pH-Responsive Theranostic Polymer-Caged Nanobins: Enhanced Cytotoxicity and T 1 MRI Contrast by Her2 Targeting

Autor: Patrick L. Hankins, Richard W. Ahn, Anthony J. Chipre, Daniel J. Mastarone, Elden P. Swindell, Thomas V. O'Halloran, Thomas J. Meade, Bong Jin Hong, Keith W. MacRenaris, SonBinh T. Nguyen
Rok vydání: 2013
Předmět:
Zdroj: Particle & Particle Systems Characterization. 30:770-774
ISSN: 0934-0866
DOI: 10.1002/ppsc.201300158
Popis: Recent advances in nanotechnology, materials science, and biotechnology have enabled the design of theranostic nanoparticles that co-deliver therapeutic compounds and imaging probes in a single platform to heterogeneous disease sites such as tumors, simultaneously treating and enabling non-invasive monitoring of the response to treatment.[1] This can allow the clinician to detect previously unseen tumor sites and immediately adjust the treatment regimen to improve the margin for success. Magnetic resonance imaging (MRI) has emerged as an ideal imaging modality for this application due to its high-resolution, real-time 3D tomography capability, excellent penetration depth, and independence from ionizing radiation (CT) or radionuclides (PET-CT/SPECT).[2] In contrast, optical imaging techniques utilizing two-photon fluorescence or intravital microscopy/endoscopy as well as bioluminescence are generally low resolution, only provide limited (or no) tomographic information, have insufficient penetration depth, and, requires multiple labels to assess the surrounding cells or tissues, thus limiting the amount of salient information that can be obtained on the tumor and its neighboring environment.[3] The aforementioned attributes make MRI the ideal imaging modality for evaluating the treatment of solid tumors.[4] However, to maximize the full potential of MRI for the evaluation of solid tumors, theranostic platforms have to overcome a number of limitations before they can be clinically successful. For in vivo imaging, the intrinsically low probe sensitivity, especially of T1 contrast agents, require efficient delivery and maximum cellular accumulation of contrast agents like gadolinium (Gd) chelates.[5] However, these contrast agents have poor cellular uptake, leading to insignificant contrast enhancements.[2] For therapy, the lack of specificity of chemotherapeutics to only the tumor tissue necessitates a high administered dose and reduces the efficacy of the drug.[6] This high-dosage requirement increases the prevalence of adverse side effects for patients and shrinks the therapeutic window.[7] The conjugation of GdIII chelates to a variety of nanostructures, including inorganic nanoparticles,[8] dendrimers,[9] viral capsids,[10] lipid nanoparticles,[11] liposomes,[12] and hydrogels,[13] has been shown to increase T1 MRI contrast compared to unconjugated GdIII chelates. Many of these platforms, however, have limited therapeutic efficacy due to insufficient drug-loading capabilities and/or lack of triggered drug-release ability under the specific conditions encountered at the tumor site. Additionally, when nanoparticles accumulate passively at the tumor site through the enhanced permeability and retention (EPR) effect[1a], their poor cellular internalization[14] and inability[15] to release the payload further limit their therapeutic efficacy. These major obstacles must be overcome for nanoparticle-based theranostic platforms to reach their full potential and become clinically viable.[1a, 16] Herein, we report the first multifunctional polymer-caged nanobin (PCN) theranostic platform that is capable of selectively targeting Her2-expressing tumor cells with high concentrations of T1 MRI contrast agents followed by the triggered release of a high payload of chemotherapeutics. We extended the PCN core-shell nanocarrier concept,[17] which comprises a doxorubicin (DXR)-loaded biocompatible liposomal core and an acid-sensitive, biodegradable polymer shell,[18] to include surface functionalization with Herceptin targeting groups and GdIII-based contrast agents (Figure 1a). In vitro testing of the Her2-targeted theranostic platform (Her-GdIII-PCNDXR) against Her2-overexpressing SK-BR-3 cells reveals an impressive 120-fold enhancement in cellular GdIII–uptake in comparison to free DOTA-GdIII, which significantly decreases T1 relaxation time and provides enhanced T1 MRI contrast for the targeted PCNs over the non-targeted nanocarriers. In addition, the 14-fold increase in cytotoxicity of the Her-GdIII-PCNDXR over the non-targeted analogue makes it a highly promising theranostic agent. Figure 1 (a) Schematic presentation of the preparation of DXR-loaded, Herceptin- and GdIII-conjugated PCN (Her-GdIII-PCNDXR). (b) Plots of the hydrodynamic diameters (DH) of BLDXR (black rectangle), PCNDXR (red circle), and Her-GdIII-PCNDXR (blue triangle) and ... Herceptin (Trastuzumab) is a monoclonal antibody that specifically binds to human epidermal growth factor receptor 2 (Her2), known to be overexpressed in ~25% of human breast cancers.[19] Recently, a promising clinical study[20] has reported that the Herceptin-conjugated chemotherapy agent Trastuzumab emtansine (T-DM1) significantly extends survival rate while reducing side effects in patients with aggressive Her2-overexpressing breast cancers, which suggests that targeting toxic chemotherapeutic agents to specific cell-surface receptors can indeed improve their therapeutic efficacies. We hypothesize that this strategy can be extended to our PCN-based theranostic nanoparticle platform[21] where the Her2-targeting functionality is expected to result in more efficient internalization of both drugs and imaging agents by Her2-overexpressing cancer cells through a receptor-mediated endocytosis pathway.[7, 22] Together with the pH-triggered drug-releasing capability[23] and high stability in physiological conditions,[17] the resulting enhanced cellular uptake would lead to major improvements in both cytotoxicity and MRI contrast enhancement at the target sites and would significantly advance the theranostic concept. While high specificity to Her2-overexpressing tumor cells has spurred usage of Herceptin as a targeting ligand for delivery nanocarriers of either drugs or imaging agents,[14, 24] only a few studies[25] have reported a Her2-targeted theranostic platform that includes both chemotherapeutics and imaging probes in a single delivery nanocarrier. Most of these platforms, however, have limited theranostic efficacy due to a lack of triggered drug release and limited ability for in vivo imaging. While a Her2-targeting, iron-oxide nanoparticle-based theranostic platform demonstrated acid-triggered drug release and MR imaing abilities[25c], this system allows T2 MR imaging and exhibits premature drug release under physiological conditions (pH 7.4 and 37 °C). To the best of our knowledge, there have been no reports of Her2-targeting theranostic platforms that combine a chemotherapeutic with a T1 MRI contrast agent and show significant enhancements in both therapy and diagnosis through triggered-release and Her2-targeting. In contrast to the iron oxide nanoparticle for T2 MR imaging, T1 MRI contrast agensts such as GdIII chelates must be further conjugated to a nanocarrier to enhance their intrinsic poor cellular internalization. The work described herein demonstrates the first smart multifunctional theranostic platform that presents facile acid-triggered drug release, high stability under physiological conditions, specific targeting of Her2-overexpresssing cancers, and enhanced T1-weighted MR imaging. Together, these four characteristics lead to outstanding in vitro theranostic performance against Her2-overexpressing breast cancer cells.
Databáze: OpenAIRE
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