kishwor poudel - Academia.edu (original) (raw)

Papers by kishwor poudel

Social Science Research Network, 2022

Expert Opinion on Drug Delivery, Feb 13, 2020

Background: Phytosterols significantly reduce the risk of cancer by directly inhibiting tumor gro... more Background: Phytosterols significantly reduce the risk of cancer by directly inhibiting tumor growth, inducing apoptosis, and inhibiting tumor metastasis. Stigmasterol (STS), a phytosterol, exhibits anticancer effects against various cancers, including breast cancer. Chemotherapeutics, including doxorubicin (DOX), might act synergistically with phytosterol against the proliferation and metastasis of breast cancer. Although such compounds can show potential anticancer activity, their combined effect with suitable formulation has not investigated yet. Methods: Hyaluronic acid (HA)-modified PEGylated DOX-STS loaded phyto-liposome was fabricated via a thin-film hydration method. The prepared phyto-liposome was optimized with regards to its physicochemical and other properties. Further, in vitro and in vivo study was carried out in breast cancer cells expressing a different level of CD44 receptors. Results: The particle size of prepared HA-DOX-STS-lipo was 173.9 ± 2.4 nm, and showed pH-depended DOX release, favoring the effective tumor targetability. The in vitro anticancer activity of HA-DOX-STS-lipo was significantly enhanced in MDA-MB-231, CD44-overexpressing cells relative to MCF-7 cells demonstrating HA-mediated targeting effect. HA-DOX-STS-lipo accumulated more and increased antitumor efficacy in the MDA-MB-231 xenograft tumor model expressing high levels of CD44, suggesting the potential of carrier system towards CD44-overexpressing tumors.

Nanomedicine: Nanotechnology, Biology and Medicine, Oct 1, 2019

Targeted, biocompatible, and synergistic "all in one" systems should be designed to combat the he... more Targeted, biocompatible, and synergistic "all in one" systems should be designed to combat the heterogeneity of cancer. In this study, we constructed a dual function nanosystem, copper sulfide nanoplatform loaded with the chemotherapeutic drug docetaxel wrapped by a conjugated polymer-peptide for targeted chemo-phototherapy. The nanoconstruct has been successfully designed with a size of 186.1 ± 5.2 nm, a polydispersity index of 0.18 ± 0.01, and zeta potential of −16.4 ± 0.1 mV. The enhanced uptake and near-infrared-responsive behavior of the nanosystem resulted in efficient drug release, photothermal ablation, effective cytotoxic activity, and potentiated reactive oxygen species generation. The induction of apoptotic markers, enhanced accumulation in the tumor site, and maximum tumor growth inhibition were seen during in vivo studies compared to nontargeted nanoformulations and free drug. Cumulatively, our results indicate that, with low systemic toxicity and better biocompatibility, this nanoconstruct could provide a promising strategy for treating prostate cancer.

Acta Biomaterialia, Apr 1, 2019

Aerosol technique-based carbonencapsulated hollow mesoporous silica nanoparticles for synergistic... more Aerosol technique-based carbonencapsulated hollow mesoporous silica nanoparticles for synergistic chemo-photothermal therapy, Acta

Journal of Controlled Release, Sep 1, 2021

Low immunogenicity and immunosuppressive tumor microenvironments are major hurdles in the applica... more Low immunogenicity and immunosuppressive tumor microenvironments are major hurdles in the application of cancer immunotherapy. To date, several immunogenic cell death (ICD) inducers have been reported to boost cancer immunotherapy by triggering ICD. ICD is characterized by the release of proinflammatory cytokines, danger-associated molecular patterns (DAMPs) and tumor associated antigens which will generate anticancer immunity by triggering adaptive immune cells. However, application of ICD inducers is limited due to severe toxicity issues and inefficient localization in the tumor microenvironment. To circumvent these challenges, stimuli-responsive nanoparticles have been exploited for improving cancer immunotherapy by limiting its toxicity. The combination of stimuli-responsive nanoparticles with an ICD inducer serves as a promising strategy for increasing the clinical applications of ICD induction in cancer immunotherapy. Here, we outline recent advances in ICD mediated by stimuli-responsive nanoparticles that may be near-infrared (NIR)-responsive, pH-responsive, redox responsive, pH and enzyme responsive, or pH and redox responsive, and evaluate their significant potential for successful clinical translation in cancer immunotherapy.

ACS Applied Materials & Interfaces, Jul 6, 2018

Cellular FADD-like interleukin-1β-converting enzyme-inhibitory protein (c-FLIP), often strongly e... more Cellular FADD-like interleukin-1β-converting enzyme-inhibitory protein (c-FLIP), often strongly expressed in numerous cancers, plays a pivotal role in thwarting apoptosis and inducing chemotherapy resistance in cancer. An integrated approach combining chemotherapy with suppression of c-FLIP levels could prove paramount in the treatment of cancers with c-FLIP overexpression. In this study, we utilized a polymeric layer-by-layer (LbL) assembly of silicasupported mesoporous titania nanoparticles (MTNst) to co-deliver paclitaxel (PTX) and microRNA 708 (miR708) for simultaneous chemotherapy and c-FLIP suppression in colorectal carcinoma. The resulting LbL miR708/PTX-MTNst showed dose-dependent cytotoxicity in HCT-116 and DLD-1 colorectal carcinoma cell lines, which was remarkably superior to that of free PTX or LbL PTX-MTNst. LbL miR708/PTX-MTNst strongly inhibited c-FLIP expression and resulted in increased expression of proapoptotic proteins. In DLD-1 xenograft tumor-bearing mice, the nanoparticles accumulated in the tumor, resulting in remarkable tumor regression, with the PTX and miR708-loaded nanoparticles showing significantly greater inhibitory effects than the free PTX or PTX-loaded nanoparticles did. Immunohistochemical analyses of the tumors further confirmed the remarkable apoptotic and anti-proliferative effects of the nanoparticles, while organ histology reinforced the biocompatibility of the system. Therefore, the LbL miR708/PTX-MTNst system, owing to its ability to deliver both chemotherapeutic drug and inhibitory miRNA to the tumor site, shows great potential to treat colorectal carcinoma in clinical settings.

Biomaterials, Feb 1, 2021

Senescent cells drive atherosclerosis at all stages and contribute to cardiovascular disease. How... more Senescent cells drive atherosclerosis at all stages and contribute to cardiovascular disease. However, the markers in these senescent aortic plaques have not been well studied, creating a huge obstacle in the exploration of a precise and efficient system for atherosclerosis treatment. Recently, CD9 has been found to induce cellular senescence and aggravated atherosclerotic plaque formation in apolipoprotein E knockout (ApoE-/-) mice. In the present study, this result has been leveraged to develop CD9 antibody-modified, hyaluronic acid-coated mesoporous silica nanoparticles with a hyaluronidase-responsive drug release profile. In invitro models of senescent foamy macrophages and senescent endothelial cells stimulated with oxidized high-density-lipoprotein, the CD9 antibody-modified mesoporous silica nanoparticles exhibit high cellular uptake; reduce the reactive oxygen species level, high-density lipoprotein oxidation, and production of TNF-α and IL-6; and attenuate the senescence process, contributing to improved cell viability. In vivo experiment demonstrated that these nanoparticles can successfully target the senescent lesion areas, deliver the anti-senescence drug rosuvastatin to the senescent atherosclerotic plaques (mainly endothelial cells and macrophages), and alleviate the progression of atherosclerosis in ApoE-/- mice. By providing deep insight regarding the markers in senescent atherosclerotic plaque and developing a nano-system targeting this lesion area, the study proposes a novel and an accurate therapeutic approach for mitigating atherosclerosis through senescent cell clearance.

ACS Applied Materials & Interfaces, Dec 8, 2020

The consolidation of nanovectors with biological membranes has recently been a subject of interes... more The consolidation of nanovectors with biological membranes has recently been a subject of interest owing to the prolonged systemic circulation time and delayed clearance by the reticuloendothelial system of such systems. Among the different biomembranes, the macrophage membrane has a similar systemic circulation time, with an additional chemotactic aptitude, targeting integrin proteins. In this study, we aimed to establish a laseractivated, disintegrable, and deeply tumor-penetrative nanoplatform. We used a highly tumor-ablative and laser-responsive disintegrable copper sulfide nanoparticle, loaded it with paclitaxel, and camouflaged it with the macrophage membrane for the fabrication of PTX@CuS@MMNPs. The in vitro paclitaxel release profile was favorable for release in the tumor microenvironment, and the release was accelerated after laser exposure. Cellular internalization was improved by membrane encapsulation. Cellular uptake, cytotoxicity, reactive oxygen species generation, and apoptosis induction of PTX@CuS@MMNPs were further improved upon laser exposure, and boosted permeation was achieved by co-administration of the tumor-penetrating peptide iRGD. In vivo tumor accumulation, tumor inhibition rate, and apoptotic marker expression induced by PTX@CuS@MMNPs were significantly improved by laser irradiation and iRGD co-administration. PTX@CuS@MMNPs induced downregulation of cellular proliferation and angiogenic markers but no significant changes in body weight, survival, or significant toxicities in vital organs after laser exposure, suggesting their biocompatibility. The disintegrability of the nanosystem, accredited to biodegradability, favored efficient elimination from the body. In conclusion, PTX@CuS@MMNPs showed promising traits in combination therapies for excellent tumor eradication.

ACS Biomaterials Science & Engineering, Sep 23, 2019

Asian Journal of Pharmaceutical Sciences, 2019

Folate-targeting self-assembled nanoparticles (NPs) using biocompatible and biodegradable natural... more Folate-targeting self-assembled nanoparticles (NPs) using biocompatible and biodegradable natural polymers chitosan (Cs) and chondroitin sulfate (Chs) were developed to address the major challenge in cancer treatment, the selective delivery of nanoparticles to the target site. In this study, we successfully incorporated a hydrophobic drug, bortezomib (Bor), into folic acid (FA)-conjugated Cs/Chs self-assembled NPs (Bor/Cs/Chs-FA) for colorectal cancer therapy. The particle size and polydispersity index of Bor/Cs/Chs-FA were ∼196.5 ± 1.2 nm and ∼0.21 ± 0.5, respectively. A pH-dependent release profile was observed, facilitating cancer cell-targeted drug release under an acidic tumor microenvironment. Moreover, in vitro data revealed enhanced cellular uptake and apoptosis in folate receptor-expressing colorectal cancer cells (HCT-116 and HT-29) as compared to that in lung cancer cells (A549), which do not express folate receptors. Furthermore, intravenous administration of Bor/Cs/Chs-FA in a HCT-116 bearing xenograft mouse model showed that the NPs were a safe and effective drug delivery system. The results suggest that folate-targeted nanoparticle can be effectively applied for efficient chemotherapy of colorectal cancer.

International Journal of Pharmaceutics, Oct 1, 2018

This review outlines recently developed Prussian blue nanoparticle (PB NPs)-based multimodal imag... more This review outlines recently developed Prussian blue nanoparticle (PB NPs)-based multimodal imaging-guided chemo-photothermal strategies for cancer diagnosis and treatment in order to provide insight into the future of the field. The primary limitation of existing therapeutics is the lack of selectivity in drug delivery: they target healthy and cancerous cells alike. In this paper, we provide a thorough review of diverse synthetic and surface engineering techniques for PB NP fabrication. We have elucidated the various targeting approaches employed to deliver the therapeutic and imaging ligands into the tumor area, and outlined methods for enhancement of the tumor ablative ability of the NPS, including several important combinatorial approaches. In addition, we have summarized different in vitro and in vivo effects of PB NP-based therapies used to overcome both systemic and tumor-associated local barriers. An important new approach-PB NP-based immune drug delivery, which is an exciting and promising strategy to overcome cancer resistance and tumor recurrence-has been discussed. Finally, we have discussed the current understanding of the toxicological effects of PB NPs and PB NP-based therapeutics. We conclude that PB NP-based multimodal imaging-guided chemo-photothermal therapy offers new treatment strategies to overcome current hurdles in cancer diagnosis and treatment.

International Journal of Pharmaceutics, Aug 1, 2021

Anticancer regimens have been substantially enriched through monoclonal antibodies targeting immu... more Anticancer regimens have been substantially enriched through monoclonal antibodies targeting immune checkpoints, programmed cell death-1/programmed cell death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4. Inconsistent clinical efficacy after solo immunotherapy may be compensated by nanotechnology-driven combination therapy. We loaded human serum albumin (HSA) nanoparticles with paclitaxel (PTX) via nanoparticle albumin-bound technology and pooled them with anti-PD-L1 monoclonal antibody through a pH-sensitive linker for targeting and immune response activation. Our tests demonstrated satisfactory preparation of paclitaxel-loaded, PD-L1-targeted albumin nanoparticles (PD-L1/PTX@HSA). They had small particle size (∼200 nm) and polydispersity index (∼0.12) and successfully incorporated each constituent. Relative to normal physiological pH, the formulation exhibited higher drug-release profiles favoring cancer cell-targeted release at low pH. Modifying nanoparticles with programmed cell death-ligand 1 increased cancer cell internalization in vitro and tumor accumulation in vivo in comparison with non-PD-L1-modified nanoparticles. PD-L1/PTX@HSA constructed by nanoparticle albumin-bound technology displayed successful tumor inhibition efficacy both in vitro and in vivo. There was successful effector T-cell infiltration, immunosuppressive programmed cell death-ligand 1, and regulatory T-cell suppression because of cytotoxic T-lymphocyte antigen-4 synergy. Moreover, PD-L1/PTX@HSA had low organ toxicity. Hence, the anti-tumor immune responses of PD-L1/PTX@HSA combined with chemotherapy and cytotoxic T-lymphocyte antigen-4 is a potential anti-tumor strategy for improving quantitative and qualitative clinical efficacy.

ACS Applied Materials & Interfaces, May 10, 2021

Amalgamation of the reactive oxygen species (ROS)-responsive stimulus with nanoparticles has gain... more Amalgamation of the reactive oxygen species (ROS)-responsive stimulus with nanoparticles has gained considerable interest owing to their high tumor specificity. Hypoxia plays a pivotal role in the acceleration of intracellular ROS production. Herein, we report the construction of a cancer cell (PD-L1)- and ROS-responsive, dual-targeted, temozolomide (TMZ)-laden nanosystem which offers a better anticancer effect in a hypoxic tumor microenvironment. A dual-targeted system boosted permeation in the cancer cells. Hypoxic conditions elevating the high ROS level accelerated the in situ release of TMZ from anti-PD-L1-TKNPs. Hyperaccumulated ROS engendered from TMZ caused oxidative damage leading to mitochondria-mediated apoptosis. TMZ fabricated in the multifunctional nanosystem (anti-PD-L1-TMZ-TKNPs) provided excellent tumor accumulation and retarded tumor growth under in vivo conditions. The elevated apoptosis effect with the activation of an apoptotic marker, DNA double-strand breakage marker, and downregulation of the angiogenesis marker in the tumor tissue following treatment with anti-PD-L1-TMZ-TKNPs exerts robust anticancer effect. Collectively, the nanoconstruct offers deep tumor permeation and high drug release and broadens the application of the ROS-responsive nanosystem for a successful anticancer effect.

Colloids and Surfaces B: Biointerfaces, Sep 1, 2018

Intratumoral injection of nanoparticles is a viable alternative for treating solid tumors. In thi... more Intratumoral injection of nanoparticles is a viable alternative for treating solid tumors. In this study, we used intratumorally-injected palladium nanoparticle (Pd NP)-decorated graphene oxide (GO) (GO-Pd NPs) for the treatment of solid prostate tumors. GO was synthesized using the modified Hummer's method and GO-Pd NPs were prepared using the one pot synthesis method. Studies on physicochemical characterization and in vitro/in vivo anticancer properties were performed using GO-Pd NPs. Successful preparation of GO-Pd NPs was confirmed by transmission electron microscopy, Fourier transform infrared spectroscopy, energy dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy. Compared to GO or Pd NPs alone, GO-Pd NPs showed higher cytotoxic effects in prostate cancer 3 (PC3) cells. Irradiation of treated cells with near infrared (NIR) laser considerably enhanced apoptosis induced by synergistic photothermal effect and reactive oxygen species (ROS) generation. Intratumorally-injected GO-Pd NPs showed promising in vivo localized distribution, photothermal ablation, and anti-tumor effects in the PC3 xenograft mouse model. Furthermore, the minimal organ toxicity of GO-Pd NPs was an added advantage. Hence, GO-Pd NPs could be a potential formulation for localized treatment of prostate solid tumors.

International Journal of Pharmaceutics, May 1, 2019

Copper sulfide nanoparticles (CuS NPs), emerging nanoplatforms with dual diagnostic and therapeut... more Copper sulfide nanoparticles (CuS NPs), emerging nanoplatforms with dual diagnostic and therapeutic applications, are being actively investigated in this era of "war on cancer" owing to their versatility and adaptability. This article discusses the pros and cons of using CuS NPs in diagnostics, therapeutics, and theranostics. The first section introduces CuS NPs and discusses the features that render them more advantageous than other established nanoplatforms in cancer management. Subsequent sections include specific in vitro and in vivo results of different studies showing the potential of CuS NPs as nanoplatforms. Methods used for visualization (photoacoustic imaging and magnetic resonance imaging) of CuS NPs and treatment (phototherapy and combinatorial therapy) have also been discussed. Furthermore, the challenges and opportunities associated with using CuS NPs have been elucidated. Further investigations on CuS NPs are required to translate it for clinical applications.

Colloids and Surfaces B: Biointerfaces, Dec 1, 2021

The transmembrane proteins, CD47 and signal-regulatory protein α are overexpressed in cancer cell... more The transmembrane proteins, CD47 and signal-regulatory protein α are overexpressed in cancer cells and macrophages, respectively, and facilitate the escape of cancer cells from macrophage-mediated phagocytosis. The immunomodulatory and targeting properties of CD47, the chemotherapeutic effects of dabrafenib (D), and the anti-programmed death-1 antibodies (PD-1) pave the way for effective chemoimmunomodulation-mediated anticancer combination therapy. In this study, CD47-conjugated, D-loaded human serum albumin (HSA) nanosystems were fabricated by modified nanoparticle albumin-bound technology. Cis-aconityl-PEG-maleimide (CA), an acid-labile linker, was used to conjugate D@HSA and CD47; the resultant CD47-CA@D@HSA exhibited tumor-specificity through receptor targeting, as well as preferential cleavage and drug release in the acidic tumor microenvironment (pH 5) compared to normal physiological pH conditions (pH 6.5, 7.4). The successful preparation of nanosized (∼220 nm), narrowly dispersed (∼0.13) CD47-CA@D@HSA was proven by physicochemical characterization. In vitro and in vivo internalization, accumulation, cytotoxicity, and apoptosis were observed to be higher with CD47-conjugated nanoconstructs, than with free D or non-targeted nanoconstructs. CD47-CA@D@HSA was found to promote the infiltration of cytotoxic T cells and tumor-associated macrophages into tumors and improve in vivo tumor inhibition. Administration in combination with PD-1 further improved antitumor efficacy by promoting immune responses that blocked the immune checkpoint. No signs of toxicity were seen in mice treated with the nanoconstructs; the formulation was, therefore, thought to be biocompatible and as having potential for clinical use. The targeted chemoimmunomodulation achieved by this combination therapy was found to combat major immunosuppressive facets, making it a viable candidate for use in the treatment of cancer.

Pharmaceutics, Oct 30, 2019

In this study, we investigated the active targeted delivery of a hydrophobic drug, paclitaxel (PT... more In this study, we investigated the active targeted delivery of a hydrophobic drug, paclitaxel (PTX), via receptor-mediated endocytosis by folate receptors expressed on cancer cells using a protein-based nanoparticle system. PTX was loaded on zein nanoparticles and conjugated with folate (PTX/Zein-FA) to estimate its chemotherapeutic efficacy in folate receptor-expressing KB cancer cells. PTX/Zein-FA nanoparticles were successfully developed, with a nanoparticle size of~180 nm and narrow polydispersity index (~0.22). Accelerated release of PTX in an acidic environment was observed for PTX/Zein-FA. An in vitro cellular study of PTX/Zein-FAs in KB cells suggested that PTX/Zein-FA improved the cytotoxic activity of PTX on folate receptors overexpressed in cancer cells by inducing proapoptotic proteins and inhibiting anti-apoptotic proteins. In addition, PTX/Zein-FA exhibited anti-migratory properties and could alter the cell cycle profile of KB cells. A549 cells, which are folate receptor-negative cancer cells, showed no significant enhancement in the in vitro cellular activities of PTX/Zein-FA. We describe the antitumor efficacy of PTX/Zein-FA in KB tumor-bearing mice with minimum toxicity in healthy organs, and the results were confirmed in comparison with free drug and non-targeted nanoparticles.

Theranostics, 2018

The efficacy of combined near-infrared (NIR) and immune therapies for inhibiting tumor growth and... more The efficacy of combined near-infrared (NIR) and immune therapies for inhibiting tumor growth and recurrence has gained increasing research attention. Regulatory T cells in the tumor microenvironment constitute a major obstacle in achieving robust CD8 + T cell antitumor immunotherapy. In the present study, we designed a photoimmunotherapy-based strategy involving a combination of photothermal and photodynamic therapies, followed by Treg cell suppression, for eliciting an immune response with IR-780and imatinib-loaded layer-by-layer hybrid nanoparticles. Methods: The layer-by-layer hybrid nanoparticles were prepared through electrostatic interactions. Their photothermal effect, photodynamic effect as well as their effect on inhibiting Treg cells' suppressive function were investigated in vitro and in vivo. Their antitumor effect was evaluated using B16/BL6 and MC-38 tumor-bearing mice. Results: The layer-by-layer hybrid nanoparticles, which were pH-sensitive, enabled the release of IR-780 dye for NIR-induced photothermal and photodynamic effects, and the release of imatinib-loaded glucocorticoid-induced TNF receptor family-related protein/poly(lactic-co-glycolic acid) (GITR-PLGA) nanoparticles to initiate antitumor immunotherapy. The photothermal and photodynamic effects caused by IR-780 under NIR exposure resulted in direct tumor apoptosis/necrosis and the production of tumor-associated antigen, promoted dendritic cell maturation, and enhanced the presentation of tumor-associated antigen to T cells, while the imatinib-loaded GITR-PLGA cores reduced the suppressive function of Treg cells, and consequently activated effective CD8 + T cells towards tumors. Conclusion: With the significant photothermal, photodynamic and immunotherapies, the system successfully eradicated tumor growth, diminished tumor recurrence, and improved survival in vivo. The proposed nanoparticles provide a novel and versatile approach to boost antitumor photoimmunotherapy.

Chemical Engineering Journal, Jun 1, 2023

Journal of Hazardous Materials, Mar 1, 2023