Glycosylated Porphyrin Derivatives for Sonodynamic Therapy: ROS Generation and Cytotoxicity Studies in Breast Cancer Cells.

Sonodynamic therapy (SDT) is a promising alternative to photodynamic therapy for achieving site-specific cytotoxic therapy. Porphyrin derivative molecules have been reported extensively in photodynamic therapy. We have previously shown that the glycosylation of porphyrin-based sonosensitizers can enhance their cellular uptake. However, the sonodynamic potential of these water-soluble glycosylated porphyrins has not been investigated. In this study, we characterized the sonodynamic response of two water-soluble glycosylated porphyrin derivatives. Ultrasound (US) exposure was performed (1 MHz frequency, intensities of 0.05-1.1 W/cm2) for 0-3 min in continuous mode. Reactive oxygen species (ROS) generation was quantified via ultraviolet-visible (UV-vis) spectrophotometry. MTT assay was used to quantify cytotoxicity caused by sonodynamic effects from these derivatives in the human mammary carcinoma (SUM-159) cell line in vitro. ROS generation from the porphyrin derivatives was demonstrated at a concentration of 15 µM. No significant cytotoxic effects were observed with the sonosensitizer alone or US exposure alone over the tested range of intensities and duration. The free base porphyrin derivative caused 60-70% cell death, whereas the zinc-porphyrin derivative with Zn metal conjugation caused nearly 50% cytotoxicity when exposed at 0.6 W/cm2 intensity for 3 min. These studies demonstrate the potential of anticancer SDT with soluble glycosylated porphyrins.

Vitamin-H Channeled Self-Therapeutic P-gp Inhibitor Curcumin-Derived Nanomicelles for Targeting the Tumor Milieu by pH- and Enzyme-Triggered Hierarchical Disassembly.

An effective nanocarrier-mediated drug delivery to cancer cells primarily faces limitations like the presence of successive drug delivery barriers, insufficient circulation time, drug leakage, and decreased tumor penetration capacity. With the aim of addressing this paradox, a self-therapeutic, curcumin-derived copolymer was synthesized by conjugation with PEGylated biotin via enzyme- and acid-labile ester and acetal linkages. This copolymer is a prodrug of curcumin and self-assembles into ∼150-200 nm-sized nanomicelles; it is capable of encapsulating doxorubicin (DOX) and hence can be designated as self-therapeutic. pH- and enzyme-responsive linkages in the polymer skeleton assist in its hierarchical disassembly only in the tumor microenvironment. Further, the conjugation of biotin and poly(ethylene glycol) (PEG) imparts features of tumor specificity and improved circulation times to the nanocarrier. The dynamic light scattering (DLS) analysis supports this claim and demonstrates rapid swelling and disruption of micelles under acidic pH. UV-vis spectroscopy provided evidence of an accelerated acetal degradation at pH 4.0 and 5.0. The in vitro release studies revealed a controlled release of DOX under acidic conditions and curcumin release in response to the enzyme. The value of the combination index calculated on HepG2 cells was found to be <1, and hence, the drug pair curcumin and DOX acts synergistically for tumor regression. To prove the efficiency of acid-labile linkages and the prodrug strategy for effective cancer therapy, curcumin-derived polymers devoid of sensitive linkages were also prepared. The prodrug stimuli-responsive nanomicelles showed enhanced cell cytotoxicity and tumor penetration capability on HepG2 cells as well as drug-resistant MCF-7 cell lines and no effect on normal NIH/3T3 fibroblasts as compared to the nonresponsive micelles. The results were also supported by in vivo evidence on a hepatocellular carcinoma (HCC)-induced nude mice model. An evident decrease in MMP-2, MMP-9, and α-fetoprotein (AFP), the biomarkers specific to tumor progression, was observed along with metastasis upon treatment with the drug-loaded dual-responsive nanomicelles. These observations corroborated with the SGOT and SGPT data as well as the histoarchitecture of the liver tissue in mice.

Emerging hybrid biomaterials for oxidative stress induced photodynamic therapy.

Cancer therapy has undergone tremendous advancements in the past few years. The drawbacks of most of these therapies have encouraged researchers to obtain further insight into the complex chemical, biochemical and biological processes ongoing in the evolving cancer cells. These studies have led to an advent of reactive oxygen species mediated therapies to target and disrupt the cancer pathology. Photodynamic therapy (PDT) has emerged as a potent candidate for oxidative stress mediated non-invasive technique for rapid diagnosis and treatment of cancer. Towards this, biomacromolecules derived hybrid nanomaterials have contributed largely in the development of various therapeutics and theranostics for efficacious cancer management that can assist PDT. This review summarizes various hybrid biomaterials and advanced techniques that have been explored widely in the past few years for PDT application. The article also mentions some of the important in-vitro and in-vivo developments and observations explored by employing these materials for PDT application. The article also describes the interactions of these materials at the biological interface and the probable mechanism that assist in generation of oxidative stress and subsequent cell death.

Carbon nanotube embedded cyclodextrin polymer derived injectable nanocarrier: A multiple faceted platform for stimulation of multi-drug resistance reversal.

A combination of cocktail chemotherapy (CCT), photothermal therapy (PTT) and inhibition of angiogenesis was investigated as an effective approach to combat major challenges of multidrug resistance and non-targeted drug delivery encountered in conventional cancer therapy. An injectable nanocarrier was developed through functionalization of carbon nanotubes (CNTs) with rationally modified carbohydrate (ß-Cyclodextrin-CD) derived pH and thermo responsive polymer. Embedding CNT to CD polymer offers a nanocarrier which effectively demonstrated CCT, high NIR triggered photothermal efficiency, anti-angiogenic potential for selective tumor homing as well as enhanced multi-drug resistance (MDR) reversal with minimal toxic effects on normal cells. The simultaneously loading with curcumin and doxorubicin hydrochloride exhibited synergistic effect for triggering antitumor effect in vitro and demonstrated down regulation of growth factors associated with angiogenesis ex-ovo. In-vivo studies ascertained that the nanocarrier synthesized with the rational for MDR reversal can lead to enhanced cancer cell death via multiple approaches.

Maleic Anhydride Cross-Linked ß-Cyclodextrin-Conjugated Magnetic Nanoadsorbent: An Ecofriendly Approach for Simultaneous Adsorption of Hydrophilic and Hydrophobic Dyes.

A magnetic nanoadsorbent with a cross-linked ß-Cyclodextrin maleic anhydride polymer capable of simultaneous removal of hydrophilic and hydrophobic dyes was developed with high efficacy and desorption/recycling efficiency. The effect of various parameters (concentration, adsorbent dosage, contact time, pH, and temperature) was evaluated to assess the optimum adsorption conditions. The superparamagnetic nanoadsorbent (SPNA) could be easily separated by magnetic decantation and showed maximum removal of malachite green with 97.2% adsorption efficiency. Studies on simultaneous adsorption of dyes from a mixture were performed and the adsorption capacity was calculated. Interestingly, the phenomenon of competitive adsorption was observed. The adsorption process can be fitted well into the Langmuir isotherm model and follows pseudo-second-order kinetics. SPNA could be effectively regenerated and recycled at least five times without any significant loss in removal efficiency. SPNA could be an ideal adsorbent for water remediation because of excellent dye removal efficiency in addition to chemical stability, ease of synthesis, and better reusability.

ß-cyclodextrin based dual-responsive multifunctional nanotheranostics for cancer cell targeting and dual drug delivery.

Multifunctional nanoconjugates possessing an assortment of key functionalities such as magnetism, florescence, cell-targeting, pH and thermo-responsive features were developed for dual drug delivery. The novelty lies in careful conjugation of each of the functionality with magnetic Fe3O4 nanoparticles by virtue of urethane linkages instead of silica in a simple one pot synthesis. Further ß-cyclodextrin (CD) was utilized to carry hydrophobic as well as hydrophilic drug. Superlative release of DOX could be obtained under acidic pH conditions and elevated temperature, which coincides with the tumor microenvironment. Mathematical modelling studies revealed that the drug release kinetics followed diffusion mechanism for both hydrophobic drug and hydrophilic drug. A number of fluorophores onto a single nanoparticle produced a strong fluorescence signal to optically track the nanoconjugates. Enhanced internalization due to folate specificity could be observed by fluorescence imaging. Further their accumulation driven by magnet near tumor site led to magnetic hyperthermia. in vitro studies confirmed the nontoxicity and hemocompatibility of the nanoconjugates. Remarkable cell death was observed with drug-loaded nanoconjugates at very low concentrations in cancer cells. The internalization and cellular uptake of poor bioavailable anticancer agent curcumin were found to be remarkably enhanced on dosing the drug loaded nanoconjugates as compared to free curcumin. Site specific drug delivery due to folate conjugation and subsequent significant suppression in tumor growth was demonstrated by in vivo studies.

A review on carbohydrate embedded polyurethanes: An emerging area in the scope of biomedical applications.

Polyurethanes (PUs) are expanding to newer horizons in the field of biomedical sciences, particularly due to their exceptional set of properties that deem fit for applications in the said field. On the other hand, carbohydrates find increasing attention as components of biomedical devices due to their easy availability from renewable resources. The manipulation of PUs by carbohydrate has solved the major concern of biodegradability, biocompatibility and economy. This review summarizes the recent trends in PUs embedded with carbohydrates ranging from monosaccharide to polysaccharides, including supramolecular host such as cyclodextrin etc. Diverse approaches for embedding them in PUs in various forms have been listed. In recent decade, significant research has been carried out to employ such polymers in biomedical applications such as drug delivery devices, implants, scaffolds for tissue engineering etc. This knowledge could facilitate the selection of more efficient approach for synthesis of polymeric systems based on the biological macromolecules.