Quantum dots (QDs), semiconductor nanocrystals, are fluorescent nanoparticles of growing interest as an imaging tool of a diseased tissue. However, a major concern is their biocompatibility, cytotoxicity, and fluorescence instability in biological milieu, impeding their use in biomedical applications, in general, and for inflammation imaging, in particular. In addition, for an efficient fluorescent signal at the desired tissue, and avoiding systemic biodistribution and possible toxicity, targeting is desired. We hypothesized that phagocytic cells of the innate immunity system (mainly circulating monocytes) can be exploited as transporters of specially designed liposomes containing QDs to the inflamed tissue. We developed a liposomal delivery system of QDs (LipQDs) characterized with high encapsulation yield, enhanced optical properties including far-red emission wavelength and fluorescent stability, high quantum yield, and protracted fluorescent decay lifetime. Treatment with LipQDs, rather than free QDs, exhibited high accumulation and retention following intravenous administration in carotid-injured rats (an inflammatory model). QD-monocyte colocalization was detected in the inflamed arterial segment only following treatment with LipQDs. No cytotoxicity was observed following LipQD treatment in cell cultures, and changes in liver enzymes and gross histopathological changes were not detected in mice and rats, respectively. Our results suggest that the LipQD formulation could be a promising strategy for imaging inflammation.
The majority of developed and approved anticancer nanomedicines have been designed to exploit the dogma of the enhanced permeability and retention (EPR) effect, which is based on the leakiness of the tumor’s blood vessels accompanied by impeded lymphatic drainage. However, the EPR effect has been under scrutiny recently because of its variable manifestation across tumor types and animal species and its poor translation to human cancer therapy. To facilitate the EPR effect, systemically injected NPs should overcome the obstacle of rapid recognition and elimination by the mononuclear phagocyte system (MPS). We hypothesized that circulating monocytes, major cells of the MPS that infiltrate the tumor, may serve as an alternative method for achieving increased tumor accumulation of NPs, independent of the EPR effect. We describe here the accumulation of liposomal quantum dots (LipQDs) designed for active delivery via monocytes, in comparison to LipQDs designed for passive delivery (via the EPR effect), following IV administration in a mammary carcinoma model. Hydrophilic QDs were synthesized and entrapped in functionalized liposomes, conferring passive (“stealth” NPs; PEGylated, neutral charge) and active (monocyte-mediated delivery; positively charged) properties by differing in their lipid composition, membrane PEGylation, and charge (positively, negatively, and neutrally charged). The various physicochemical parameters affecting the entrapment yield and optical stability were examined in vitro and in vivo. Biodistribution in the blood, various organs, and in the tumor was determined by the fluorescence intensity and Cd analyses. Following the treatment of animals (intact and mammary-carcinoma-bearing mice) with disparate formulations of LipQDs (differing by their lipid composition, neutrally and positively charged surfaces, and hydrophilic membrane), we demonstrate comparable tumor uptake of QDs delivered by the passive and the active routes (mainly by Ly-6Chi monocytes). Our findings suggest that entrapping QDs in nanosized liposomal formulations, prepared by a new facile method, imparts superior structural and optical stability and a suitable biodistribution profile leading to increased tumor uptake of fluorescently stable QDs.
Major advances have been achieved in understanding the mechanisms and risk factors leading to cardiovascular disorders and consequently developing new therapies. A strong inflammatory response occurs with a substantial recruitment of innate immunity cells in atherosclerosis, myocardial infarction, and restenosis. Monocytes and macrophages are key players in the healing process that ensues following injury. In the inflamed arterial wall, monocytes, and monocyte-derived macrophages have specific functions in the initiation and resolution of inflammation, principally through phagocytosis, and the release of inflammatory cytokines and reactive oxygen species. In this review, we will focus on delivery systems, mainly nanoparticles, for modulating circulating monocytes/monocyte-derived macrophages. We review the different strategies of depletion or modulation of circulating monocytes and monocyte subtypes, using polymeric nanoparticles and liposomes for the therapy of myocardial infarction and restenosis. We will further discuss the strategies of exploiting circulating monocytes for biological targeting of nanocarrier-based drug delivery systems for therapeutic and diagnostic applications.
Non-viral, polymeric-based, siRNA nanoparticles (NPs) have been proposed as promising gene delivery systems. Encapsulating siRNA in targeted NPs could confer improved biological stability, extended half-life, enhanced permeability, effective tumor accumulation, and therapy. In this work, a peptide derived from apolipoprotein B100 (ApoB-P), the protein moiety of low-density lipoprotein, was used to target siRNA-loaded PEGylated NPs to the extracellular matrix/proteoglycans (ECM/PGs) of a mammary carcinoma tumor. siRNA against osteopontin (siOPN), a protein involved in breast cancer development and progression, was encapsulated into PEGylated poly(d,l-lactic-co-glycolic acid) (PLGA) NPs using the double emulsion solvent diffusion technique. The NPs obtained possessed desired physicochemical properties including ~200 nm size, a neutral surface charge, and high siOPN loading of ~5 µg/mg. ApoB-P-targeted NPs exhibited both enhanced binding to isolated ECM and internalization by MDA-MB-231 human mammary carcinoma cells, in comparison to non-targeted NPs. Increased accumulation of the targeted NPs was achieved in the primary mammary tumor of mice xenografted with MDA-MB-231 mammary carcinoma cells as well as in the lungs, one of the main sites affected by metastases. siOPN NPs treatment resulted in significant inhibition of tumor growth (similar bioactivity of both formulations), accompanied with significant reduction of OPN mRNA levels (~40% knockdown of mRNA levels). We demonstrated that targeted NPs possessed enhanced tumor accumulation with increased therapeutic potential in mice models of mammary carcinoma.
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