH dependent release characteristics with higher at mild acidic environment and enhanced toxicity towards cancer cells (MCF-7) as compared to normal cells (CHO). Moreover, the CasNPs are non-toxic in nature and the developed nanoformulation of drug exhibits substantial cellular internalization and enhanced toxicity towards MCF-7 cells over pure drug, indicating their potential applications.

Glutamic acid-coated Fe3O4 nanoparticles for tumor-targeted imaging and therapeutics.

We have developed surface functionalised Fe3O4 magnetic nanoparticles (MNPs) based system that can be used for tumor-targeted multimodal therapies and MR imaging. Biocompatible, non-essential amino acid (glutamic acid) was introduced onto the surface of Fe3O4 MNPs to provide functional sites for binding of chemotherapeutic drugs. These glutamic acid-coated Fe3O4 MNPs (GAMNPs) exhibit good water-dispersibility, magnetic responsivity and pH dependent charge conversal feature. The magnetic core as well as organic shell of GAMNPs was characterized by XRD, TEM, DLS, FTIR, PPMS and UV-visible spectroscopy and zeta-potential analyzer etc. The broad spectrum anticancer drugs, doxorubicin hydrochloride (DOX) and methotrexate (MTX) were electrostatically and covalently conjugated to the surface of GAMNPs, respectively for combination chemotherapy. These dual drugs loaded system (DOX-MTX-GAMNPs) shows pH dependent release behaviour of both the drugs and enhanced toxicity towards breast cancer cell line (MCF-7) as compared to their individual treatment. Fluorescence microscopy and flow cytometric analyses confirmed the successful uptake of drug loaded system into MCF-7 cell lines. Further MTX being analogue of folic acid, its co-delivery with DOX would help in internalization of both the drugs into MCF-7 cells. These GAMNPs also show good heating efficiency under AC magnetic field (Intrinsic loss power, ILP = 0.95 and 0.73 and 0.48 nHm2/Kg at Fe concentration of 0.5, 1 and 2 mg/ml, respectively) and transverse relaxivity (r2 = 152 mM-1 s-1) indicating their potential capability for hyperthermia therapy and MRI tracking. Furthermore, it has been observed that the combination of chemotherapeutic drugs and hyperthermia leads to an enhancement of cytotoxicity in MCF-7 cells.

Biopolymer assisted synthesis of silica-carbon composite by spray drying.

Spray drying had been used to synthesize silica-carbon black nanocomposite micrometric granules with a uniform distribution of the two components. This was achieved by hindering the preferential diffusion of hydrophobic carbon and hydrophilic silica particles in the water droplets during evaporative assembly by introducing gum arabic as a stabilizing agent and network former. Both positive and negatively charged silica nanoparticles were used to check the stability of the sol and its effect on the morphology of the spray dried granules. X-ray and neutron scattering, complemented with electron microscopy, were used to investigate the correlation and distribution of the nanoparticles within the granules. Porous silica granules, having surface area of 157 m2/g, were obtained after removal of carbon black by calcination. An environment-friendly solar absorbing coating had been prepared using as synthesized granules.

pH sensitive surfactant-stabilized Fe3O4 magnetic nanocarriers for dual drug delivery.

Highly water-dispersible surfactant-stabilized Fe3O4 magnetic nanocarriers (SMNCs) were prepared by self-assembly of anionic surfactant, sodium dodecyl sulphate (SDS) on hydrophobic (oleic acid coated) nanoparticles and their biomedical applications were investigated. These nanocarriers have an average size of about 10nm and possess tunable surface charge properties. The formation of an organic coating of SDS was evident from infrared spectroscopy, dynamic light scattering, zeta-potential and thermogravimetric measurements. These nanocarriers were used for loading of both hydrophilic and hydrophobic anticancer agents such as doxorubicin hydrochloride (DOX) and curcumin (CUR), respectively. DOX was conjugated onto the surface of nanocarriers through electrostatic interaction, whereas CUR was encapsulated into the hydrophobic interlayer between oleic acid and SDS. The toxicity and cellular internalization of drug loaded nanocarriers were investigated against WEHI-164 cancer cell line. Specifically, the drug loading, pH sensitive drug release and cellular internalization studies suggested that these nanocarriers are suitable for dual drug delivery. Furthermore, they show good heating ability under AC magnetic field, thus can be used as effective heating source for hyperthermia treatment of cancer.

PEG coated vesicles from mixtures of Pluronic P123 and l-α-phosphatidylcholine: structure, rheology and curcumin encapsulation.

PEG coated vesicles are important vehicles for the passive targeting of anticancer drugs. With a view to prepare PEG decorated vesicles using co-assembly of block copolymers and lipids, here we investigated the microstructure of aggregates formed in mixtures comprising lipids (l-α-phosphatidylcholine) and block copolymers (Pluronic P123), in the polymer rich regime. DLS and SANS studies show that the structure of the aggregates can be tuned from micelles to rod-like micelles or vesicles by changing the lipid to polymer composition. Rheological studies on gels formed by mixtures of polymer and lipid suggest incorporation of the lipid into the polymer matrix. The encapsulation efficiencies of polymer incorporated liposomes for curcumin and doxorubicin hydrochloride (DOX) are evaluated at different drug to carrier ratios. The pH dependent sustained release of both the drugs from the PEGylated liposomes suggests their application in the development of cost effective formulations for anticancer drug delivery.