Early detection is a crucial element for the timely diagnosis and successful treatment of all human cancers but is limited by the sensitivity of current imaging methodologies. We have synthesized and studied bioresorbable calcium phosphate nanoparticles (CPNPs) in which molecules of the near-infrared (NIR) emitting fluorophore, indocyanine green (ICG), are embedded. The ICG-CPNPs demonstrate exceptional colloidal and optical characteristics. Suspensions consisting of 16 nm average diameter particles are colloidally stable in physiological solutions (phosphate buffered 0.15 M saline (PBS), pH 7.4) with carboxylate or polyethylene glycol (PEG) surface functionality. ICG-doped CPNPs exhibit significantly greater intensity at the maximum emission wavelength relative to the free constituent fluorophore, consistent with the multiple molecules encapsulated per particle. The quantum efficiency per molecule of the ICG-CPNPs is 200% greater at 0.049 +/- 0.003 over the free fluorophore in PBS. Photostability based on fluorescence half-life of encapsulated ICG in PBS is 500% longer under typical clinical imaging conditions relative to the free dye. PEGylated ICG-CPNPs accumulate in solid, 5 mm diameter xenograft breast adenocarcinoma tumors via enhanced retention and permeability (EPR) within 24 h after systemic tail vein injection in a nude mouse model. Ex situ tissue imaging further verifies the facility of the ICG-CPNPs for deep-tissue imaging with NIR signals detectable from depths up to 3 cm in porcine muscle tissue. Our ex vivo and in vivo experiments verify the promise of the NIR CPNPs for diagnostic imaging in the early detection of solid tumors.
Encapsulation of imaging agents and drugs in calcium phosphate nanoparticles (CPNPs) has potential as a nontoxic, bioresorbable vehicle for drug delivery to cells and tumors. The objectives of this study were to develop a calcium phosphate nanoparticle encapsulation system for organic dyes and therapeutic drugs so that advanced fluoresence methods could be used to assess the efficiency of drug delivery and possible mechanisms of nanoparticle bioabsorption. Highly concentrated CPNPs encapsulating a variety of organic fluorophores were successfully synthesized. Well-dispersed CPNPs encapsulating Cy3 amidite exhibited nearly a 5-fold increase in fluorescence quantum yield when compared to the free dye in PBS. FCS diffusion data and cell staining were used to show pH-dependent dissolution of the particles and cellular uptake, respectively. Furthermore, an experimental hydrophobic cell growth inhibitor, ceramide, was successfully delivered in vitro to human vascular smooth muscle cells via encapsulation in CPNPs. These studies demonstrate that CPNPs are effective carriers of dyes and drugs for bioimaging and, potentially, for therapeutic intervention.
Paradigm-shifting modalities to more efficiently deliver drugs to cancerous lesions require the following attributes: nanoscale-size, targetability and stability under physiological conditions. Often, these nanoscale drug delivery vehicles are limited due to agglomeration, poor solubility or cytotoxicity. Thus, we have designed a methodology to encapsulate hydrophobic antineoplastic chemotherapeutics within a 20-30 nm diameter, pH-responsive, non-agglomerating, non-toxic calcium phosphate nanoparticle matrix. In the present study, we report on calcium phosphate nanocomposite particles (CPNP) that encapsulate both fluorophores and chemotherapeutics, are colloidally stable in physiological solution for extended time at 37°C and can efficaciously deliver hydrophobic antineoplastic agents, such as ceramide, in several cell model systems.
The early diagnosis of cancer is the critical element in successful treatment and long term favorable patient prognoses. The high rate of mortality is mainly attributed to the tendency for late diagnoses as symptoms may not occur until the disease has metastasized, as well as the lack of effective systemic therapies. Late diagnosis is often associated with the lack of timely sensitive imaging modalities. The promise of nanotechnology is presently limited by the inability to simultaneously seek, treat and image cancerous lesions. This study describes the design and synthesis of fluorescent calcium phosphosilicate nanocomposite particles (CPNPs) that can be systemically targeted to breast and pancreatic cancer lesions. The CPNPs are a ~20nm diameter composite composed of an amorphous calcium phosphate matrix doped with silicate in which a near infra-red imaging agent indocyanine green (ICG) is embedded. In the present studies, we describe and validate CPNP bioconjugation of human holotransferrin, anti-CD71 antibody, and short gastrin peptides via an avidin-biotin-or a novel PEG-maleimide-coupling strategy. The conjugation of biotinylated human holotransferrin (diferric transferrin) and biotinylated anti-CD71 antibody (anti-transferrin receptor antibody) to avidin conjugated CPNPs (Avidin-CPNPs) permits targeting of transferrin receptors, which are highly expressed on breast cancer cells. Similarly, the conjugation of biotinylated pentagastrin to AvidinCPNPs and decagastrin (gastrin-10) to PEG-CPNPs via PEG-maleimide coupling permits targeting of gastrin receptors, which are over-expressed in pancreatic cancer lesions. These bioconjugated CPNPs have the potential to perform as a theranostic modality, simultaneously enhancing drug delivery, targeting and imaging of breast and pancreatic cancer tumors. Keywords bioconjugation; transferrin receptor; gastrin receptor; breast cancer; pancreatic cancer; calcium phosphate; whole animal imaging Calcium phosphate nanoparticles (CPNPs) have been engineered to be a non-toxic vehicle for the delivery of a diverse range of therapeutic and imaging agents in biological systems. [1][2][3][4] Previous studies have shown that encapsulation within CPNPs improved the lifetime and RESULTS AND DISCUSSION Physical Characterization of CPNPsCitrate functionalized CPNPs were utilized as a platform for functionalization, which allowed the characterization of bioconjugation via zeta potential analysis (Figure 1). Figure 1 shows the zeta potential distribution of Citrate-CPNPs prior to bioconjugation (blue line), and the zeta (violet). Prior to bioconjugation, the Citrate-CPNPs display a negative mean zeta potential value of −16 ± 1.3 mV, which is consistent with previous reports. 1 However, after bioconjugation, the Avidin-CPNPs displayed a relatively high positive mean zeta potential value of +29 ± 8.7 mV. The isoelectric point for avidin is pH 10. Thus, the shift from a negative zeta potential to a positive zeta potential distribution is strong evidence of avidin bioconjugation on...
Leukemia is one of the most common and aggressive adult cancers, as well as the most prevalent childhood cancer. Leukemia is a cancer of the hematological system and can be divided into a diversity of unique malignancies based on the onset of the disease as well as the specific cell lineages involved. Cancer stem cells, including recently identified leukemia stem cells (LSCs), are hypothesized to be responsible for cancer development, relapse, and resistance to treatment, and new therapeutics targeting these cellular populations are urgently needed. Nontoxic and nonaggregating calcium phosphosilicate nanoparticles (CPSNPs) encapsulating the near-infrared fluoroprobe indocyanine green (ICG) were recently developed for diagnostic imaging and drug delivery as well as for photodynamic therapy (PDT) of solid tumors. Prior studies revealed that specific targeting of CPSNPs allowed for enhanced accumulation within breast cancer tumors, via CD71 targeting, or pancreatic cancer tumors, via gastrin receptor targeting. In the present study, ICG-loaded CPSNPs were evaluated as photosensitizers for PDT of leukemia. Using a novel bioconjugation approach to specifically target CD117 or CD96, surface features enhanced on leukemia stem cells, in vitro ICG-CPSNP PDT of a murine leukemia cell line and human leukemia samples were dramatically improved. Furthermore, the in vivo efficacy of PDT was dramatically enhanced in a murine leukemia model by utilizing CD117-targeted ICG-CPSNPs, resulting in 29% disease-free survival. Altogether, this study demonstrates that leukemia-targeted ICG-loaded CPSNPs offer the promise to effectively treat relapsing and multidrug-resistant leukemia and to improve the life of leukemia patients.
The ability to apply nanomaterials as targeted delivery agents for drugs and other therapeutics holds promise for a wide variety of diseases, including many types of cancer. A nanodelivery vehicle must demonstrate in vivo efficacy, diminished or no toxicity, stability, improved pharmacokinetics, and controlled-release kinetics. In this issue, Lee et al. construct polymer nanobins that fulfill these requirements and demonstrate effective delivery of doxorubicin in vivo to breast cancer cells. This Perspective explores the outlook for these nanobins as well as other technologies in this field and the challenges that lie ahead.
Near infrared imaging has presented itself as a powerful diagnostic technique with potential to serve as a minimally invasive, nonionizing method for sensitive, deep tissue diagnostic imaging. This potential is further realized with the use of nanoparticle (NP)-based near infrared (NIR) contrast agents that are not prone to the rapid photobleaching and instability of their organic counterparts. This review discusses applications that have successfully demonstrated the utility of nanoparticles for NIR imaging, including NIR-emitting semiconductor quantum dots (QDs), resonant gold nanoshells, and dye-encapsulating nanoparticles. NIR QDs demonstrate superior optical performance with exceptional fluorescence brightness stability. However, the heavy metal composition and high propensity for toxicity hinder future application in clinical environments. NIR resonant gold nanoshells also exhibit brilliant signal intensities and likewise have none of the photo- or chemical-instabilities characteristic of organic contrast agents. However, concerns regarding ineffectual clearance and long-term accumulation in nontarget organs are a major issue for this technology. Finally, NIR dye-encapsulating nanoparticles synthesized from calcium phosphate (CP) also demonstrate improved optical performances by shielding the component dye from undesirable environmental influences, thereby enhancing quantum yields, emission brightness, and fluorescent lifetime. Calcium phosphate nanoparticle (CPNP) contrast agents are neither toxic, nor have issues with long-term sequestering, as they are readily dissolved in low pH environments and ultimately absorbed into the system. Though perhaps not as optically superior as QDs or nanoshells, these are a completely nontoxic, bioresorbable option for NP-based NIR imaging that still effectively improves the optical performance of conventional organic agents.
Visible-light photoredox reactions have been demonstrated to be powerful synthetic tools to access pharmaceutically relevant compounds. However, many photoredox reactions involve insoluble starting materials or products that complicate the use of continuous flow methods. By integrating a new solid-feeding strategy and a continuous stirred-tank reactor (CSTR) cascade, we realize a new solid-handling platform for conducting heterogeneous photoredox reactions in flow. Residence time distributions for single phase and solid particles characterize the hydrodynamics of the heterogeneous flow in the CSTR cascade. Silyl radical-mediated metallaphotoredox cross-electrophile coupling reactions with an inorganic base as the insoluble starting material demonstrate the use of the platform. Gram-scale synthesis is achieved in 13 h of stable operation.
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