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Article ; Online: Development and in-depth characterization of BRAFi-resistant melanoma cell lines in vitro and in vivo.

Saraswat, Aishwarya / Patel, Ketan

2024 Volume 438, Issue 1, Page(s) 114033

Abstract: Regardless of the clinical response and improved patient survival observed following treatment with BRAFi like Vemurafenib (Vem), rapid development of resistance still remains as a major obstacle in melanoma therapy. In this context, we developed and ... ...

Abstract	Regardless of the clinical response and improved patient survival observed following treatment with BRAFi like Vemurafenib (Vem), rapid development of resistance still remains as a major obstacle in melanoma therapy. In this context, we developed and characterized two acquired Vem-resistant melanoma cell lines, A375V and SK-MEL-28V, and an intrinsically Vem-resistant cell line, RPMI-7951. Altered morphology and growth rate of the resistant cell lines displayed spindle-shaped cells with filopodia formation and enhanced proliferation rate as compared to parental cells. Further in vitro characterization in 2D models confirmed the emergence of a resistant phenotype in melanoma cells. To mimic the in vivo tumor microenvironment, spheroids were developed for both parental and resistant cell lines to recognize materialization of invadopodia structures demonstrating elevated invasiveness and proliferation of resistant cells-based spheroids, especially A375V. Importantly, we validated A375V cell line in vivo to prove its tumorigenicity and drug resistance in tumor xenograft model. Taken together, our established clinically relevant Vem-resistant tumor model could be beneficial to elucidate drug resistance mechanisms, screen and identify novel anticancer therapies to overcome BRAFi resistance in melanoma.
Language	English
Publishing date	2024-04-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2024.114033
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Article ; Online: Delineating effect of headgroup and preparation method on transfection versus toxicity of DNA-loaded lipid nanocarriers.

Saraswat, Aishwarya / Patel, Ketan

Nanomedicine (London, England)

2023 Volume 18, Issue 26, Page(s) 1921–1940

Abstract: Aim: ...

Abstract	Aim:
MeSH term(s)	Lipids ; Transfection ; DNA/genetics ; Liposomes ; Plasmids/genetics ; Nanoparticles
Chemical Substances	Lipids ; DNA (9007-49-2) ; Liposomes
Language	English
Publishing date	2023-12-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2277839-1
ISSN	1748-6963 ; 1743-5889
ISSN (online)	1748-6963
ISSN	1743-5889
DOI	10.2217/nnm-2023-0219
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Zs.A 6617: Show issues

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Article ; Online: Human solid tumors and clinical relevance of the enhanced permeation and retention effect: a 'golden gate' for nanomedicine in preclinical studies?

Gawali, Poonam / Saraswat, Aishwarya / Bhide, Shruti / Gupta, Sanjay / Patel, Ketan

Nanomedicine (London, England)

2023 Volume 18, Issue 2, Page(s) 169–190

Abstract: Nanocarriers passively accumulate in solid tumors through irregular wide fenestrations in neovasculature and increased retention due to poor lymphatic drainage, a phenomenon termed the enhanced permeation and retention (EPR) effect. Although several ... ...

Abstract	Nanocarriers passively accumulate in solid tumors through irregular wide fenestrations in neovasculature and increased retention due to poor lymphatic drainage, a phenomenon termed the enhanced permeation and retention (EPR) effect. Although several preclinical reports have described the role of EPR in nanomedicine, its role in human solid tumor is obscure. There are several distinct factors for tumors in mice versus humans, including size, heterogeneity and nanomedicine pharmacokinetics. This review focuses on preclinical and clinical studies demonstrating the role of the EPR effect and passive targeting. The article illustrates the gaps that limit clinical effectiveness of the EPR effect and elaborates strategies to boost its efficiency, relaying future clinical outcomes for designing clinically applicable EPR-based nanomedicine.
MeSH term(s)	Humans ; Animals ; Mice ; Antineoplastic Agents/therapeutic use ; Antineoplastic Agents/pharmacokinetics ; Nanomedicine ; Clinical Relevance ; Drug Delivery Systems ; Neoplasms/drug therapy ; Neoplasms/blood supply ; Permeability
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2023-04-12
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2277839-1
ISSN	1748-6963 ; 1743-5889
ISSN (online)	1748-6963
ISSN	1743-5889
DOI	10.2217/nnm-2022-0257
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Article ; Online: Cannabidiol Inhibits

Saraswat, Aishwarya / Vartak, Richa / Patki, Manali / Patel, Ketan

Cannabis and cannabinoid research

2021 Volume 8, Issue 6, Page(s) 1008–1018

Abstract: Introduction: ...

Abstract	Introduction:
MeSH term(s)	Humans ; Cannabidiol/pharmacology ; Microsomes, Liver/metabolism ; Cytochrome P-450 CYP3A/metabolism ; Cytochrome P-450 CYP3A Inhibitors/metabolism ; SARS-CoV-2/metabolism ; COVID-19/metabolism ; Midazolam/metabolism ; Liver/metabolism
Chemical Substances	Cannabidiol (19GBJ60SN5) ; remdesivir (3QKI37EEHE) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Cytochrome P-450 CYP3A Inhibitors ; Midazolam (R60L0SM5BC)
Language	English
Publishing date	2021-12-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2867624-5
ISSN	2378-8763 ; 2578-5125
ISSN (online)	2378-8763
ISSN	2578-5125
DOI	10.1089/can.2021.0109
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Article: Galactose-decorated liver tumor-specific nanoliposomes incorporating selective BRD4-targeted PROTAC for hepatocellular carcinoma therapy.

Saraswat, Aishwarya / Vemana, Hari Priya / Dukhande, Vikas V / Patel, Ketan

Heliyon

2022 Volume 8, Issue 1, Page(s) e08702

Abstract: This research deals with the development of asialoglycoprotein receptors (ASGPR) directed nanoliposomes incorporating a novel BRD4 (Bromodomain-containing protein 4) protein-targeted PROTAC (Proteolysis Targeting Chimera), ARV-825 (ARV) (GALARV), and to ... ...

Abstract	This research deals with the development of asialoglycoprotein receptors (ASGPR) directed nanoliposomes incorporating a novel BRD4 (Bromodomain-containing protein 4) protein-targeted PROTAC (Proteolysis Targeting Chimera), ARV-825 (ARV) (GALARV), and to investigate the anticancer efficacy of GALARV for specific delivery in hepatocellular carcinoma. GALARV were prepared using the modified hydration method and characterized for their physicochemical properties as well as anticancer activity using 2D and 3D cell culture models. ARV and GALARV (93.83 ± 10.05 nm) showed significant
Language	English
Publishing date	2022-01-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2021.e08702
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Article ; Online: Topical Cream Carrying Drug-Loaded Nanogels for Melanoma Treatment.

Rahman, Sadia / Haque, Tasmima N / Sugandhi, Vrashabh V / Saraswat, Aishwarya L / Xin, Xiaoban / Cho, Hyunah

Pharmaceutical research

2023 Volume 40, Issue 10, Page(s) 2291–2301

Abstract: In this study, nanogel creams carrying paclitaxel (PTX) and temozolomide (TMZ) were prepared for the topical treatment of melanoma. PTX and TMZ were first loaded in poly-(D,L-lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly-(D,L-lactide-co- ... ...

Abstract	In this study, nanogel creams carrying paclitaxel (PTX) and temozolomide (TMZ) were prepared for the topical treatment of melanoma. PTX and TMZ were first loaded in poly-(D,L-lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly-(D,L-lactide-co-glycolide) (PLAG-b-PEG-b-PLGA) thermosensitive nanogels, which made a transition from a free-flowing sol (formation of micellar network) at 25°C with the z-average particle size of c.a. 96 nm to a gel (aggregation of micelles) at 33°C with the z-average particle size of c.a. 427 nm. An anhydrous absorption ointment base, aquaphor, was then added to drug-loaded nanogels to form nanogel creams carrying PTX and TMZ. Nanogel creams permitted controlled release of the payloads and improved the penetration of the payloads through the rodent skin compared to drug(s)-loaded nanogels. PTX and TMZ in a combination were synergistically effective in inhibiting SK-MEL28, A375, and B16-F10 melanoma cancer cells in vitro. Topically applied nanogel creams carrying TMZ/PTX (4 mg/1.5 mg/dose) showed a trend of tumor volume inhibition on B16-F10-bearing xenograft mice in vivo.
MeSH term(s)	Humans ; Animals ; Mice ; Nanogels ; Drug Carriers ; Polyethylene Glycols ; Paclitaxel ; Micelles ; Melanoma/drug therapy ; Cell Line, Tumor
Chemical Substances	polyethylene glycol polyethyleneimine nanogel ; Nanogels ; Drug Carriers ; polyethylene glycol-poly(lactide-co-glycolide) ; Polyethylene Glycols (3WJQ0SDW1A) ; Paclitaxel (P88XT4IS4D) ; Micelles
Language	English
Publishing date	2023-04-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	843063-9
ISSN	1573-904X ; 0724-8741 ; 0739-0742
ISSN (online)	1573-904X
ISSN	0724-8741 ; 0739-0742
DOI	10.1007/s11095-023-03506-z
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Article ; Online: Development of a safe pediatric liquisolid self-nanoemulsifying system of triclabendazole for the treatment of fascioliasis.

Daware, Snehal / Patki, Manali / Saraswat, Aishwarya / Palekar, Siddhant / Patel, Ketan

International journal of pharmaceutics

2022 Volume 626, Page(s) 122163

Abstract: Fascioliasis, a common parasitic infection observed in the pediatric patient population, is a leading cause of concern in countries with poor/unhealthy water resources. To treat this condition first line agent such as triclabendazole (TBZ) has been the ... ...

Abstract	Fascioliasis, a common parasitic infection observed in the pediatric patient population, is a leading cause of concern in countries with poor/unhealthy water resources. To treat this condition first line agent such as triclabendazole (TBZ) has been the choice therapy. However, there is a major hurdle in exploiting TBZ. Characterized with poor aqueous solubility (0.1 mg/L), its solubility has been the rate limiting factor, rendering requirement of large doses of TBZ. To address the same, the focus of the current study was to develop a self-nano emulsifying drug delivery system (TBZ-SNEDDS) for TBZ and developing dose customizable pediatric dispersible color-coded tablets. TBZ-SNEDDS were successfully formulated by using Kolliphor®EL, as a surfactant, a lipid phase of medium chain triglyceride and α-tocopherol in the ratio of (1:1), with dimethylacetamide (DMA) as a solvent. It was observed during in vitro release studies that there was a significant effect of fed conditions on the rate of TBZ release from the formulation. greater than 85 % TBZ was observed to release in fed conditions in comparison to fasted conditions. As currently TBZ is prescribed on a weight-based dosage regimen, it is imperative to develop a dose-customizable fast dissolving pediatric formulation. Hence, TBZ-SNEDDS could prove to be pivotal in helping countless children around the world in desperate conditions to get cheap yet effective therapy.
MeSH term(s)	Child ; Humans ; alpha-Tocopherol ; Biological Availability ; Drug Delivery Systems ; Emulsions ; Fascioliasis ; Lipids ; Nanoparticles ; Particle Size ; Solubility ; Solvents ; Surface-Active Agents ; Tablets ; Triclabendazole ; Triglycerides
Chemical Substances	alpha-Tocopherol (H4N855PNZ1) ; Emulsions ; Lipids ; Solvents ; Surface-Active Agents ; Tablets ; Triclabendazole (4784C8E03O) ; Triglycerides
Language	English
Publishing date	2022-09-05
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	428962-6
ISSN	1873-3476 ; 0378-5173
ISSN (online)	1873-3476
ISSN	0378-5173
DOI	10.1016/j.ijpharm.2022.122163
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Article ; Online: Galactose-decorated liver tumor-specific nanoliposomes incorporating selective BRD4-targeted PROTAC for hepatocellular carcinoma therapy

Aishwarya Saraswat / Hari Priya Vemana / Vikas V. Dukhande / Ketan Patel

Heliyon, Vol 8, Iss 1, Pp e08702- (2022)

2022

Abstract	This research deals with the development of asialoglycoprotein receptors (ASGPR) directed nanoliposomes incorporating a novel BRD4 (Bromodomain-containing protein 4) protein-targeted PROTAC (Proteolysis Targeting Chimera), ARV-825 (ARV) (GALARV), and to investigate the anticancer efficacy of GALARV for specific delivery in hepatocellular carcinoma. GALARV were prepared using the modified hydration method and characterized for their physicochemical properties as well as anticancer activity using 2D and 3D cell culture models. ARV and GALARV (93.83 ± 10.05 nm) showed significant in vitro cytotoxicity and apoptosis in hepatocellular carcinoma cells. GALARV also demonstrated a substantially higher intracellular concentration of ARV compared to non-targeted nanoliposomes (∼3 fold) and ARV alone (∼4.5 fold), showed good physical stability and negligible hemolysis. Immunoblotting results depicted substantial downregulation of target BRD4 protein, oncogenic c-Myc, apoptotic Bcl-2, and survivin proteins. Notably, GALARV treatment resulted in significant apoptosis and subsequent inhibition of the cell viability of 3D tumor spheroids of hepatocellular carcinoma. These results suggest that GALARV is a novel actively targeted PROTAC-based nanotherapeutic approach for hepatocellular carcinoma.
Keywords	ARV-825 ; BRD4 ; PROTAC ; Galactosylated nanoliposomes ; Active drug delivery ; Hepatocellular carcinoma ; Science (General) ; Q1-390 ; Social sciences (General) ; H1-99
Subject code	500
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Drug delivery challenges and formulation aspects of proteolysis targeting chimera (PROTACs).

Saraswat, Aishwarya L / Vartak, Richa / Hegazy, Rehab / Patel, Akanksha / Patel, Ketan

Drug discovery today

2022 Volume 28, Issue 1, Page(s) 103387

Abstract: Proteolysis targeting chimeras (PROTACs) have been extensively explored for targeted proteasomal degradation of disease-related proteins with enormous potential in the treatment of intractable diseases. However, PROTACs are poorly soluble and permeable ... ...

Abstract	Proteolysis targeting chimeras (PROTACs) have been extensively explored for targeted proteasomal degradation of disease-related proteins with enormous potential in the treatment of intractable diseases. However, PROTACs are poorly soluble and permeable bulky molecules facing several bioavailability challenges irrespective of the route of administration. Our review lays out crucial challenges in the delivery of target protein degraders and nanoformulation approaches to overcome physicochemical and biological hurdles that can aid in transporting these target-protein degraders to the disease site. We have elaborated on the current formulation approaches and further highlighted the prospective delivery strategies that could be probed for disease-specific targeted delivery of PROTACs.
MeSH term(s)	Proteolysis ; Proteolysis Targeting Chimera ; Prospective Studies ; Proteins/metabolism
Chemical Substances	Proteolysis Targeting Chimera ; Proteins
Language	English
Publishing date	2022-09-29
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1324988-5
ISSN	1878-5832 ; 1359-6446
ISSN (online)	1878-5832
ISSN	1359-6446
DOI	10.1016/j.drudis.2022.103387
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Article ; Online: Stromal disruption facilitating invasion of a 'nano-arsenal' into the solid tumor.

Fu, Yige / Saraswat, Aishwarya L / Monpara, Jasmin / Patel, Ketan

Drug discovery today

2021 Volume 27, Issue 4, Page(s) 1132–1141

Abstract: Owing to the indispensable role of nanotechnology in cancer therapy, it is imperative to comprehend every aspect limiting its therapeutic potential. Several preclinical reports have demonstrated the enhanced permeability and retention (EPR)-mediated ... ...

Abstract	Owing to the indispensable role of nanotechnology in cancer therapy, it is imperative to comprehend every aspect limiting its therapeutic potential. Several preclinical reports have demonstrated the enhanced permeability and retention (EPR)-mediated preferential tumor uptake of nanoparticles. However, the therapeutic outcome of nanotherapeutics is severely compromised by heterogeneous drug distribution and insufficient penetration of nanomedicine in a solid tumor owing to the dense tumor extracellular matrix (ECM). Herein, we elaborate on various preclinically investigated tumor stromal disrupting strategies, which we call 'cannons', to compromise the impenetrable 'fortress-like' solid tumor microenvironment. We have described and summarized major approaches to enhance the penetration of a 'nano-arsenal' in solid tumors. ECM remodeling strategies could be very beneficial in enhancing the therapeutic efficacy of monoclonal antibodies and translational nanomedicine.
MeSH term(s)	Antineoplastic Agents/therapeutic use ; Drug Delivery Systems ; Extracellular Matrix ; Humans ; Nanomedicine/methods ; Nanoparticles ; Neoplasms/drug therapy ; Neoplasms/pathology ; Tumor Microenvironment
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2021-11-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1324988-5
ISSN	1878-5832 ; 1359-6446
ISSN (online)	1878-5832
ISSN	1359-6446
DOI	10.1016/j.drudis.2021.11.015
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