Size-Optimized Ultrasmall Porous Silica Nanoparticles Depict Vasculature-Based Differential Targeting in Triple Negative Breast Cancer.

Rapid sequestration and prolonged retention of intravenously injected nanoparticles by the liver and spleen (reticuloendothelial system (RES)) presents a major barrier to effective delivery to the target site and hampers clinical translation of nanomedicine. Inspired by biological macromolecular drugs, synthesis of ultrasmall (diameter ≈12-15 nm) porous silica nanoparticles (UPSNs), capable of prolonged plasma half-life, attenuated RES sequestration, and accelerated hepatobiliary clearance, is reported. The study further investigates the effect of tumor vascularization on uptake and retention of UPSNs in two mouse models of triple negative breast cancer with distinctly different microenvironments. A semimechanistic mathematical model is developed to gain mechanistic insights into the interactions between the UPSNs and the biological entities of interest, specifically the RES. Despite similar systemic pharmacokinetic profiles, UPSNs demonstrate strikingly different tumor responses in the two models. Histopathology confirms the differences in vasculature and stromal status of the two models, and corresponding differences in the microscopic distribution of UPSNs within the tumors. The studies demonstrate the successful application of multidisciplinary and complementary approaches, based on laboratory experimentation and mathematical modeling, to concurrently design optimized nanomaterials, and investigate their complex biological interactions, in order to drive innovation and translation.

Nanostructured polyvinylpyrrolidone-curcumin conjugates allowed for kidney-targeted treatment of cisplatin induced acute kidney injury.

Acute kidney injury (AKI) leads to unacceptably high mortality due to difficulties in timely intervention and less efficient renal delivery of therapeutic drugs. Here, a series of polyvinylpyrrolidone (PVP)-curcumin nanoparticles (PCurNP) are designed to meet the renal excretion threshold (∼45 kDa), presenting a controllable delivery nanosystem for kidney targeting. Renal accumulation of the relatively small nanoparticles, 89Zr-PCurNP M10 with the diameter between 5 and 8 nm, is found to be 1.7 times and 1.8 times higher than the accumulation of 89Zr-PCurNP M29 (20-50 nm) and M40 (20-50 nm) as revealed by PET imaging. Furthermore, serum creatinine analysis, kidney tissues histology, and tubular injury scores revealed that PCurNP M10 efficiently treated cisplatin-induced AKI. Herein, PCurNP offers a novel and simple strategy for precise PET image-guided drug delivery of renal protective materials.

Moving Beyond the Pillars of Cancer Treatment: Perspectives From Nanotechnology.

Nanotechnology has made a significant impact on basic and clinical cancer research over the past two decades. Owing to multidisciplinary advances, cancer nanotechnology aims to address the problems in current cancer treatment paradigms, with the ultimate goal to improve treatment efficacy, increase patient survival, and decrease toxic side-effects. The potential for use of nanomedicine in cancer targeting and therapy has grown, and is now used to advance the four traditional pillars of cancer treatment: surgery, chemotherapy, radiation therapy and the newest pillar, immunotherapy. In this review we provide an overview of notable advances of nanomedicine in improving drug delivery, radiation therapy and immunotherapy. Potential barriers in the translation of nanomedicine from bench to bedside as well as strategies to overcome these barriers are also discussed. Promising preclinical findings highlight the translational and clinical potential of integrating nanotechnology approaches into cancer care.

Targeted α-therapy of prostate cancer using radiolabeled PSMA inhibitors: a game changer in nuclear medicine.

Prostate cancer (PCa) is one of the most common malignancies in men and is a major contributor to cancer related deaths worldwide. Metastatic spread and disease progression under androgen deprivation therapy signify the onset of metastatic castration resistant prostate cancer (mCRPCa)-the lethal form of the disease, which severely deteriorates the quality of life of patients. Over the last decade, tremendous progress has been made toward identifying appropriate molecular targets that could enable efficient in vivo targeting for non-invasive imaging and therapy of mCPRCa. In this context, a promising enzymatic target is prostate specific membrane antigen (PSMA), which is overexpressed on PCa cells, in proportion to the stage and grade of the tumor progression. This is especially relevant for mCRPCa, which has significant overexpression of PSMA. For therapy of mCRPCa, several nuclear medicine clinics all over the world have confirmed that 177Lu-labeled-PSMA enzyme inhibitors (177Lu-PSMA-617 and 177Lu-PSMA I&T) have a favorable dosimetry and convincing therapeutic response. However, ~30% of patients were found to be short or non-responders and dose escalation was severely limited by chronic hematological toxicity. Such limitations could be better overcome by targeted alpha therapy (TAT) which has the potential to bring a paradigm shift in treatment of mCRPCa patients. This concise review presents an overview of the successes and challenges currently faced in TAT of mCRPCa using radiolabeled PSMA inhibitors. The preclinical and clinical data reported to date are quite promising, and it is expected that this therapeutic modality will play a pivotal role in advanced stage PCa management in the foreseeable future.

Activatable Hybrid Nanotheranostics for Tetramodal Imaging and Synergistic Photothermal/Photodynamic Therapy.

A multifunctional core-satellite nanoconstruct is designed by assembling copper sulfide (CuS) nanoparticles on the surface of [89 Zr]-labeled hollow mesoporous silica nanoshells filled with porphyrin molecules, for effective cancer imaging and therapy. The hybrid nanotheranostic demonstrates three significant features: (1) simple and robust construction from biocompatible building blocks, demonstrating prolonged blood retention, enhanced tumor accumulation, and minimal long-term systemic toxicity, (2) rationally selected functional moieties that interact together to enable simultaneous tetramodal (positron emission tomography/fluorescence/Cerenkov luminescence/Cerenkov radiation energy transfer) imaging for rapid and accurate delineation of tumors and multimodal image-guided therapy in vivo, and (3) synergistic interaction between CuS-mediated photothermal therapy and porphyrin-mediated photodynamic therapy which results in complete tumor elimination within a day of treatment with no visible recurrence or side effects. Overall, this proof-of-concept study illustrates an efficient, generalized approach to design high-performance core-satellite nanohybrids that can be easily tailored to combine a wide variety of imaging and therapeutic modalities for improved and personalized cancer theranostics in the future.

Reassembly of 89 Zr-Labeled Cancer Cell Membranes into Multicompartment Membrane-Derived Liposomes for PET-Trackable Tumor-Targeted Theranostics.

Nanoengineering of cell membranes holds great potential to revolutionize tumor-targeted theranostics, owing to their innate biocompatibility and ability to escape from the immune and reticuloendothelial systems. However, tailoring and integrating cell membranes with drug and imaging agents into one versatile nanoparticle are still challenging. Here, multicompartment membrane-derived liposomes (MCLs) are developed by reassembling cancer cell membranes with Tween-80, and are used to conjugate 89 Zr via deferoxamine chelator and load tetrakis(4-carboxyphenyl) porphyrin for in vivo noninvasive quantitative tracing by positron emission tomography imaging and photodynamic therapy (PDT), respectively. Radiolabeled constructs, 89 Zr-Df-MCLs, demonstrate excellent radiochemical stability in vivo, target 4T1 tumors by the enhanced permeability and retention effect, and are retained long-term for efficient and effective PDT while clearing gradually from the reticuloendothelial system via hepatobiliary excretion. Toxicity evaluation confirms that the MCLs do not impose acute or chronic toxicity in intravenously injected mice. Additionally, 89 Zr-labeled MCLs can execute rapid and highly sensitive lymph node mapping, even for deep-seated sentinel lymph nodes. The as-developed cell membrane reassembling route to MCLs could be extended to other cell types, providing a versatile platform for disease theranostics by facilely and efficiently integrating various multifunctional agents.