Emerging Roles of Gossypol in Therapy: Innovations in Prodrug Design and Nanoformulation Frontiers.

Stimuli activatable systems have the potential to deliver drugs to targeted areas by releasing therapeutic agents in response to diseased specific microenvironments such as the acidic environment commonly found in diseased tissues. This review article focuses on gossypol, a bioactive compound with inherent toxicity due to its formyl groups. It highlights the potential of imine-linked gossypol-based prodrugs and nanoparticle formulations for targeted delivery and controlled release. The unique presence of polyphenolic cores on gossypol can be utilized to prepare nanoparticles. This review offers valuable insights into designing safer and more effective drug delivery systems by elucidating the masking effect and stimuli-responsive release mechanisms. Numerous examples demonstrate the conversion of formyl groups to imines, creating prodrugs that mask reactive functionalities and offer pH-responsive release. This insight can guide the design of combination therapeutics, where a second drug with an amine terminal group can form imine-linked prodrugs. Additionally, the second part discusses the use of polyphenolic moieties to create stable nanoparticles from infinite polymeric networks. Through a comprehensive examination of gossypol's properties and applications, this review emphasizes the broader implications of such a masking strategy for optimizing the therapeutic benefits of many similar bioactive compounds while minimizing adverse effects.

Synthetically Tunable Suprahybrid Nanoparticle Platform for the Efficacious Delivery of Therapeutics.

The discovery of lipid-hybrid nanosystems has offered potential solutions to various drug delivery and theranostic challenges. However, in many instances, the commonly used lipids and other components in these systems often pose challenges related to their solubility, physicochemical properties, immune compatibility, and limited synthetic tunability. In this work, we introduce a synthetically tunable supramolecular scaffold with amphiphilic characteristics based on the calix[4]arene macrocyclic system. We designed and synthesized two novel calix[4]arene-polyethylene glycol (PEG) conjugates, termed Cal-P1 and Cal-P2, and these were characterized utilizing a wide range of spectroscopic and analytical methods. The rational design of Cal-P1 and Cal-P2 demonstrates their utility in forming stable blended nanospheres with sustained drug release characteristics. The synergistic blending of PLGA and the calixarene scaffold (Cal-P1 and Cal-P2) in constructing long-lasting and controlled-release nanoparticles (NPs), which are optimized for encapsulating Nile Red dye, and their successful internalization and retention in HeLa cancer cells are demonstrated through in vitro assays. The potential of these NPs as sustained therapeutic carriers is investigated in vivo, showing improved retention compared to free dye with negligible toxicity. The successful design and construction of Cal-P1 and Cal-P2 nanosystems represent a new paradigm for addressing drug loading challenges, opening up opportunities for the development of highly efficient, synthetically tunable alternative adjuvants for drug encapsulation and delivery.

Nanocarriers for tracking and treating diseases.

Site directed drug delivery with high efficacy is the biggest challenge in the area of current pharmaceuticals. Biodegradable polymer-based controlled release nanoparticle platforms could be beneficial for targeted delivery of therapeutics and contrast agents for a myriad of important human diseases. Biodegradable nanoparticles, which can be engineered to load multiple drugs with varied physicochemical properties, contrast agents, and cellular or intracellular component targeting moieties, have emerged as potential alternatives for tracking and treating human diseases. In this review, we will highlight the current advances in the design and execution of such platforms for their potential application in the diagnosis and treatment of variety of diseases ranging from cancer to Alzheimer's and we will provide a critical analysis of the associated challenges for their possible clinical translation.

Quinoline driven fluorescence turn on 1,3-bis-calix[4]arene conjugate-based receptor to discriminate Fe3+ from Fe2+.

The synthesis and characterization of a triazole linked quinoline appended calix[4]arene conjugate, L, and its fluorescence turn on receptor property for Fe(3+) have been demonstrated. The selective and sensitive discrimination of Fe(3+) has been shown using fluorescence and absorption titration experiments. The Fe(3+) binding to L has been further shown by ITC and ESI MS. The mode of binding of Fe(3+) by calix[4]arene conjugate has been shown by absorption, (1)H NMR and visual color change and the species were modeled based on DFT computations. The {L + Fe(3+)} has been shown to label cells with fluorescence imaging. Moreover the utility of this conjugate has been demonstrated by the combination logic gate system.

Ratiometric fluorescence off-on-off sensor for Cu2+ in aqueous buffer by a lower rim triazole linked benzimidazole conjugate of calix[4]arene.

A benzimidazole appended triazole linked 1,3-diconjugate of calix[4]arene (L) has been synthesized and characterized. The conjugate L has been found to recognize Cu(2+) among the thirteen different metal ions studied by exhibiting ratiometric fluorescence changes through newly generated excimer band at ∼380 nm. Fluorescence off-on-off behavior has been clearly demonstrated on the basis of the binding variability of Cu(2+) to L. The binding has been elicited through the changes observed in the fluorescence, ESI MS and (1)H NMR titrations. All the other metal ions studied do not show any new band and further do not interfere with the recognition of Cu(2+) by L, even when these are present in the same medium. The structural features of both the mono- and di-nuclear complexes were established by DFT computational calculations and found to display highly distorted geometry about the copper centers that deviate from both the tetrahedral and the square planar.

A Zn2+ specific triazole based calix[4]arene conjugate (L) as a fluorescence sensor for histidine and cysteine in HEPES buffer milieu.

A highly fluorescent Zn(2+) complex of the triazole linked salicyl-imino-thiophenyl conjugate of calix[4]arene, [ZnL] has been demonstrated to be a chemo-sensing ensemble for the recognition of His and Cys among the naturally occurring amino acids in HEPES buffer milieu. The recognition behaviour of the [ZnL] towards these amino acids has been shown on the basis of fluorescence, absorption and visual fluorescent colour changes. The species of recognition were shown by ESI MS titrations, AFM & TEM microscopy and cell studies.

Imino-phenolic-pyridyl conjugates of calix[4]arene (L1 and L2) as primary fluorescence switch-on sensors for Zn2+ in solution and in HeLa cells and the recognition of pyrophosphate and ATP by [ZnL2].

Pyridyl-based triazole-linked calix[4]arene conjugates, viz. L(1) and L(2), were synthesized and characterized. These two conjugates were shown to be selective and sensitive for Zn(2+) among the 12 metal ions studied in HEPES buffer medium by fluorescence, absorption, and visual color change with the detection limit of ~31 and ~112 ppb, respectively, by L(1) and L(2). Moreover, the utility of the conjugates L(1) and L(2) in showing the zinc recognition in live cells has also been demonstrated using HeLa cells as monitored by fluorescence imaging. The zinc complexes of L(1) and L(2) were isolated, and the structure of [ZnL(1)] has been established by single-crystal XRD and that of [ZnL(2)] by DFT calculations. TDDFT calculations were performed in order to demonstrate the electronic properties of receptors and their zinc complexes. The isolated zinc complexes, viz. [ZnL(1)] and [ZnL(2)], have been used as molecular tools for the recognition of anions on the basis of their binding affinities toward Zn(2+). [ZnL(2)] was found to be sensitive and selective toward phosphate-bearing ions and molecules and in particular to pyrophosphate (PPi) and ATP among the other 18 anions studied; however, [ZnL(1)] was not sensitive toward any of the anions studied. The selectivity has been shown on the basis of the changes observed in the emission and absorption spectral studies through the removal of Zn(2+) from [ZnL(2)] by PPi. Thus, [ZnL(2)] has been shown to detect PPi up to 278 ± 10 ppb at pH 7.4 in aqueous methanolic (1/2 v/v) HEPES buffer.

Triazole-linked-thiophene conjugate of calix[4]arene: its selective recognition of Zn2+ and as biomimetic model in supporting the events of the metal detoxification and oxidative stress involving metallothionein.

Supramolecular calix[4]arene conjugate (L) has been developed as a sensitive and selective sensor for Zn(2+) in HEPES buffer among the 12 metal ion by using fluorescence, absorption and ESI MS and also by visual fluorescent color. The structural, electronic, and emission properties of the calix[4]arene conjugates L and its zinc complex, [ZnL], have been demonstrated using ab initio density functional theory (DFT) combined with time-dependent density functional theory (TDDFT) calculations. The TDDFT calculations reveal the switch on fluorescence behavior of L is mainly due to the utilization of the lone pair of electrons on imine moiety by the Zn(2+). The resultant fluorescent complex, [ZnL], has been used as a secondary sensing chemo-ensemble for the detection of -SH containing molecules by removing Zn(2+) from [ZnL] and forming {Cys/DTT·Zn} adducts as equivalent to those present in metallothioneins. The displacement followed by the release of the coordinated zinc from its Cys/DTT complex by heavy metal ion (viz. Cd(2+) and Hg(2+)), as in the metal detoxification process or by ROS (such as H(2)O(2)) as in the oxidative stress, has been well demonstrated using the conjugate L through the fluorescence intensity retrieval wherein the fluorescence intensity is the same as that observed with [ZnL], which in turn mimics the zinc sensing element (MTF) in biology.

Drug resistance among Mycobacterium tuberculosis isolates from private clinics and a dots center in Delhi, India.

The aim of this study was to ascertain the incidence of drug resistance of Mycobacterium tuberculosis isolates from patients in Delhi, India, being treated with DOTS and in private clinics, since a large proportion of patients with tuberculosis in India seek help from private healthcare sectors. Sputum samples were collected from 60 cases of tuberculosis attending a DOTS center and 42 patients from private clinics. Of these, 35 patients from the DOTS center and 12 patients from private clinics had a second sputum sample collected following two months of therapy. The isolated M. tuberculosis strains were assayed for isoniazid (INH), rifampicin (RIF), streptomycin (SM) and ethambutol (EMB) susceptibility by the proportion method. The frequencies of multidrug resistance (MDR) in the M. tuberculosis strains obtained from those treated with DOTS and in private centers were 12.7% and 5% (p > 0.5), respectively. Isolates obtained after two months of therapy showed a similar rate of MDR (12.5%) at the DOTS center, although the number of patients followed-up at the private centers was small, none of these had MDR after two months of therapy. Future studies including a larger number of patients at private centers are needed to further evaluate the prevalence of drug resistance in M. tuberculosis from private clinics.

A lower rim triazole linked calix[4]arene conjugate as a fluorescence switch on sensor for Zn2+ in blood serum milieu.

A fluorescence turn-on receptor based on triazole linked calix[4]arene (L) for selective recognition of Zn(2+) in aqueous-methanolic HEPES buffer has been developed and showed its utility for sensing Zn(2+) in blood serum milieu.