Shashwat S. Banerjee

Poly(ethylene glycol)-Prodrug Conjugates: Concept, Design, and Applications

Poly(ethylene glycol) (PEG) is the most widely used polymer in delivering anticancer drugs clinically. PEGylation (i.e., the covalent attachment of PEG) of peptides proteins, drugs, and bioactives is known to enhance the aqueous solubility of hydrophobic drugs, prolong circulation time, minimize nonspecific uptake, and achieve specific tumor targetability through the enhanced permeability and retention effect. Numerous PEG-based therapeutics have been developed, and several have received market approval. A vast amount of clinical experience has been gained which has helped to design PEG prodrug conjugates with improved therapeutic efficacy and reduced systemic toxicity. However, more efforts in designing PEG-based prodrug conjugates are anticipated. In light of this, the current paper highlights the synthetic advances in PEG prodrug conjugation methodologies with varied bioactive components of clinical relevance. In addition, this paper discusses FDA-approved PEGylated delivery systems, their intended clinical applications, and formulations under clinical trials.

Multifunctional pH-sensitive magnetic nanoparticles for simultaneous imaging, sensing and targeted intracellular anticancer drug delivery

A novel multifunctional magnetic nanocarrier was fabricated for synchronous cancer therapy and sensing. The nanocarrier, programed to display a response to environmental stimuli (pH value), was synthesized by coupling doxorubicin (DOX) to adipic dihydrazide-grafted gum arabic modified magnetic nanoparticles (ADH-GAMNP) via the hydrolytically degradable pH-sensitive hydrazone bond. The resultant nanocarrier, DOX-ADH-GAMNP, had a mean diameter of 13.8 nm and the amount of DOX coupled was about 6.52 mg g(-1). Also, it exhibited pH triggered release of DOX in an acidic environment (pH 5.0) but was relatively stable at physiological pH (pH 7.4). Furthermore, both GAMNP and DOX were found to possess fluorescence properties when excited in the near-infrared region due to the two-photon absorption mechanism. The coupling of DOX to GAMNP resulted in a reversible self-quenching of fluorescence through the fluorescence resonant energy transfer (FRET) between the donor GAMNP and acceptor DOX. The release of DOX from DOX-ADH-GAMNP when exposed to acidic media indicated the recovery of fluorescence from both GAMNP and DOX. The change in the fluorescence intensity of DOX-ADH-GAMNP on the release of DOX can act as a potential sensor to sense the delivery of the drug. The analysis of zeta potential and plasmon absorbance in different pH conditions also confirmed the pH sensitivity of the product. This multifunctional nanocarrier is a significant breakthrough in developing a drug delivery vehicle that combines drug targeting as well as sensing and therapy at the same time.

A multifunctional magnetic nanocarrier bearing fluorescent dye for targeted drug delivery by enhanced two-photon triggered release

We report a novel nanoformulation for targeted drug delivery which utilizes nanophotonics through the fusion of nanotechnology with biomedical application. The approach involves an energy-transferring magnetic nanoscopic co-assembly fabricated of rhodamine B (RDB) fluorescent dye grafted gum arabic modified Fe(3)O(4) magnetic nanoparticle and photosensitive linker by which dexamethasone drug is conjugated to the magnetic nano-assembly. The advantage offered by this nanoformulation is the indirect photo-triggered-on-demand drug release by efficient up-converting energy of the near-IR (NIR) light to higher energy and intraparticle energy transfer from the dye grafted magnetic nanoparticle to the linker for drug release by cleavage. The synthesized nanoparticles were found to be of ultra-small size (13.33 nm) and are monodispersed in an aqueous suspension. Dexamethasone (Dexa) drug conjugated to RDB-GAMNP by photosensitive linker showed appreciable release of Dexa by photo-triggered response on exposure to radiation having a wavelength in the NIR region whereas no detectable release was observed in the dark. Photo-triggered response for the nanoformulation not bearing the rhodamine B dye was drastically less as less Dexa was released on exposure to NIR radiation which suggest that the photo-cleavage of linker and release of Dexa mainly originated from the indirect excitation through the uphill energy conversions based on donor-acceptor model FRET. The promising pathway of nanophotonics for the on-demand release of the drug makes this nanocarrier very promising for applications in nanomedicine.

Enhancing Surface Interactions with Colon Cancer Cells on a Transferrin-Conjugated 3D Nanostructured Substrate

A transferrin-conjugated PEG-Fe(3) O(4) nanostructured matrix is developed to explore cellular responses in terms of enhanced cell adhesion, specific interactions between ligands in the matrix and molecular receptors on the cell membrane, comparison of cell shapes on 2D and 3D surfaces, and effect of polymer architecture on cell adhesion. Integration of such advanced synthetic nanomaterials into a functionalized 3D matrix to control cell behavior on surfaces will have implications in nanomedicine.

Budding trends in integrated pest management using advanced micro- and nano-materials: Challenges and perspectives

One of the most vital supports to sustain human life on the planet earth is the agriculture system that has been constantly challenged in terms of yield. Crop losses due to insect pest attack even after excessive use of chemical pesticides, are major concerns for humanity and environment protection. By the virtue of unique properties possessed by micro and nano-structures, their implementation in Agri-biotechnology is largely anticipated. Hence, traditional pest management strategies are now forestalling the potential of micro and nanotechnology as an effective and viable approach to alleviate problems pertaining to pest control. These technological innovations hold promise to contribute enhanced productivity by providing novel agrochemical agents and delivery systems. Application of these systems engages to achieve: i) control release of agrochemicals, ii) site-targeted delivery of active ingredients to manage specific pests, iii) reduced pesticide use, iv) detection of chemical residues, v) pesticide degradation, vi) nucleic acid delivery and vii) to mitigate post-harvest damage. Applications of micro and nano-technology are still marginal owing to the perception of low economic returns, stringent regulatory issues involving safety assessment and public awareness over their uses. In this review, we highlight the potential application of micro and nano-materials with a major focus on effective pest management strategies including safe handling of pesticides.

Structure effect of carbon nanovectors in regulation of cellular responses

Carbon nanostructures such as multiwalled carbon nanotubes (CNT) and graphene (G) are potential candidates in a large number of biomedical applications. However, there is limited understanding and connection between the physicochemical properties of diverse carbon nanostructures and biological systems, particularly with regard to cellular responses. It is also crucial to understand how the structure and surface composition of carbon nanostructures affect the cellular internalization process. Here, through in vitro cellular entry kinetics and cytotoxicity studies using MCF-7 breast cancer cells and H460 human lung cancer cells, we show that the structure and surface composition of CNT and G conjugates with various molecules such as PAMAM dendrimers (G4) and G4-poly(ethylene glycol) (PEG) are directly related to their cellular internalization ability and toxicity. Interestingly, the cellular association of CNT and G nanoconjugates was observed to be structure and surface composition dependent. We found that CNT conjugates internalized more compared to G conjugates. Furthermore, G4 conjugated CNT internalized more compared to G4-PEG conjugated CNT, whereas, higher internalization was found for G4-PEG conjugated G than G4 conjugated G. We have also correlated the cytotoxicity and cellular uptake mechanisms of CNT, G, and their conjugates through zeta potential measurements, fluorescence quenching studies and by fluorescence-activated cell sorting. Altogether these studies suggest different biological activities of the carbon nanostructures, with the shape and surface composition playing a primary role.

Prodrug Conjugate Strategies in Targeted Anticancer Drug Delivery Systems

Chemotherapy is the mainstay in the treatment of various cancers for several decades; however, it suffers several clinical limitations. For example, anticancer drugs are often nonselective and are taken up by all forms of cells. Non-selectivity of the agents usually results in significant toxicity to normal cells, thus resulting in poor prognosis for patients. Hence, to improve the therapeutic efficacy of chemotherapy, improving the selectivity of anticancer drug is highly desired. Prodrug conjugation is one of the most beneficial strategies to enhance selectivity and efficacy of a chemotherapy drug. The classical prodrug approach is to overcome physicochemical (e.g., solubility, chemical instability) or biopharmaceutical problems (e.g., bioavailability, toxicity) associated with common anticancer drugs via a simple chemical modification. On the other hand, here we discuss targeted prodrug systems for delivering anticancer agents specifically to tumor cells, thereby sparing normal cells. This chapter focuses on various synthetic strategies in designing targeted prodrug conjugates and its rationale for cancer treatment. Various tumor-targeting ligands that are currently being explored are critically discussed.