Multifunctional Theranostic Nanoparticles Research Articles

Bio-AFM of Cancer Cells and Multifunctional Theranostics

Biological atomic force microscopy (Bio-AFM) can quantify changes in cellular and macromolecular morphology and elasticity at the nanoscale and over a broad time scale, from fast dynamics to long-term cellular evolutions. Herein, we report quantitative Bio-AFM characterization of mechanobiological features of lung cancer and other cells in response to chemotherapeutics and multifunctional theranostic nanoparticles. Multidrug resistance (MDR) presents a daunting challenge for successful cancer management. Comprehensive investigation of mechanobiological characters of cancer cells with MDR provides insights in directing anti-cancer therapy. In our study, we have embarked on using multimodal and multiphasic Bio-AFM to identify cellular biomechanical markers and to investigate interactions among cells and theranostic nanoparticles as an aid to developing more efficient therapeutics. We have found a spectrum of distinct biomechanical signatures, such as stiffness moduli and adhesions that differ under physiological conditions between drug sensitive and resistant cancer cells. Multifunctional theranostic nanoparticles, such as polymeric nanovehicles (1), single-walled carbon nanotubes (SWCNTs), and carbon dots (Cdots) with various surface coatings are observed to have differential influences on cellular responses. As part of work to broaden the applicability of Bio-AFM for cellular imaging, we are investigating the development of docetaxel-sensitivity and resistance in a non-small-cell lung cancer cell line. Ref (1) “Polymeric Nanovehicle Regulated Spatiotemporal Real-Time Imaging of the Differentiation Dynamics of Transplanted Neural Stem Cells after Traumatic Brain Injury.” Wang Z, Wang Y, Wang Z, Zhao J, Gutkind JS, Srivatsan A, Zhang G, Liao HS, Fu X, Jin A, Tong X, Niu G, Chen X. ACS Nano. 2015. 9:6683-95. doi:10.1021/acsnano.5b00690

Multiple layer-by-layer lipid-polymer hybrid nanoparticles for improved FOLFIRINOX chemotherapy in pancreatic tumor models

Multifunctional theranostic nanoparticles for dual-modality imaging and magnetic targeted photodynamic therapy Zexuan Ding, Peng Liu, Huqiang Yi, Yayun Wu, Pengfei Zhang, Lintao Cai, Guangdong Key Laboratory of Nanomedicine, CAS Key Laboratory of Health Informatics, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, P.R. China, Nano Science and Technology Institute, University of Science & Technology of China, Suzhou, P.R. China E-mail address: lt.cai@siat.ac.cn (L. Cai)

Multifunctional theranostic nanoparticles for dual-modality imaging and magnetic targeted photodynamic therapy

Multifunctional theranostic nanoparticles for dual-modality imaging and magnetic targeted photodynamic therapy

Molecular imaging-guided photothermal/photodynamic therapy against tumor by iRGD-modified indocyanine green nanoparticles

Multifunctional near-infrared (NIR) nanoparticles demonstrate great potential in tumor theranostic applications. To achieve the sensitive detection and effective phototherapy in the early stage of tumor genesis, it is highly desirable to improve the targeting of NIR theranostic agents to biomarkers and to enhance their accumulation in tumor. Here we report a novel targeted multifunctional theranostic nanoparticle, internalized RGD (iRGD)-modified indocyanine green (ICG) liposomes (iRGD–ICG-LPs), for molecular imaging-guided photothermal therapy (PTT) and photodynamic therapy (PDT) therapy against breast tumor. The iRGD peptides with high affinity to αvβ3 integrin and effective tumor-internalized property were firstly used to synthesize iRGD-PEG2000-DSPE lipopeptides, which were further utilized to fabricate the targeted ICG liposomes. The results indicated that iRGD–ICG-LPs exhibited excellent stability and could provide an accurate and sensitive detection of breast tumor through NIR fluorescence molecular imaging. We further employed this nanoparticle for tumor theranostic application, demonstrating significantly higher tumor accumulation and tumor inhibition efficacy through PTT/PDT effects. Histological analysis further revealed much more apoptotic cells, confirming the advantageous anti-tumor effect of iRGD–ICG-LPs over non-targeted ICG-LPs. Notably, the targeting therapy mediated by iRGD provides almost equivalent anti-tumor efficacy at a 12.5-fold lower drug dose than that by monoclonal antibody, and no tumor recurrence and obvious treatment-induced toxicity were observed in our study. Our study provides a promising strategy to realize the sensitive detection and effective treatment of tumors by integrating molecular imaging into PTT/PDT therapy.

Engineered Hybrid Nanoparticles for On-Demand Diagnostics and Therapeutics.

Together with the simultaneous development of nanomaterials and molecular biology, the bionano interface brings about various applications of hybrid nanoparticles in nanomedicine. The hybrid nanoparticles not only present properties of the individual components but also show synergistic effects for specialized applications. Thus, the development of advanced hybrid nanoparticles for targeted and on-demand diagnostics and therapeutics of diseases has rapidly become a hot research topic in nanomedicine. The research focus is to fabricate novel classes of programmable hybrid nanoparticles that are precisely engineered to maximize drug concentrations in diseased cells, leading to enhanced efficacy and reduced side effects of chemotherapy for the disease treatment. In particular, the hybrid nanoparticle platforms can simultaneously target diseased cells, enable the location to be imaged by optical methods, and release therapeutic drugs to the diseased cells by command. This Account specially discusses the rational fabrication of integrated hybrid nanoparticles and their applications in diagnostics and therapeutics. For diagnostics applications, hybrid nanoparticles can be utilized as imaging agents that enable detailed visualization at the molecular level. By the use of suitable targeting ligands incorporated on the nanoparticles, targeted optical imaging may be feasible with improved performance. Novel imaging techniques such as multiphoton excitation and photoacoustic imaging using near-infrared light have been developed using the intrinsic properties of particular nanoparticles. The use of longer-wavelength excitation sources allows deeper penetration into the human body for disease diagnostics and at the same time reduces the adverse effects on normal tissues. Furthermore, multimodal imaging techniques have been achieved by combining several types of components in nanoparticles, offering higher accuracy and better spatial views, with the aim of detecting life-threatening diseases before symptoms appear. For therapeutics applications, various nanoparticle-based treatment methods such as photodynamic therapy, drug delivery, and gene delivery have been developed. The intrinsic ability of organic nanoparticles to generate reactive oxygen species has been utilized for photodynamic therapy, and mesoporous silica nanoparticles have been widely used for drug loading and controlled delivery. Herein, the development of controlled-release systems that can specifically deliver drug molecules to target cells and release then upon triggering is highlighted. By control of the release of loaded drug molecules at precise sites (e.g., cancer cells or malignant tumors), side effects of the drugs are minimized. This approach provides better control and higher efficacy of drugs in the human body. Future personalized medicine is also feasible through gene delivery methods. Specific DNA/RNA-carrying nanoparticles are able to deliver them to target cells to obtain desired properties. This development may create an evolution in current medicine, leading to more personalized healthcare systems that can reduce the population screening process and also the duration of drug evaluation. Furthermore, nanoparticles can be incorporated with various components that can be used for simultaneous diagnostics and therapeutics. These multifunctional theranostic nanoparticles enable real-time monitoring of treatment process for more efficient therapy.

IGF1 Receptor Targeted Theranostic Nanoparticles for Targeted and Image-Guided Therapy of Pancreatic Cancer.

Overcoming resistance to chemotherapy is a major and unmet medical challenge in the treatment of pancreatic cancer. Poor drug delivery due to stromal barriers in the tumor microenvironment and aggressive tumor biology are additional impediments toward a more successful treatment of pancreatic cancer. In attempts to address these challenges, we developed IGF1 receptor (IGF1R)-directed, multifunctional theranostic nanoparticles for targeted delivery of therapeutic agents into IGF1R-expressing drug-resistant tumor cells and tumor-associated stromal cells. These nanoparticles were prepared by conjugating recombinant human IGF1 to magnetic iron oxide nanoparticles (IONPs) carrying the anthracycline doxorubicin (Dox) as the chemotherapeutic payload. Intravenously administered IGF1-IONPs exhibited excellent tumor targeting and penetration in an orthotopic patient-derived xenograft (PDX) model of pancreatic cancer featuring enriched tumor stroma and heterogeneous cancer cells. IGF1R-targeted therapy using the theranostic IGF1-IONP-Dox significantly inhibited the growth of pancreatic PDX tumors. The effects of the intratumoral nanoparticle delivery and therapeutic responses in the orthotopic pancreatic PDX tumors could be detected by magnetic resonance imaging (MRI) with IONP-induced contrasts. Histological analysis showed that IGF1R-targeted delivery of Dox significantly inhibited cell proliferation and induced apoptotic cell death of pancreatic cancer cells. Therefore, further development of IGF1R-targeted theranostic IONPs and MRI-guided cancer therapy as a precision nanomedicine may provide the basis for more effective treatment of pancreatic cancer.

Abstract 4472: Targeted multifunctional lipid-PLGA hybrid nanosystems for metastatic breast cancer imaging and therapy

Abstract Introduction: Targeted theranostic nanoparticles based on near-infrared fluorescence is a novel concept in next-generation medicine that combines diagnostics and therapeutics simultaneously to radically change the way we diagnose, image and treat the breast cancer. Often these targeted therapies are efficacious and at the same time less toxic than traditional regimens. Our aim is to formulate a multifunctional theranostic agent capable of tumor targeting and tumor imaging along with anticancer therapy for metastatic breast cancer. Methods: We engineered lipo-polymeric composite multifunctional nanoparticles co-encapsulated with long lived dyes (like ADOTA) together with a combination of anticancer drugs, docetaxel and curcumin by nanoprecipitation. These anticancer agents have been found to show synergistic anti-angiogenic effects. Further, curcumin has the potential to downregulate P-glycoprotein expression which helps in reversing drug resistance seen with drugs like docetaxel, thereby potentiating the activity of the drug at lower concentrations. The formulated composite nanoparticles are conjugated to Annexin A2 (AnxA2) peptide (LCKLSL) to enable specific targeting to tumor site. LCKLSL hexapeptide in the amino-terminal domain of the AnxA2motif is essential for tissue plasminogen activator binding. Therefore AnxA2 peptide will serve as a useful therapeutic target against invasion and metastasis. Results: Multifunctional nanoparticles were successfully formulated and then characterized for drug loading efficiency, particle size, encapsulation efficiency, surface morphology, zeta potential and in vitro drug release profiles. The results show smooth and spherical nanoparticles when seen under TEM with drug encapsulation of 50% for curcumin and 19% for docetaxel. The particle size distribution showed uniform distribution with average size being110±10nm. Zeta potential varied between -35±5mV. Percent AnxA2 peptide attachment on the nanoparticles was determined by using Flow cytometry and found to be 74%. Intracellular uptake in breast cancer cell line (MDA MB231) was carried out and showed robust uptake. The nanoparticle formulations were further evaluated by cytotoxic studies and synergy between anticancer drugs was established. Mouse xenograft studies showed significant tumor regreesion for AnxA2 targeted curcumin and docetaxel loaded hybrid nanoparticles as compared to untreated mice. Conclusion: This study would help validate these targeted theranostic nanoparticles in metastatic breast cancer mouse model thus highlighting the immense clinical potential of targeted multifunctional theranostic nanoparticles for imaging and therapy of metastatic breast cancer. Note: This abstract was not presented at the meeting. Citation Format: Amalendu P. Ranjan, Anindita Mukerjee, Jamboor K. Vishwanatha. Targeted multifunctional lipid-PLGA hybrid nanosystems for metastatic breast cancer imaging and therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4472. doi:10.1158/1538-7445.AM2014-4472

Lipid-AuNPs@PDA nanohybrid for MRI/CT imaging and photothermal therapy of hepatocellular carcinoma.

Multifunctional theranostic nanoparticles represent an emerging agent with the potential to offer extremely sensitive diagnosis and targeted cancer therapy. Herein, we report the synthesis and characterization of a multifunctional theranostic agent (referred to as LA-LAPNHs) for targeted magnetic resonance imaging/computed X-ray tomography (MRI/CT) dual-mode imaging and photothermal therapy of hepatocellular carcinoma. The LA-LAPNHs were characterized as having a core-shell structure with the gold nanoparticles (AuNPs)@polydopamine (PDA) as the inner core, the indocyanine green (ICG), which is electrostatically absorbed onto the surface of PDA, as the photothermal therapeutic agent, and the lipids modified with gadolinium-1,4,7,10-tetraacetic acid and lactobionic acid (LA), which is self-assembled on the outer surface as the shell. The LA-LAPNHs could be selectively internalized into the hepatocellular cell line (HepG2 cells) but not into HeLa cells due to the specific recognition ability of LA to asialoglycoprotein receptor. Additionally, the dual-mode imaging ability of the LA-LAPNH aqueous solution was confirmed by enhanced MR and CT imaging showing a shorter T1 relaxation time and a higher Hounsfield unit value, respectively. In addition, the LA-LAPNHs showed significant photothermal cytotoxicity against liver cancer cells with near-infrared irradiation due to their strong absorbance in the region between 700 and 850 nm. In summary, this study demonstrates that LA-LAPNHs may be a promising candidate for targeted MR/CT dual-mode imaging and photothermal therapy of hepatocellular carcinoma.

Multifunctional theranostic gold nanoparticles for targeted CT imaging and photothermal therapy

Gold nanoparticles have emerged as some of the most extensively utilized nanoplatforms for the diagnosis, imaging, monitoring and treatment of malignant diseases. In particular, in computed tomography (CT) imaging and in therapy (PTT), the exploitation of the various, advantageous properties of gold nanoparticles have resulted in numerous advances in each of these fields. The purpose of this review is to assess the status of gold-nanoparticle mediated CT and PTT, highlight several promising outcomes and motivate the combination of these two functionalities in the same nanoparticle platform. The given examples of research based advances and the encouraging results of in vitro and in vivo studies provide much excitement and promise for future theranostic (therapy + diagnostic) clinical applications, as well as for image-guided therapy and/or surgery, and their monitoring.

Multifunctional Theranostic Nanoparticles for Brain Tumors

Antiangiogenic approaches have been extensively exploited to provide a rationally designed therapy for the treatment of brain cancer. The brain tumor endothelium, with characteristics of high proliferation, high permeability, and high expression of proangiogenic factors (such as vascular endothelial growth factor, VEGF), is a particularly appealing therapeutic target for this strategy. Many antibody drugs, which primarily target the interaction between VEGF and its receptors, have been investigated in clinical trials but have shown only modest effects. Recent research published by Agemy et al.1 has alternatively harnessed a tumor-homing peptide (CGKRK) to specifically deliver multifunctional theranostic nanoparticles composed of iron oxide nanoworm (NW) and mitochondria-targeted cytotoxic peptide D[KLAKLAK]2 to glioblastoma multiforme (GBM) endothelium. Moreover, with the help of a tumor-penetrating peptide (iRGD), the NWs were capable of infiltrating the tumor tissue after extravasation for tumor cell eradication. This strategy was evaluated in lentivirus-induced, transplantable, and orthotopic brain tumor models. Complete tumor ablation was achieved in the first model and significant prolongation of survival was observed in the latter two models, suggesting promise for eventual clinical application.

Abstract SY20-02: Theranostic nanoparticles for targeted therapy of pancreatic and triple-negative breast cancers

Abstract SY20-02: Theranostic nanoparticles for targeted therapy of pancreatic and triple-negative breast cancers