Baran D. Sumer

Theranostic nanomedicine for cancer

Baran Sumer1, Jinming Gao2† †Author for correspondence 1Department of Otolaryngology, Head and Neck Surgery, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA Tel.: +1 214 648 3102; Fax: +1 214 648 2246; E-mail: baran.sumer@ utsouthwestern.edu 2Department of Pharmacology, Harold C Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75093, USA Tel.: +1 214 645 6370; Fax: +1 214 645 6347; E-mail: jinming.gao@ utsouthwestern.edu ‘Over recent decades, there has been explosive development of a variety of nanotechnology platforms to diagnose and treat cancer.’

A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals

Stimuli-responsive nanomaterials are increasingly important in a variety of applications such as biosensing, molecular imaging, drug delivery and tissue engineering. For cancer detection, a paramount challenge still exists in search of methods that can illuminate tumors universally regardless of their genotypes and phenotypes. Here we capitalized on the acidic, angiogenic tumor microenvironment to achieve broad detection of tumor tissues in a wide variety of mouse cancer models. This was accomplished using ultra-pH sensitive fluorescent nanoprobes that have tunable, exponential fluorescence activation upon encountering subtle, physiologically relevant pH transitions. These nanoprobes were silent in the circulation, then dramatically activated (>300 fold) in response to neovasculature or to the low extracellular pH in tumors. Thus, we have established non-toxic, fluorescent nanoreporters that can non-linearly amplify tumor microenvironmental signals, permitting identification of tumor tissue independently of histological type or driver mutation, and detection of acute treatment responses much more rapidly than conventional imaging approaches.

Tunable, Ultrasensitive pH-Responsive Nanoparticles Targeting Specific Endocytic Organelles in Living Cells†

In recent years, multifunctional nanoparticles have received considerable attention in many applications such as biosensors, diagnostic nanoprobes and targeted drug delivery.[1] These efforts have been driven to a large extent by the need to improve biological specificity in diagnosis and therapy through the precise, spatio-temporal control of agent delivery. In order to achieve this goal, continuous efforts have been dedicated to develop stimuli-responsive nanoplatforms.[2] Environmental stimuli that were exploited include pH,[3] temperature,[4] enzymatic expression,[5] redox reaction[6] and light induction.[7] Among these activating signals, pH trigger is one of the most extensively studied stimuli based on two types of pH differences: (a) pathological (e.g. tumor) vs. normal tissues and (b) acidic intracellular compartments.[8] For example, due to the unusual acidity of the tumor extracellular microenvironment (pHe ≈ 6.5), several pHe-responsive nanosystems were reported to increase the sensitivity of tumor imaging or the efficacy of therapy.[9]

Multifunctional micellar nanomedicine for cancer therapy.

Polymeric micelles are supramolecular, core-shell nanoparticles that offer considerable advantages for cancer diagnosis and therapy. Their relatively small size (10–100 nm), ability to solubilize hydrophobic drugs as well as imaging agents, and improved pharmacokinetics provide a useful bioengineering platform for cancer applications. Several polymeric micelle formulations are currently undergoing phase I/II clinical trials, which have shown improved antitumor efficacy and reduced systemic toxicity. This minireview will focus on recent advancements in the multifunctional design of micellar nanomedicine with tumor targeting, stimulated drug release, and cancer imaging capabilities. Such functionalization strategies result in enhanced micellar accumulation at tumor sites, higher drug bioavailability, as well as improved tumor diagnosis and visualization of therapy. Ultimately, integrated nanotherapeutic systems (e.g., theranostic nanomedicine) may prove essential to address the challenges of tumor heterogeneity and adaptive resistance to achieve efficacious treatment of cancer.

Shape-specific polymeric nanomedicine: emerging opportunities and challenges.

Size and shape are fundamental properties of micro/nanoparticles that are critically important for nanomedicine applications. Extensive studies have revealed the effect of particle size on spherical particles with respect to circulation, extravasation and distribution in vivo. In contrast, the importance of particle shape has only recently begun to emerge. For example, cylindrically-shaped filomicelles (diameter 22–60 nm, length 8–18 μm) have shown persistent blood circulation for up to one week after intravenous injection, much longer than their spherical counterparts. Disc-shaped nanoparticles have demonstrated higher in vivo targeting specificity to endothelial cells expressing intercellular adhesion molecule receptors in mice than spherical particles of similar size. In this Minireview, we will discuss the recent advances in the fabrication of shape-specific nanoparticles and their unique biological and pharmacological properties. Computational models are presented to provide mechanistic understanding of the shape effects on cell targeting under flow conditions. Shape-specific nanoparticles have the potential to significantly improve the performance of nanomedicine in diagnostic imaging and targeted drug delivery applications.

Nanoscopic Micelle Delivery Improves the Photophysical Properties and Efficacy of Photodynamic Therapy of Protoporphyrin IX

Nanodelivery systems have shown considerable promise in increasing the solubility and delivery efficiency of hydrophobic photosensitizers for photodynamic therapy (PDT) applications. In this study, we report the preparation and characterization of polymeric micelles that incorporate protoporphyrin IX (PpIX), a potent photosensitizer, using non-covalent encapsulation and covalent conjugation methods. Depending on the incorporation method and PpIX loading percentage, PpIX existed as a monomer, dimer or aggregate in the micelle core. The PpIX state directly affected the fluorescence intensity and (1)O(2) generation efficiency of the resulting micelles in aqueous solution. Micelles with lower PpIX loading density (e.g. 0.2%) showed brighter fluorescence and higher (1)O(2) yield than those with higher PpIX loading density (e.g. 4%) in solution. However, PDT efficacy in H2009 lung cancer cells showed an opposite trend. In particular, 4% PpIX-conjugated micelles demonstrated the largest PDT therapeutic window, as indicated by the highest phototoxicity and relatively low dark toxicity. Results from this study contribute to the fundamental understanding of nanoscopic structure-property relationships of micelle-delivered PpIX and establish a viable micelle formulation (i.e. 4% PpIX-conjugated micelles) for in vivo evaluation of antitumor efficacy.

Ultra-pH-sensitive nanoprobe library with broad pH tunability and fluorescence emissions.

pH is an important physiological parameter that plays a critical role in cellular and tissue homeostasis. Conventional small molecular pH sensors (e.g., fluorescein, Lysosensor) are limited by broad pH response and restricted fluorescent emissions. Previously, we reported the development of ultra-pH-sensitive (UPS) nanoprobes with sharp pH response using fluorophores with small Stokes shifts (<40 nm). In this study, we expand the UPS design to a library of nanoprobes with operator-predetermined pH transitions and wide fluorescent emissions (400–820 nm). A copolymer strategy was employed to fine tune the hydrophobicity of the ionizable hydrophobic block, which led to a desired transition pH based on standard curves. Interestingly, matching the hydrophobicity of the monomers was critical to achieve a sharp pH transition. To overcome the fluorophore limitations, we introduced copolymers conjugated with fluorescence quenchers (FQs). In the micelle state, the FQs effectively suppressed the emission of fluorophores regardless of their Stokes shifts and further increased the fluorescence activation ratios. As a proof of concept, we generated a library of 10 nanoprobes each encoded with a unique fluorophore. The nanoprobes cover the entire physiologic range of pH (4–7.4) with 0.3 pH increments. Each nanoprobe maintained a sharp pH transition (on/off < 0.25 pH) and high fluorescence activation ratio (>50-fold between on and off states). The UPS library provides a useful toolkit to study pH regulation in many pathophysiological indications (e.g., cancer, lysosome catabolism) as well as establishing tumor-activatable systems for cancer imaging and drug delivery.

Photoactivation switch from type II to type I reactions by electron-rich micelles for improved photodynamic therapy of cancer cells under hypoxia

Photodynamic therapy (PDT) is an emerging clinical modality for the treatment of a variety of diseases. Most photosensitizers are hydrophobic and poorly soluble in water. Many new nanoplatforms have been successfully established to improve the delivery efficiency of PS drugs. However, few reported studies have investigated how the carrier microenvironment may affect the photophysical properties of photosensitizer (PS) drugs and subsequently, their biological efficacy in killing malignant cells. In this study, we describe the modulation of type I and II photoactivation processes of the photosensitizer, 5,10,15,20-tetrakis(meso-hydroxyphenyl)porphyrin (mTHPP), by the micelle core environment. Electron-rich poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) micelles increased photoactivations from type II to type I mechanisms, which significantly increased the generation of O(2)(-) through the electron transfer pathway over (1)O(2) production through energy transfer process. The PDPA micelles led to enhanced phototoxicity over the electron-deficient poly(D,L-lactide) control in multiple cancer cell lines under argon-saturated conditions. These data suggest that micelle carriers may not only improve the bioavailability of photosensitizer drugs, but also modulate photophysical properties for improved PDT efficacy.

Multi-chromatic pH-activatable 19F-MRI nanoprobes with binary ON/OFF pH transitions and chemical-shift barcodes

Magnetic resonance imaging (MRI) is a powerful noninvasive imaging technique that has greatly impacted basic biological research as well clinical diagnosis of cancer and other diseases.[1] Conventional MR contrast agents are T1 (e.g. Gd-DTPA) or T2-based (e.g. iron oxide), which cause significant longitudinal or transverse relaxation of protons, respectively.[2] Despite their success in many biological applications, one potential limitation is the lack of multi-chromatic features that allows for simultaneous detection of multiple signals. Recently, 19F has received significant attention in MR imaging and spectroscopy studies.[3] Compared to 1H-MRI, 19F-MRI has little biological background due to the low levels of endogenous fluorine in the body. Moreover, 19F has 100% natural abundance and its gyromagnetic ratio (40.06 MHz/T) is second only to 1H, which makes it more sensitive for detection over other nuclei.[3f]

Successful Translation of Fluorescence Navigation During Oncologic Surgery: A Consensus Report

Navigation with fluorescence guidance has emerged in the last decade as a promising strategy to improve the efficacy of oncologic surgery. To achieve routine clinical use, the onus is on the surgical community to objectively assess the value of this technique. This assessment may facilitate both Food and Drug Administration approval of new optical imaging agents and reimbursement for the imaging procedures. It is critical to characterize fluorescence-guided procedural benefits over existing practices and to elucidate both the costs and the safety risks. This report is the result of a meeting of the International Society of Image Guided Surgery (www.isigs.org) on February 6, 2015, in Miami, Florida, and reflects a consensus of the participants’ opinions. Our objective was to critically evaluate the imaging platform technology and optical imaging agents and to make recommendations for successful clinical trial development of this highly promising approach in oncologic surgery.