R. A. Mashelkar

Rapid self-healing hydrogels

Synthetic materials that are capable of autonomous healing upon damage are being developed at a rapid pace because of their many potential applications. Despite these advancements, achieving self-healing in permanently cross-linked hydrogels has remained elusive because of the presence of water and irreversible cross-links. Here, we demonstrate that permanently cross-linked hydrogels can be engineered to exhibit self-healing in an aqueous environment. We achieve this feature by arming the hydrogel network with flexible-pendant side chains carrying an optimal balance of hydrophilic and hydrophobic moieties that allows the side chains to mediate hydrogen bonds across the hydrogel interfaces with minimal steric hindrance and hydrophobic collapse. The self-healing reported here is rapid, occurring within seconds of the insertion of a crack into the hydrogel or juxtaposition of two separate hydrogel pieces. The healing is reversible and can be switched on and off via changes in pH, allowing external control over the healing process. Moreover, the hydrogels can sustain multiple cycles of healing and separation without compromising their mechanical properties and healing kinetics. Beyond revealing how secondary interactions could be harnessed to introduce new functions to chemically cross-linked polymeric systems, we also demonstrate various potential applications of such easy-to-synthesize, smart, self-healing hydrogels.

Fullerenol-cytotoxic conjugates for cancer chemotherapy.

In the present study, we report the novel application of polyhydroxylated fullerenes (fullerenols) in cancer drug delivery. The facile synthetic procedure for generating multiple hydroxyl groups on the fullerene cage offers scope for high drug loading in addition to conferring hydrophilicity. Doxorubicin, a first line cancer chemotherapeutic, was conjugated to fullerenols through a carbamate linker, achieving ultrahigh loading efficiency. The drug-fullerenol conjugate was found to be relatively stable in phosphate buffer saline but temporally released the active drug when incubated with tumor cell lysate. The fullerenol-doxorubicin conjugate suppressed the proliferation of cancer cell-lines in vitro through a G2-M cell cycle block, resulting in apoptosis. Furthermore, in an in vivo murine tumor model, fullerenol-doxorubicin exhibited comparable antitumor efficacy as free drug without the systemic toxicity of free doxorubicin. Additionally, we demonstrate that the fullerenol platform can be extended to other chemotherapeutic agents, such as the slightly water-soluble cisplatin, and can emerge as a new paradigm in the management of cancer.

Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy

The MAPK signal transduction cascade is dysregulated in a majority of human tumors. Here we report that a nanoparticle-mediated targeting of this pathway can optimize cancer chemotherapy. We engineered nanoparticles from a unique hexadentate-polyD,L-lactic acid-co-glycolic acid polymer chemically conjugated to PD98059, a selective MAPK inhibitor. The nanoparticles are taken up by cancer cells through endocytosis and demonstrate sustained release of the active agent, resulting in the inhibition of phosphorylation of downstream extracellular signal regulated kinase. We demonstrate that nanoparticle-mediated targeting of MAPK inhibits the proliferation of melanoma and lung carcinoma cells and induces apoptosis in vitro. Administration of the PD98059-nanoparticles in melanoma-bearing mice inhibits tumor growth and enhances the antitumor efficacy of cisplatin chemotherapy. Our study shows the nanoparticle-mediated delivery of signal transduction inhibitors can emerge as a unique paradigm in cancer chemotherapy.

Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity

Nanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherapeutics. Here we propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension. Using cisplatin as a template, we describe the synthesis of a unique platinum (II) tethered to a cholesterol backbone via a unique monocarboxylato and O→Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]. The nanoparticles formed exhibit lower IC50 values compared with carboplatin or cisplatin in vitro, and are active in cisplatin-resistant conditions. Additionally, the nanoparticles exhibit significantly enhanced in vivo antitumor efficacy in murine 4T1 breast cancer and in K-RasLSL/+/Ptenfl/fl ovarian cancer models with decreased systemic- and nephro-toxicity. Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a next-generation platinum-based agent in the clinics.

Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy

Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O → Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 ± 0.16 μM) comparable to that of free cisplatin (3.87 ± 0.37 μM), and superior to carboplatin (14.75 ± 0.38 μM). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-rasLSL/+/Ptenfl/fl ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer.

Nanoparticle-mediated targeting of phosphatidylinositol-3-kinase signaling inhibits angiogenesis

ObjectiveDysregulation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a hallmark of human cancer, occurring in a majority of tumors. Activation of this pathway is critical for transformation and also for the angiogenic switch, which is a key step for tumor progression. The objective of this study was to engineer a PI3K inhibitor-loaded biodegradable nanoparticle and to evaluate its efficacy.Methods and resultsHere we report that a nanoparticle-enabled targeting of the PI3K pathway results in inhibition of downstream Akt phosphorylation, leading to inhibition of proliferation and induction of apoptosis of B16/F10 melanoma. It, however, failed to exert a similar activity on MDA-MB-231 breast cancer cells, resulting from reduced internalization and processing of nanoparticles in this cell line. Excitingly, the nanoparticle-enabled targeting of the PI3K pathway resulted in inhibition of endothelial cell proliferation and tubulogenesis, two key steps in tumor angiogenesis. Furthermore, it inhibited both B16/F10- and MDA-MB-231-induced angiogenesis in a zebrafish tumor xenotransplant model.ConclusionOur study, for the first time, shows that targeting of the PI3K pathway using nanoparticles can offer an attractive strategy for inhibiting tumor angiogenesis.

New insights into kinetics and thermodynamics of interfacial polymerization

Abstract A comprehensive model is developed for interfacial polymerization (IP), which provides new insights into the kinetics of film formation, the molecular weight distribution of the polymer as well as the mechanism of polymer precipitation. We incorporate a more general reaction scheme as well as polymer phase separation both by nucleation of the polymer-rich phase as well as by spinodal decomposition. The model predictions are verified against experimental data for unstirred Nylon 6–10 system. The model predicts that spinodal decomposition is the dominant mechanism of polymer phase separation at short reaction times. Film growth by nucleation of the polymer-rich phase dominates at larger times. The model also predicts the dominance of the nucleation mode of film growth with dilution of the organic phase. This model provides a further step towards a rational design and prediction of properties of membranes/capsules produced by interfacial polymerization.

Novel separation strategies based on molecularly imprinted adsorbents

The use of molecularly imprinted polymers (MIPs) for the separation of structurally similar substrates is demonstrated, with a model system comprising removal of phenol from anisole. It is shown experimentally that the shape and size of the cavity determines the selectivity of separation. Hydrogen bonding plays a key role in achieving the separation. For the MIPs synthesised in this work, equilibrium sorption, packed-bed flow experiments as well as batch experiments were conducted. The results were analysed in the framework of a suitable mathematical model. Agreement between the experimental and predicted breakthrough curves was sound. MIPs could be used to achieve such separations in commercially important systems, especially for the removal of trace impurities. The recovery as well as selectivity can be further improved by selecting sorbents resistant to swelling.

Slipping fluids: a unified transient network model

Wall slip in polymer solutions and melts play an important role in fluid flow, heat transfer and mass transfer near solid boundaries. Several different physical mechanisms have been suggested for wall slip in entangled systems. We look at the wall slip phenomenon from the point of view of a transient network model, which is suitable for describing both, entangled solutions and melts. We propose a model, which brings about unification of different mechanisms for slip. We assume that the surface is of very high energy and the dynamics of chain entanglement and disentanglement at the wall is different from those in the bulk. We show that severe disentanglement in the annular wall region of one radius of gyration thickness can give rise to non-monotonic flow curve locally in that region. By proposing suitable functions for the chain dynamics so as to capture the right physics, we show that the model can predict all features of wall slip, such as flow enhancement, diameter-dependent flow curves, discontinuous increase in flow rate at a critical stress, hysteresis in flow curves, the possibility of pressure oscillations in extrusion and a second critical wall shear stress at which another jump in flow rate can occur.

The life time of a dissolving polymeric particle

Abstract The life time of a dissolving polymeric particle in a hydrodynamic field is predicted by building up a model that includes the phenomenon of reptation of the macromolecules, disengagement of these molecules from the gel—liquid interface and also diffusion in the boundary layer surrounding the gel—liquid interface. The model predictions have been verified through some preliminary experiments. A striking experimental observation is that below a critical particle size, the dissolution time does not depend on the particle dimension, a finding that is in sharp contrast to the dissolution of ordinary low molecular weight systems. The minimum time for dissolution in the particle size independent region is shown to satisfy the prediction emanating from scaling theories. The implications of the findings in engineering practice have been discussed.