Advances in Nanogel as Drug Delivery System for Cancer Therapeutics: An Overview.

Nanogels have gotten much attention as nanoscopic drug carriers, especially for delivering bioactive mediators to specific sites or at certain times. The versatility of polymer systems and the ease with which their physicochemical properties can be changed have resulted in versatile nano gel formulations. Nanogels offer exceptional stability, drug-loading capacity, biological consistency, strong penetration ability, and the ability to respond to environmental stimuli. Nanogels have shown great promise in various sectors, including gene delivery, chemotherapeutic medication delivery, diagnostics, organ targeting, and many more. This review focuses on various types of nanogels, preparation methods, including drug loading methods, various modes of biodegradation mechanisms, and primary mechanisms of drug release from nanogels. The article also focuses on the historical data for herb-related nanogels that are used to treat various disorders with great patient compliance, delivery rate, and efficacy.

Synthesis and ex vivo evaluation of PLGA chitosan surface modulated double walled transdermal Pluronic nanogel for the controlled delivery of Temozolomide.

A surface modulated biodegradable transdermal strategy has been exploited for improving the biopharmaceutical properties of Temozolomide augmented in Poly Lactic-co-glycolic acid (PLGA) chitosan double walled nanogel (PCNGL). The PCNGL was synthesized by dual approach methodology showing consistent nanosize particle range of 210 nm and PDI 0.325 ± 0.43 with cationic zeta potential values +29.34 ± 0.79 mV. The PCNGL showed qualitative endothermic & exothermic temperature dependent degradation peaks by thermogravimetry analysis. Blood hemolysis and coagulation assay showed 3.37 ± 0.19 as hemolytic ratio, validating biologically safe margin for transdermal delivery. The in vitro drug release showed 85% transdermal release at slightly acidic pH mimicking skin microenvironment. The ex vivo studies displayed noteworthy penetration potential validated by concentration depth assay and confocal laser scanning microscopy, exhibiting 80% Temozolomide uptake in porcine epidermal tissue. The current research demonstrated the biodegradable controlled delivery of chemotherapeutic Temozolomide leading to biologically safe transdermal therapy.

Exploring siRNA Umpired Nanogels: A Tale of Barrier Combating Carrier.

Potential short interfering RNAs (siRNA) modulating gene expression have emerged as a novel therapeutic arsenal against a wide range of maladies and disorders containing cancer, viral infections, bacterial ailments and metabolic snags at the molecular level. Nanogel, in the current medicinal era, displayed a comprehensive range of significant drug delivery prospects. Biodegradation, swelling and de-swelling tendency, pHsensitive drug release and thermo-sensitivity are some of the renowned associated benefits of nanogel drug delivery system. Global researches have also showed that nanogel system significantly targets and delivers the biomolecules including DNAs, siRNA, protein, peptides and other biologically active molecules. Biomolecules delivery via nanogel system explored a wide range of pharmaceutical, biomedical engineering and agro-medicinal application. The siRNAs and DNAs delivery plays a vivacious role by addressing the hitches allied with chronic and contemporary therapeutic like generic possession and low constancy. They also incite release kinetics approach from slow-release while mingling to rapid release at the targets will be beneficial as interference RNAs delivery carriers. Therefore, in this research, we focused on the latest improvements in the delivery of siRNA loaded nanogels by enhancing the absorption, stability, sensitivity and combating the hindrances in cellular trafficking and release process.

Discovering pH triggered charge rebound surface modulated topical nanotherapy against aggressive skin papilloma.

A modified facile biomimetic Temozolomide Chitosan nanogel (TCNL) was developed offering pH responsive, charge attracted and microenvironment dependent tumor targeting nanotherapy. USFDA approved chemotherapeutic TMZ (Temozolomide) was encapsulated in a cationic biocompatible chitosan nanogel subsequently surface modified with nonionic Transcutol by inotropic gelation method and evaluated for its combined anti-metastatic and antitumor efficiency. The in-vitro results authenticated that TMZ encapsulated TCNL was effectively uptake and distributed in HaCaT cell line inducing high apoptosis and necrosis of tumor cells prior to the electron microscopic (TEM & SEM) and thermal evaluations (DSC, DTA & TG) suggesting spherical and thermo-stable nanogel system. An accelerated sustained release pattern of TMZ from TCNL was displayed in mildly acidic conditions (pH 6) signifying ultra-sensitivity of TCNL. In-vivo evaluation over 16 week DMBA/croton oil tumor induced mice model showed noteworthy tumor targeting with down regulation of overexpressed COX-2, cytokines and nuclear factors on western blot analysis. Moreover, advanced gamma scintigraphy analysis displayed significant drug accommodation and expressing potent tumor accumulation, suppression and metastasis effect on carcinogenic mice. The TCNL outcomes displayed effective tumor targeting on transdermal delivery for operative nanotherapy against skin cancer.

pH triggered and charge attracted nanogel for simultaneous evaluation of penetration and toxicity against skin cancer: In-vitro and ex-vivo study.

The current research is focused to develop and investigate the toxicity and penetration potential of biocompatible chitosan nanogel encapsulating capecitabine by ionic interaction mechanism exhibiting pH triggered transdermal targeting. The nanogel (CPNL) was synthesized by ion gelation mechanism using Pluronic F 127 and surface decoration by Transcutol as non-ionic penetration enhancer. The CPNL possesses fine morphology and nano size range when evaluated by TEM, SEM and DLS analysis with cationic charge and slightly acidic pH assayed by zeta potential and pH analysis. It showed pH responsive drug release characteristics mimicking the skin cancer micro-environment. The MTT assay and apoptotic index of CPNL on HaCaT cell line elaborated optimal cell toxicity and retention on 24h of exposure. The ex-vivo skin penetration analysis exhibited noteworthy diffusion and penetration caliber through concentration depth profile, steady state flux and fluorescent skin imaging on porcine tissue. Overall outcomes suggested CPNL as a potent alternative biocompatible, transdermal nanotherapy against skin cancer displaying significant penetration caliber with enhance toxicity on cancerous cell.

pH Responsive 5-Fluorouracil Loaded Biocompatible Nanogels For Topical Chemotherapy of Aggressive Melanoma.

Combating melanoma via topical route is a highly challenging task due to low selectivity, poor efficacy and impeding biological environment of the skin. In the present study, we engineered a chitosan based pH responsive biodegradable nanogel (FCNGL), encapsulated with 5-FU that was effective even at very low drug doses (0.2% w/v) against melanoma. The FCNGL was synthesized by ion gelation technique exhibited nano-size particle distribution and sustained drug release kinetics. Hemolysis and coagulation analysis revealed high safety whereas MTT and apoptosis assays exhibited the efficacy of FCNGL. DMBA-Croton oil Swiss albino mice model was employed for in vivo assessment followed by gamma scintigraphic screening. Tumor burden and pharmacokinetic antioxidant stress levels along with whole-body gamma scintigraphy imaging using 99 mTc labelled nanogel exhibited selective accumulation in melanoma tumor nodules. The pH responsive behaviour of the nanogels resulted in triggered release of 5-FU in slightly acidic microenvironment, resulting in selective drug accumulation at the melanoma site. Immunohistochemistry (IHC) analysis of tumor showed improvement of subcutaneous layer alignment and regeneration of the epithelial skin layer when compared with standard 5% 5-FU and control mice group. Overall our preclinical data using the FCNGL portends to be a promising platform for efficient and sustained delivery of 5-FU for topical chemotherapy that can result in high efficacy, patient compliance and safety in the clinical set up.

pH responsive biodegradable nanogels for sustained release of bleomycin.

Site specific drug delivery with desired therapeutic effect still remains challenging task due to suboptimal release, tissue toxicity, low selectivity and meager therapeutic efficacy in skin cancers. The aim of the current study was to fabricate pH responsive, self-assembled, chemically cross-linked biodegradable chitosan nanogel loaded with bleomycin to target the dermal area of the skin. The nanogel synthesized by ion gelation technique and was characterized for drug loading, swelling and thermal stability followed by in vitro analysis. HaCaT (Human Keratinocyte cell) and HDF (Human dermal fibroblast) cell line were used for the biocompatibility and cytocompatibility evaluation prior to the hemolysis assay and coagulation assessment. The nanogel had a size range of 150nm as determined by TEM and DLS. The nanogel possessed optimum thermal stability as analyzed by thermogravimetry (TG) and differential thermal analysis (DTA). Biodegradation was confirmed by lysozyme enzyme degradation assays. The drug entrapment efficacy was about 55% in the swollen state. The In vitro drug release profile revealed sustained release pattern. The hemolysis of 2.39% and prothrombin time (PT) and activated partial thromboplastin time (APTT) of 12.9 and 31s revealed the biocompatibility of nanogels. The cell uptake and localization profile was validated by fluorescence and confocal microscopy using HDF and HaCaT cell lines. Finally, the MTT assay demonstrated the cytocompatibility of nanogels. In conclusion, the present findings suggest that biodegradable chitosan nanogels with stimuli responsive nature can release the anticancer drug cargo in a sustained and controlled manner and offer promising potentials for treating skin cancers. STATEMENT OF SIGNIFICANCE: Drug delivery to the targeted site is a major challenge in clinical medicine. The newly constructed pH responsive biodegradable nanogel consisting of bleomycin revealed pH triggered drug release in a sustained manner to the dermal area offering novel approach against skin cancer. The nanogel system is biodegradable in nature possessing high drug entrapment efficiency and offers patient compliance with biocompatible and cytocompatible characteristics. This nanogel system can thus be highly useful for delivery of anticancer drugs to the skin in a controlled and sustained manner.

Assessment of penetration potential of pH responsive double walled biodegradable nanogels coated with eucalyptus oil for the controlled delivery of 5-fluorouracil: In vitro and ex vivo studies.

Penetration enhancers coated biodegradable polymeric nanogels loaded with cytotoxic drugs applied via the topical route, can be a promising strategy for improving the chemotherapeutic efficiency of skin cancers. The major objective of proposed research was to investigate the in vitro and ex vivo chemotherapeutic potential of double walled PLGA-chitosan biodegradable nanogel entrapped with 5-fluororuacil (5-FU) coated with eucalyptus oil, topically applied onto the skin. 5-FU was first entrapped in PLGA core by solvent evaporation technique followed by coating with cationic chitosan for ionic interaction with anionic skin cancer cell membrane. A surface coating of eucalyptus oil (1%) was employed to improve the penetration efficacy of the nanogel into stratum corneum. The surface modified biodegradable double walled nanogel was characterized for particle size, charge and thermal properties followed by pH dependent in vitro analysis. Human keratinocyte (HaCaT) cell line was employed for the bio- and cyto-compatibility testing prior to the hemolysis assay and coagulation assessment. A porcine skin ex vivo screening was performed for assessing the penetration potential of the nanogels. DLS and TEM revealed a particle size about 170nm for the double walled nanogels. The nanogels also exhibited high thermal stability as analyzed by thermogravimetry (TG) and differential thermal analysis (DTA). The drug entrapment efficacy was about ~40%. The drug release showed sustained release pattern noted up to 24h. The low hemolysis of 2.39% with short prothrombin time (PT) and activated partial thromboplastin time (APTT) of 14.2 and 35.5s respectively, revealed high biocompatibility of the nanogels. The cellular uptake and localization was assessed by confocal microscopy. The cytotoxicity (MTT assay) on HaCaT cell line demonstrated high cytocompatibilty of the nanogels. An ex vivo evaluation using porcine skin displayed efficient and steady state flux of 5-FU from the biodegradable nanogles into the skin, while the histology of the porcine skin revealed enhanced penetration potential of eucalyptus oil coated PLGA-chitosan double walled nanogels. Taken together the in vivo and ex vivo results portend promising potential for the utility of the biodegradable nanogels for treating skin cancers.

Nanoemulsion: A Novel Eon in Cancer Chemotherapy.

Cancer refers to an assemblage of lethal diseases characterized by abnormal growth of cells. The most celebrated adverse effects accredited to the cytotoxic class of anticancer agents are constructed owing to their inability to differentiate between the abnormally multiplying cancerous cell mass and the rapidly dividing healthy cells of the human body. Consequently, unknown targets chemotherapy for cancer play host to a multitude of adverse effects ranging from nausea, alopecia to torturous ages associated with the current treatment etiquette. Nano-pharmaceuticals constitute the advanced scale drug targeting technologies. Nanoemulsion is an important tool in the nano-technological arena designed for clinical and therapeutic application. Currently among different nano-carriers, nanoemulsions are extensively envisaged as efficient drug delivery systems for the targeted delivery of lipophilic cytotoxic antineoplastic agents. Beauties of nanoemulsion include optical clarity, biocompatibility, non-immunogenic, biodegradable, drug encapsulation, sustained and controlled release, nanometric size, large surface area, ease of preparation and thermodynamic stability. After excessive delving, the research fraternity has acknowledged nanoemulsions as proficient nanocarriers capable of effectively addressing the low bioavailability and noncompliance issues associated with the conventional anticancerous chemotherapeutic dosage forms. This review attempts to shed new light on the current status of nanoemulsion in the cancer therapeutics, and commercial field on the basis of morphology, formulation, characteristics and characterization parameters.