Carboxylated chitosan-mediated improved efficacy of mesoporous silica nanoparticle-based targeted drug delivery system for breast cancer therapy.

Nanoparticle-based targeting of overexpressed cell-surface receptors is a promising strategy that provides precise delivery of drugs to cancer cells. In the present study, we developed highly reproducible and monodispersed, chitosan-coated (pH-responsive), doxorubicin-loaded, aptamer-mesoporous silica nanoparticle (MSN) bioconjugates for actively targeting breast cancer cells harboring overexpression of EGF receptors (EGFR/HER2). The developed targeted MSNs demonstrated higher uptake and cytotoxicity of triple negative and HER2 positive breast cancer cells when compared to non-targeted MSNs. The chitosan coating imparted pH-responsiveness and endo/lysosomal escape ability to MSNs, which augmented cytosolic delivery of an anticancer drug. Partial carboxylation of chitosan coated on MSNs allowed for a greater release of drug in a shorter duration of time while retaining pH-responsiveness and endo/lysosomal escape ability. Overall, the coating of carboxylated-chitosan over MSNs enabled tunable drug release kinetics, conjugation of aptamers (targeting agents), and endo/lysosomal escape which together significantly enhanced the efficacy of the developed drug delivery system.

A Synergistic Combination of Niclosamide and Doxorubicin as an Efficacious Therapy for All Clinical Subtypes of Breast Cancer.

Drug resistance is one of the major hurdles in the success of cancer chemotherapy. Notably, aberrantly expressed Wnt/ß-catenin signaling plays a major role in the initiation and maintenance of oncogenesis along with development of chemoresistance. Therefore, the combinatorial approach of targeting Wnt/ß-catenin pathway along with using a chemotherapeutic agent seems to be a promising strategy to improve cancer therapy. In the present study, we evaluated the combination of niclosamide (Nic), an FDA-approved antihelminthic drug repurposed as a Wnt signaling inhibitor, and doxorubicin (Dox), a conventional anticancer agent, in all clinical subtypes of breast cancer viz. triple negative breast cancer, HER2 positive breast cancer, and hormone receptor positive breast cancer. The results demonstrated that the combination induced apoptosis and caused synergistically enhanced death of all breast cancer cell types at multiple combinatorial concentrations using both the sequential and concurrent treatment regimens. Mechanistically, downregulation of Wnt/ß-catenin signaling and cell cycle arrest at G0/G1 phase by Nic and increase in reactive oxygen species by both Nic and Dox along with the inherent cytotoxicity of Dox mediated the synergism between the two drugs in both the treatment regimens. Overall, the combination of Nic and Dox holds promise to be developed as an efficient therapeutic option for breast cancer irrespective of its clinical subtype.

Mesoporous Silica Nanoparticle-Based Combination of Niclosamide and Doxorubicin: Effect of Treatment Regimens on Breast Cancer Subtypes.

Overexpressed Wnt/ß-catenin signaling acts as a major cancer driver and plays an important role in the development of resistance against cancer chemotherapy. Therefore, the combinatorial approach of downregulating Wnt/ß-catenin signaling along with using a chemotherapeutic agent may improve cancer therapy. However, systemic administration of free anticancer agents is nonspecific and poses serious side effects. Hence, the present study aimed at developing mesoporous silica nanoparticle (MSN)-based targeted combination therapy of a Wnt signaling inhibitor, niclosamide (Nic), and a conventional anticancer agent, doxorubicin (Dox). The results demonstrated the reproducible synthesis of highly stable and monodispersed sub-100 nm spherical shaped NPs. In vitro cytotoxicity studies demonstrated that the individual drug formulations caused concentration-dependent cytotoxicity to all of the three breast cancer subtypes, with higher concentrations being more cytotoxic. Further, sequential and concurrent combination of Nic-loaded MSNs with Dox-loaded MSNs was synergistic and caused significantly enhanced death in all breast cancer subtypes. Quantification of the combinatorial efficacy suggested that multiple combinatorial pairs were synergistic in all of the breast cancer types for both (sequential and concurrent) treatment regimens. However, the extent of synergism varied between the two treatment regimens in different clinical subtypes of breast cancer. Overall, the combination of Nic-loaded MSNs with Dox-loaded MSNs holds promise to be developed as an efficient therapeutic option for breast cancer irrespective of the clinical subtype in both sequential and concurrent treatment regimens.

Role of Physicochemical Properties of Protein in Modulating the Nanoparticle-Bio Interface.

Nanoparticles, on exposure to the biological milieu, tend to interact with macromolecules to form a biomolecular corona. The biomolecular corona confers a unique biological identity to nanoparticles, and its protein composition plays a deterministic role in the biological fate of nanoparticles. The physiological behavior of proteins stems from their physicochemical properties, including surface charge, hydrophobicity, and structural stability. However, there is insufficient understanding about the role of physicochemical properties of proteins in biomolecular corona formation. We hypothesized that the physicochemical properties of proteins would influence their interaction with nanoparticles and have a deterministic effect on nanoparticle-cell interactions. To test our hypothesis, we used model proteins from different structural classes to understand the effect of secondary structure elements of proteins on the nanoparticle-protein interface. Further, we modified the surface of proteins to study the role of protein surface characteristics in governing the nanoparticle-protein interface. For this study, we used mesoporous silica nanoparticles as a model nanoparticle system. We observed that the surface charge of proteins governs the nature of the primary interaction and the extent of subsequent secondary interactions causing structural rearrangements of the protein. We also observed that the secondary structural contents of proteins significantly affected both the extent of secondary interactions at the nanoparticle-protein interface and the dispersion state of the nanoparticle-protein complex. Further, we studied the interactions of different protein-coated nanoparticles with different cells (fibroblast, carcinoma, and macrophage). We observed that different cells internalized the nanoparticle-protein complex as a function of secondary structural components of the protein. The type of model protein had a significant effect on their internalization by macrophages. Overall, we observed that the physicochemical characteristics of proteins had a significant role in modulating the nanoparticle-bio-interface at the level of both biomolecular corona formation and nanoparticle internalization by cells.

Fundamentals, challenges, and nanomedicine-based solutions for ocular diseases.

The eye consists of sensitive, compactly adjoined tissue structures which act as strong physical (static) and physiological (dynamic) barriers that prevent entry of foreign bodies into the eye. Together, these barriers reduce the bioavailability of topically and intraocularly administered medicaments thus demanding frequent drug administration for the treatment of chronic eye diseases. Hence, development of drug delivery systems (DDS) that can be retained in ocular tissues for longer durations can help to reduce the frequency of drug administration, whereas, delivery systems that traverse through ocular barriers may offer higher bioavailability of administered drugs to otherwise inaccessible ocular tissues. These objectives can be partially/fully achieved using nanoparticulate/colloidal DDS. Colloidal DDS, due to their nanodimensions, undergo internalization by cells which enables transport of drugs through ocular barriers. Furthermore, nanoparticles can prolong duration of drug release and can increase residence time of entrapped cargo molecules in ocular tissues. Together, these aspects facilitate a higher bioavailability, prolonged therapeutic effect and reduced frequency of drug administration for the effective treatment of chronic ocular diseases. Hence, nanocarriers have been widely explored for ophthalmic drug delivery applications. In this review, we discuss the anatomy of ocular tissues along with their barrier properties. We then discuss ocular diseases along with the various routes of drug administration and pathways of drug transport in the eye. The next section discusses the influence of physicochemical properties of therapeutic molecules on their ocular distribution and conventional and advanced (nanoparticulate/colloidal DDS) drug formulations that are used for the treatment of ocular diseases. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.