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1.
Cancer Lett ; 589: 216810, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38494151

ABSTRACT

Pancreatic cancer is characterized by desmoplasia; crosstalk between pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs) leads to the deposition of extracellular matrix proteins in the tumor environment resulting in poor vascularity. Targeting either PCCs or PSCs individually has produced mixed results, and there is currently no effective strategy to target both cell types simultaneously. Previously, we demonstrated, through in vitro cell culture experiments, that a specific gold nanoparticle-based nanoformulation containing the anti-EGFR antibody cetuximab (C225) as a targeting agent and gemcitabine as a chemotherapeutic agent effectively targets both PCCs and PSCs simultaneously. Herein, we extend our studies to test the ability of these in vitro tested nano formulations to inhibit tumor growth in an orthotopic co-implantation model of pancreatic cancer in vivo. Orthotopic tumors were established by co-implantation of equal numbers of PCCs and PSCs in the mouse pancreas. Among the various formulations tested, 5 nm gold nanoparticles coated with gemcitabine, cetuximab and poly-ethylene glycol (PEG) of molecular weight 1000 Da, which we named ACGP441000, demonstrated optimal efficacy in inhibiting tumor growth. The current study reveals an opportunity to target PCCs and PSCs simultaneously, by exploiting their overexpression of EGFR as a target, in order to inhibit pancreatic cancer growth.


Subject(s)
Metal Nanoparticles , Pancreatic Neoplasms , Animals , Mice , Gemcitabine , Gold , Cetuximab/pharmacology , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Tissue Distribution , Cell Line, Tumor , Pancreatic Neoplasms/pathology , Drug Delivery Systems/methods , Pancreatic Stellate Cells/metabolism
3.
ACS Nano ; 17(10): 9326-9337, 2023 05 23.
Article in English | MEDLINE | ID: mdl-37129853

ABSTRACT

The RAS-transformed cells utilize macropinocytosis to acquire amino acids to support their uncontrolled growth. However, targeting RAS to inhibit macropinocytosis remains a challenge. Here, we report that gold nanoparticles (GNP) inhibit macropinocytosis by decreasing KRAS activation. Using surface-modified and unmodified GNP, we showed that unmodified GNP specifically sequestered both wild-type and mutant KRAS and inhibited its activation, irrespective of growth factor stimulation, while surface-passivated GNP had no effect. Alteration of KRAS activation is reflected on downstream signaling cascades, macropinocytosis and tumor cell growth in vitro, and two independent preclinical human xenograft models of pancreatic cancer in vivo. The current study demonstrates NP-mediated inhibition of macropinocytosis and KRAS activation and provides translational opportunities to inhibit tumor growth in a number of cancers where activation of KRAS plays a major role.


Subject(s)
Metal Nanoparticles , Pancreatic Neoplasms , Humans , Gold/pharmacology , Proto-Oncogene Proteins p21(ras)/genetics , Pinocytosis , Pancreatic Neoplasms/pathology , Cell Proliferation , Cell Line, Tumor , Mutation
4.
Mater Today (Kidlington) ; 56: 79-95, 2022 Jun.
Article in English | MEDLINE | ID: mdl-36188120

ABSTRACT

The tumor microenvironment (TME) plays a key role in the poor prognosis of many cancers. However, there is a knowledge gap concerning how multicellular communication among the critical players within the TME contributes to such poor outcomes. Using epithelial ovarian cancer (EOC) as a model, we show how crosstalk among cancer cells (CC), cancer associated fibroblasts (CAF), and endothelial cells (EC) promotes EOC growth. We demonstrate here that co-culturing CC with CAF and EC promotes CC proliferation, migration, and invasion in vitro and that co-implantation of the three cell types facilitates tumor growth in vivo. We further demonstrate that disruption of this multicellular crosstalk using a gold nanoparticle (GNP) inhibits these pro-tumorigenic phenotypes in vitro as well as tumor growth in vivo. Mechanistically, GNP treatment reduces expression of several tumor-promoting cytokines and growth factors, resulting in inhibition of MAPK and PI3K-AKT activation and epithelial-mesenchymal transition - three key oncogenic signaling pathways responsible for the aggressiveness of EOC. The current work highlights the importance of multicellular crosstalk within the TME and its role for the aggressive nature of EOC, and demonstrates the disruption of these multicellular communications by self-therapeutic GNP, thus providing new avenues to interrogate the crosstalk and identify key perpetrators responsible for poor prognosis of this intractable malignancy.

5.
Mol Aspects Med ; 83: 100993, 2022 02.
Article in English | MEDLINE | ID: mdl-34281720

ABSTRACT

Endocytosis mechanisms are one of the methods that cells use to interact with their environments. Endocytosis mechanisms vary from the clathrin-mediated endocytosis to the receptor independent macropinocytosis. Macropinocytosis is a niche of endocytosis that is quickly becoming more relevant in various fields of research since its discovery in the 1930s. Macropinocytosis has several distinguishing factors from other receptor-mediated forms of endocytosis, including: types of extracellular material for uptake, signaling cascade, and niche uses between cell types. Nanoparticles (NPs) are an important tool for various applications, including drug delivery and disease treatment. However, surface engineering of NPs could be tailored to target them inside the cells exploiting different endocytosis pathways, such as endocytosis versus macropinocytosis. Such surface engineering of NPs mainly, size, charge, shape and the core material will allow identification of new adapter molecules regulating different endocytosis process and provide further insight into how cells tweak these pathways to meet their physiological need. In this review, we focus on the description of macropinocytosis, a lesser studied endocytosis mechanism than the conventional receptor mediated endocytosis. Additionally, we will discuss nanoparticle endocytosis (including macropinocytosis), and how the physio-chemical properties of the NP (size, charge, and surface coating) affect their intracellular uptake and exploiting them as tools to identify new adapter molecules regulating these processes.


Subject(s)
Clathrin , Nanoparticles , Biological Transport , Clathrin/metabolism , Endocytosis/physiology , Humans , Nanoparticles/chemistry , Pinocytosis
6.
Cancer Nanotechnol ; 12(1): 1, 2021.
Article in English | MEDLINE | ID: mdl-33456622

ABSTRACT

BACKGROUND: Ovarian cancer is one of the deadliest gynecological malignancies. While the overall survival of ovarian cancer patients has slightly improved in recent years in the developed world, it remains clinically challenging due to its frequent late diagnosis and the lack of reliable diagnostic and/or prognostic markers. The aim of this study was to identify potential new molecular target proteins (NMTPs) responsible for the poor outcomes. When nanoparticles (NP) are exposed to biological fluids, a protein coat, termed the protein corona (PC), forms around the NP, and the PC represents a tool to identify NMTPs. This study investigates the influence of pre-processing conditions, such as lysis conditions and serum/plasma treatment, on the PC composition and the resulting identification of NMTPs. RESULTS: Using gel electrophoresis, pre-processing conditions, including cell-lysis techniques and enrichment of low-abundance proteins (LAPs) by immunocentrifugation of serum/plasma, were shown to alter the relative amounts and compositions of proteins. PCs formed when 20 nm gold-NPs (GNPs) were incubated with lysate proteins from either RIPA- or urea lysis. Proteomic analysis of these PCs showed 2-22-fold enrichment of NMTPs in PCs from urea lysates as compared to RIPA lysates. Enriched NMTPs were then classified as cellular components, biological and molecular functions-associated proteins. The impact of enriched LAPs (eLAPs) on both PC composition and NMTP identification was shown by comparative proteomic analysis of original plasma, eLAPs, and PCs derived from eLAPs; eLAPs-PCs enhanced the abundance of NMTPs approximately 13%. Several NMTPs, including gasdermin-B, dermcidin, and kallistatin, were identified by this method demonstrating the potential use of this PC approach for molecular target discovery. CONCLUSION: The current study showed that the pre-processing conditions modulate PC composition and can be used to enhance identification of NMTPs.

7.
Bioact Mater ; 6(2): 326-332, 2021 Feb.
Article in English | MEDLINE | ID: mdl-32954051

ABSTRACT

Cancer-associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment (TME) and an important contributor to cancer progression and therapeutic resistance. Regulation of CAF activation is a promising strategy to influence cancer outcomes. Here, we report that ovarian cancer cells (OCs) and TME cells promote the activation of ovarian CAFs, whereas gold nanoparticles (GNPs) of 20 nm in diameter inhibit the activation, as demonstrated by the changes in cell morphology, migration, and molecular markers. GNPs exert the effect by altering the levels of multiple fibroblast activation or inactivation proteins, such as TGF-ß1, PDGF, uPA and TSP1, secreted by OCs and TME cells. Thus, GNPs represent a potential tool to help understand multicellular communications existing in the TME as well as devise strategies to disrupt the communication.

8.
J Control Release ; 322: 122-136, 2020 06 10.
Article in English | MEDLINE | ID: mdl-32165239

ABSTRACT

When nanoparticles are introduced into biological systems, host proteins tend to associate on the particle surface to form a protein layer termed the "protein corona" (PC). Identifying the proteins that constitute the PC can yield useful information about nanoparticle processing, bio-distribution, toxicity and clearance. Similarly, characterizing and identifying proteins within the PC from patient samples provides opportunities to probe disease proteomes and identify molecules that influence the disease process. Thus, nanoparticles represent unique probing tools for discovery of molecular targets for diseases. Here, we report a first review on target identification using nanoparticles in biological samples based on analysing physico chemical interactions. We also summarize the evolution of the PC surrounding various nano-systems, comment on PC signature, address PC complexity in fluids, and outline challenges associated with analysing the PC. In addition, the influence on PC formation of various nanoparticle parameters is summarized; nanoparticle characteristics considered include size, charge, temperature, and surface modifications for both organic and inorganic nanomaterials. We also discuss the advantages of nanotechnology, over other more invasive and laborious methods, for identifying potential diagnostic and therapeutic targets.


Subject(s)
Nanoparticles , Protein Corona , Humans , Kinetics , Nanotechnology , Proteins
9.
Int J Nanomedicine ; 15: 991-1003, 2020.
Article in English | MEDLINE | ID: mdl-32103952

ABSTRACT

INTRODUCTION AND OBJECTIVE: Pancreatic cancer (PC) is characterized by a robust desmoplastic environment, which limits the uptake of the standard first-line chemotherapeutic drug gemcitabine. Enhancing gemcitabine delivery to the complex tumor microenvironment (TME) is a major clinical challenge. Molecular crosstalk between pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs) plays a critical role in desmoplastic reaction in PCs. Herein, we report the development of a targeted drug delivery system to inhibit the proliferation of PCCs and PSCs in vitro. Using gold nanoparticles as the delivery vehicle, the anti-EGFR antibody cetuximab (C225/C) as a targeting agent, gemcitabine as drug and polyethylene glycol (PEG) as a stealth molecule, we created a series of targeted drug delivery systems. METHODS: Fabricated nanoconjugates were characterized by various physicochemical techniques such as UV-Visible spectroscopy, transmission electron microscopy, HPLC and instrumental neutron activation analysis (INAA). RESULTS AND CONCLUSION: Targeted gemcitabine delivery systems containing mPEG-SH having molecular weights of 550 Da or 1000 Da demonstrated superior efficacy in reducing the viability of both PCCs and PSCs as compared to their non-targeted counterparts. EGFR-targeted pathway was further validated by pre-treating cells with C225 followed by determining cellular viability. Taken together, in our current study we have developed a PEGylated targeted nanoconjugate ACG44P1000 that showed enhanced selectivity towards pancreatic cancer cells and pancreatic stellate cells, among others, for gemcitabine delivery. We will investigate the ability of these optimized conjugates to inhibit desmoplasia and tumor growth in vivo in our future studies.


Subject(s)
Antineoplastic Agents/administration & dosage , Drug Delivery Systems/methods , Nanoconjugates/chemistry , Pancreatic Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Cetuximab/administration & dosage , Cetuximab/chemistry , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Deoxycytidine/chemistry , Drug Carriers/chemistry , Gold/chemistry , Humans , Metal Nanoparticles/administration & dosage , Metal Nanoparticles/chemistry , Metal Nanoparticles/toxicity , Nanoconjugates/administration & dosage , Pancreatic Neoplasms/pathology , Pancreatic Stellate Cells/pathology , Polyethylene Glycols/chemistry , Tumor Microenvironment/drug effects , Gemcitabine
10.
Bioconjug Chem ; 30(6): 1724-1733, 2019 06 19.
Article in English | MEDLINE | ID: mdl-31067032

ABSTRACT

It is currently recognized that perpetual cross talk among key players in tumor microenvironment such as cancer cells (CCs), cancer associated fibroblasts (CAFs), and endothelial cells (ECs) plays a critical role in tumor progression, metastasis, and therapy resistance. Disruption of the cross talk may be useful to improve the outcome of therapeutics for which limited options are available. In the current study we investigate the use of gold nanoparticles (AuNPs) as a therapeutic tool to disrupt the multicellular cross talk within the TME cells with an emphasis on inhibiting angiogenesis. We demonstrate here that AuNPs disrupt signal transduction from TME cells (CCs, CAFs, and ECs) to ECs and inhibit angiogenic phenotypes in vitro. We show that conditioned media (CM) from ovarian CCs, CAFs, or ECs themselves induce tube formation and migration of ECs in vitro. Migration of ECs is also induced when ECs are cocultured with CCs, CAFs, or ECs. In contrast, CM from the cells treated with AuNPs or cocultured cells pretreated with AuNPs demonstrate diminished effects on ECs tube formation and migration. Mechanistically, AuNPs deplete ∼95% VEGF165 from VEGF single-protein solution and remove up to ∼45% of VEGF165 from CM, which is reflected on reduced activation of VEGF-Receptor 2 (VEGFR2) as compared to control CM. These results demonstrate that AuNPs inhibit angiogenesis via blockade of VEGF-VEGFR2 signaling from TME cells to endothelial cells.


Subject(s)
Gold/therapeutic use , Metal Nanoparticles/therapeutic use , Neovascularization, Pathologic/therapy , Ovarian Neoplasms/therapy , Tumor Microenvironment , Cell Movement , Endothelial Cells/metabolism , Endothelial Cells/pathology , Female , Humans , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Signal Transduction , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism
11.
Nanoscale Adv ; 1(9): 3555-3567, 2019 Sep 11.
Article in English | MEDLINE | ID: mdl-36133563

ABSTRACT

Glioblastoma multiforme (GBM), the highly invasive form of glioma, exhibits the highest mortality in patients with brain malignancies. Increasing glioma patients' survivability is challenging, as targeting only tumor-associated malignant cells would not reduce the overall aggressiveness of the tumor mass. This is due to the inadequacy in countering pro-proliferative, invasive and metastatic factors released by tumor-mass associated macrophages (TAMs). Hence, strategically, dual targeting both tumor cells and TAMs is necessary for effective glioma treatment and increased survivability. Conventional FR-targeting systems can easily target cancer cells that overtly express folate receptors (FRs). However, FRs are expressed only moderately in both glioma cells and in TAMs. Hence, it is more challenging to coordinate dual targeting of glioma cells and TAMs with lower levels of FR expression. A recently developed carbon nanosphere (CSP) with effective blood-brain barrier (BBB) penetrability was modified with a new folic acid-cationic lipid conjugate (F8) as a targeting ligand. The uniqueness of the cationic lipid-folate conjugate is that it stably associates with the negatively charged CSP surface at about >22 mol% surface concentration, a concentration at least 5-fold higher than what is achieved for conventional FR-targeting delivery systems. This enabled dual uptake of the CSP on TAMs and tumor cells via FRs. A doxorubicin-associated FR-targeting formulation (CFD), in an orthotopic glioma model and in a glioma subcutaneous model, induced the maximum anticancer effect with enhanced average mice survivability twice that of untreated mice and without any systemic liver toxicity. Additionally, we observed a significant decrease of TAM-released pro-aggressive factors, TGF-ß, STAT3, invasion and migration related sICAM-1, and other cytokines indicating anti-TAM activity of the CFD. Taken together, we principally devised, to the best of our knowledge, the first FR-targeting nano-delivery system for targeting brain-associated TAMs and tumor cells as an efficient glioma therapeutic.

12.
Biomater Sci ; 5(9): 1898-1909, 2017 Aug 22.
Article in English | MEDLINE | ID: mdl-28715002

ABSTRACT

The folate receptor (FR) is a well-validated and common target for cancer due to its high over-expression in many different cancer cells. Herein, we developed a new FR-targeting ligand (FA8) by conjugating folic acid and a cationic lipid. Owing to its favorable structural property FA8 as a ligand could be accommodated at an unusually higher molar ratio for a ligand-targeted liposome. We then encapsulated a drug-like molecule, bis-arylidene oxindole (NME2), in the targeted liposome. The resulting formulation induced potent caspase-8 up-regulation even in FR-moderately expressing melanoma cells. The NME2-associated non-targeted liposome (i.e., without FA8) or pristine NME2 could not up-regulate caspase-8. Caspase-8, an important apoptotic protein involved in the extrinsic pathway of apoptosis-signalling and inhibition of acquired drug resistance, was induced in cancer cells due to the combination treatment of liposomally associated FA8 and NME2 through the activation and subsequent cleavage of RIP-1. Consistently, in a melanoma tumor model too wherein FR is moderately expressed, significant tumour regression was obtained with this liposomal combination of FA8 and NME2. In conclusion, we demonstrate the development of a new FR-targeting ligand molecule whose higher level of inclusion (>10 mol%) in the liposomal formulation altered the mode of anticancer action of the encapsulated drug, thereby indicating a new therapeutic possibility involving FR targeted cancer treatment.


Subject(s)
Folic Acid/administration & dosage , Folic Acid/pharmacology , Indoles/chemistry , Liposomes/chemistry , Melanoma, Experimental/pathology , Animals , Apoptosis/drug effects , Biological Transport , Caspase 8/metabolism , Cell Line, Tumor , Down-Regulation/drug effects , Drug Resistance, Neoplasm , Folate Receptors, GPI-Anchored/metabolism , Folic Acid/metabolism , Folic Acid/therapeutic use , Humans , Liposomes/pharmacokinetics , Melanoma, Experimental/drug therapy , Melanoma, Experimental/metabolism , Mice , NIH 3T3 Cells , Oxindoles , Tissue Distribution
13.
Mol Cell ; 60(4): 637-50, 2015 Nov 19.
Article in English | MEDLINE | ID: mdl-26585386

ABSTRACT

Mycobacterium tuberculosis (Mtb) adaptation to hypoxia is considered crucial to its prolonged latent persistence in humans. Mtb lesions are known to contain physiologically heterogeneous microenvironments that bring about differential responses from bacteria. Here we exploit metabolic variability within biofilm cells to identify alternate respiratory polyketide quinones (PkQs) from both Mycobacterium smegmatis (Msmeg) and Mtb. PkQs are specifically expressed in biofilms and other oxygen-deficient niches to maintain cellular bioenergetics. Under such conditions, these metabolites function as mobile electron carriers in the respiratory electron transport chain. In the absence of PkQs, mycobacteria escape from the hypoxic core of biofilms and prefer oxygen-rich conditions. Unlike the ubiquitous isoprenoid pathway for the biosynthesis of respiratory quinones, PkQs are produced by type III polyketide synthases using fatty acyl-CoA precursors. The biosynthetic pathway is conserved in several other bacterial genomes, and our study reveals a redox-balancing chemicocellular process in microbial physiology.


Subject(s)
Biofilms , Mycobacterium smegmatis/physiology , Mycobacterium tuberculosis/physiology , Polyketides/metabolism , Quinones/metabolism , Acyl Coenzyme A/metabolism , Bacterial Proteins/metabolism , Biosynthetic Pathways , Cell Hypoxia , Oxidation-Reduction , Polyketide Synthases/metabolism
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