Raj Kumar Thapa

Nanoparticle-based combination drug delivery systems for synergistic cancer treatment

Despite being a leading cause of death worldwide, cancer remains difficult to treat due to the development of drug resistance and severe adverse effects associated with conventional chemotherapy. Hence, combination chemotherapy is theoretically advantageous owing to the synergistic effects of drugs and suppression of drug resistance. Nanoparticle-mediated chemotherapeutic delivery is a promising approach for the effective treatment of various cancers because it may simultaneously enhance therapeutic effects and reduce side effects. The loading of multiple chemotherapeutic agents to these systems could additionally improve the antineoplastic efficacy. This review highlights recent advances in combination chemotherapy using small-molecule chemotherapeutic agents via nanocarrier systems, e.g., liposomes, polymeric micelles, dendrimers, polymer-drug conjugates, and mesoporous silica nanoparticles. Specifically, it emphasizes the unique properties of these systems that make them amenable to optimized treatments with respect to efficacy and safety and clarifies areas in which current therapeutic strategies can be improved.

Multilayer-Coated Liquid Crystalline Nanoparticles for Effective Sorafenib Delivery to Hepatocellular Carcinoma.

Hepatocellular carcinoma is one of the most common cancers in adults and develops due to activation of oncogenes and inactivation of tumor suppressor genes. Sorafenib (SF) is a U.S. Food and Drug Administration (FDA) approved drug for the treatment of hepatocellular carcinoma. However, its clinical use is limited by its poor aqueous solubility and undesirable side effects. Monoolein-based liquid crystalline nanoparticles (LCN) are self-assembled structures that have been determined as promising drug-delivery vehicles. Therefore, the main aim of this study was to prepare layer-by-layer (LbL) polymer-assembled SF-loaded LCNs (LbL-LCN/SF) for effective delivery of SF to hepatocellular carcinoma. Results revealed that LbL-LCN/SF presented optimum particle size (∼165 nm) and polydispersity index (PDI, ∼0.14) with appropriate polymer layer assembly confirmed by transmission electron microscopy (TEM) and atomic force microscopy (AFM). Furthermore, LbL-LCN/SF effectively controlled burst release and exhibited pH-sensitive release of SF, thereby increasing drug release in the acidic microenvironment of tumor cells. Compared to free SF and bare LCN, the hemolytic activity of LbL-LCN/SF was significantly reduced (p<0.01). Interestingly, LbL-LCN/SF was more cytotoxic to HepG2 cells than the free drug was. Additionally, high cellular uptake and greater apoptotic effects of LbL-LCN/SF in HepG2 cells indicates superior antitumor effects. Therefore, LbL-LCN/SF is a potentially effective formulation for hepatocellular carcinoma.

Graphene oxide-wrapped PEGylated liquid crystalline nanoparticles for effective chemo-photothermal therapy of metastatic prostate cancer cells.

Here, we report the preparation of PEGylated liquid crystalline nanoparticles (LCN) loaded with docetaxel (DTX) and wrapped with graphene oxide (GO), called PEG-GO/LCN/DTX, for effective chemo-photothermal therapy of metastatic prostate cancer cells. The prepared formulation exhibited a small particle size (<250 nm), high drug loading capacity (∼15%), and efficient near infrared (NIR) light-induced thermal heat. Importantly, PEG-GO/LCN/DTX successfully accumulated in prostate cancer cells and exhibited potent apoptotic and antimigration effects, mediated by the combination of the anticancer effects of DTX and the thermal heat induced by exposure of GO to NIR light. Taken together, our findings support that PEG-GO/LCN/DTX may be an effective system for treatment of metastatic prostate cancer. Moreover, the results establish a proof-of-concept for the potential chemo-photothermal functionality of PEG-GO/LCN/DTX. This hybrid system of LCN and GO could provide controlled and targeted drug delivery with enhanced NIR-induced thermal effects for effective treatment of metastatic cancers.

Nitric oxide-releasing chitosan film for enhanced antibacterial and in vivo wound-healing efficacy

Nitric oxide (NO) is a promising therapeutic agent with antibacterial and wound-healing properties. However, the gaseous state and short half-life of NO necessitate a formulation that can control its storage and release. In this study, we developed NO-releasing films (CS/NO film) composed of chitosan (CS) and S-nitrosoglutathione (GSNO) as a NO donor. Thermal analysis demonstrated molecular dispersion of GSNO in the films. In vitro release study revealed that NO release from CS/NO films followed Korsmeyer-Peppas model with Fickian diffusion kinetics. Moreover, the CS/NO film showed a stronger antibacterial activity against Pseudomonas aeruginosa (Gram-negative) and Staphylococcus aureus (Gram-positive) than the CS film. Further, the CS/NO film accelerated wound healing and epithelialization in a rat model of full-thickness wounds as compared to the CS film. Histopathological studies revealed that CS/NO films favorably enhanced the re-epithelialization and reconstruction of wounded skin. Therefore, our results suggest that CS/NO films could be a suitable formulation for treating full-thickness wounds.

Development of Bioactive PEGylated Nanostructured Platforms for Sequential Delivery of Doxorubicin and Imatinib to Overcome Drug Resistance in Metastatic Tumors

Metastasis of cancers accounts for almost all cancer-related deaths. In this study, we report a PEGylated nanostructured platform for coadministration of doxorubicin (DOX) and imatinib (IMT) intended to effectively inhibit metastatic tumors. The DOX and IMT coloaded nanostructured system (DOX/IMT-N) is characterized by an excellent encapsulation potential for both drugs and shows sequential and sustained drug release in vitro. DOX/IMT-N significantly inhibited the in vitro proliferation of MDA-MB-231 and SK-MEL-28 cells. The inhibitory effect on in vitro proliferation of the cells was significantly greater than the effect of free DOX, DOX/IMT cocktail, or the nanostructured system housing DOX only (DOX-N). DOX/IMT-N remarkably enhanced cellular drug uptake, resulting in enhanced apoptosis, caused by significant increases in the expression levels of apoptotic marker proteins. Intravenous administration of DOX/IMT-N to MBA-MB-231 xenograft tumor-bearing mice resulted in significantly improved inhibition of tumor progression compared to that with DOX, DOX/IMT, or DOX-N. Therefore, the nanostructured DOX/IMT-N system could potentially aid in overcoming drug resistance in metastatic tumors and improve the effectiveness of metastatic tumor therapeutics.

Combined phototherapy in anti-cancer treatment: therapeutics design and perspectives

Photodynamic (PDT) and photothermal (PTT) therapy are proven effective strategies for the treatment of cancer. PDT, a photochemistry-based therapy, utilises light energy based photosensitiser for the production of cytotoxic species via electron transfer to biological substrates and potential excitation or energy transfer to molecular oxygen. On the other hand, PTT utilises substances that can convert light energy into heat for efficient tumour ablation. This review provides an insight into the current research investigations of different nanocarriers utilising the synergistic effects of PTT and PDT for anticancer therapy.

Receptor-targeted, drug-loaded, functionalized graphene oxides for chemotherapy and photothermal therapy.

Cancer is one of the leading causes of death worldwide. Although different chemotherapeutic agents have been developed to treat cancers, their use can be limited by low cellular uptake, drug resistance, and side effects. Hence, targeted drug delivery systems are continually being developed in order to improve the efficacy of chemotherapeutic agents. The main aim of this study was to prepare folic acid (FA)-conjugated polyvinyl pyrrolidone-functionalized graphene oxides (GO) (FA-GO) for targeted delivery of sorafenib (SF). GO were prepared using a modified Hummer’s method and subsequently altered to prepare FA-GO and SF-loaded FA-GO (FA-GO/SF). Characterization of GO derivatives was done using ultraviolet/visible spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, atomic force microscopy, zeta potential measurements, and determination of in vitro drug release. Hemolytic toxicity, in vitro cytotoxicity, cellular uptake, and apoptotic effects of FA-GO/SF were also investigated. The results revealed that GO was successfully synthesized and that further transformation to FA-GO improved the stability and SF drug-loading capacity. In addition, the enhanced SF release under acidic conditions suggested possible benefits for cancer treatment. Conjugation of FA within the FA-GO/SF delivery system enabled targeted delivery of SF to cancer cells expressing high levels of FA receptors, thus increasing the cellular uptake and apoptotic effects of SF. Furthermore, the photothermal effect achieved by exposure of GO to near-infrared irradiation enhanced the anticancer effects of FA-GO/SF. Taken together, FA-GO/SF is a potential carrier for targeted delivery of chemotherapeutic agents in cancer.

Evaluation of the effect of tacrolimus-loaded liquid crystalline nanoparticles on psoriasis-like skin inflammation.

Psoriasis is a chronic relapsing inflammatory skin disorder affecting 2–3% of world population. In present context, a novel topical formulation that could effectively deliver tacrolimus for psoriasis treatment would be of great interest. Liquid crystalline nanoparticle (LCN) is one of the potential drug delivery systems for topical drug delivery. Herein, the effects of tacrolimus-loaded LCNs on in vitro skin permeation and retention as well as on in vivo psoriasis-like skin inflammation are studied. Characterization of nanoparticles included particle size and entrapment efficiency analysis that presented nanoparticles of 149.1 nm for monoolein-based and 204.3 nm for oleic acid added monoolein-based nanoparticles with entrapment efficiency of tacrolimus above 99%. Skin permeation and retention study has revealed a significant increase in the amount of tacrolimus permeated and retained by the use of LCNs. Tacrolimus-loaded LCNs are more effective in the treatment of psoriasis-like skin inflammation as compared to tacrolimus dissolved in propylene glycol. Hence, this study provides a basis for possible applicability of tacrolimus-loaded LCNs in the treatment of psoriasis.

Synergistic anticancer activity of combined histone deacetylase and proteasomal inhibitor-loaded zein nanoparticles in metastatic prostate cancers

The development of resistance and subsequent metastasis makes prostate cancer a leading cause of cancer-related death among men. Hence, nanoparticle-based combination chemotherapeutics could be a viable treatment strategy. We aimed to prepare vorinostat (Vor) and bortezomib (Bor) combination-loaded zein nanoparticles (ZNP, ZNP/VB) for treating metastatic prostate cancers. Our results revealed the successful preparation of ZNP/VB with a small particle size (~160nm) and polydispersity index (~0.20). Importantly, controlled and pH-dependent drug release profiles were observed. ZNP/VB exhibited high uptake in different prostate cancer cells and, thereby, exhibited higher cytotoxicity and apoptosis. Additionally, the enhanced anti-migration effect of and induction of pro-apoptotic proteins by ZNP/VB suggest its potential effectiveness in cancer treatment. ZNP/VB showed enhanced in vivo antitumor effects compared to that observed for each free drug and their combination, with minimal toxicity. Taken together, ZNP/VB could be a potential formulation for the effective treatment of metastatic prostate cancers.

Preparation of High-Payload, Prolonged-Release Biodegradable Poly(lactic-co-glycolic acid)-Based Tacrolimus Microspheres Using the Single-Jet Electrospray Method

Tacrolimus-loaded poly(lactic-co-glycolic acid) microspheres (TAC-PLGA-M) can be administered for the long-term survival of transplanted organs due to their immunosuppressive activity. The purpose of our study was to optimize the parameters of the electrospray method, and to prepare TAC-PLGA-M with a high payload and desirable release properties. TAC-PLGA-M were prepared using the electrospray method. In vitro characterization and evaluation were performed using scanning electron microscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy. Drug-loading efficiency was greater than 80% in all formulations with a maximum loading capacity of 16.81±0.37%. XRD and DSC studies suggested that the drug was incorporated in an amorphous state or was molecularly dispersed in the microspheres. The in vitro release study showed prolonged release patterns. TAC-PLGA-M with enhanced drug loading and prolonged-release patterns were successfully prepared using the electrospray method.