Brain Targeting, Antioxidant Polymeric Nanoparticles for Stroke Drug Delivery and Therapy.

Ischemic stroke is a leading cause of death and disability and remains without effective treatment options. Improved treatment of stroke requires efficient delivery of multimodal therapy to ischemic brain tissue with high specificity. Here, this article reports the development of multifunctional polymeric nanoparticles (NPs) for both stroke treatment and drug delivery. The NPs are synthesized using an reactive oxygen species (ROS)-reactive poly (2,2'-thiodiethylene 3,3'-thiodipropionate) (PTT) polymer and engineered for brain penetration through both thrombin-triggered shrinkability and AMD3100-mediated targeted delivery. It is found that the resulting AMD3100-conjugated, shrinkable PTT NPs, or ASPTT NPs, efficiently accumulate in the ischemic brain tissue after intravenous administration and function as antioxidant agents for effective stroke treatment. This work shows ASPTT NPs are capable of efficient encapsulation and delivery of glyburide to achieve anti-edema and antioxidant combination therapy, resulting in therapeutic benefits significantly greater than those by either the NPs or glyburide alone. Due to their high efficiency in brain penetration and excellent antioxidant bioactivity, ASPTT NPs have the potential to be utilized to deliver various therapeutic agents to the brain for effective stroke treatment.

Dismantlable Coronated Nanoparticles for Coupling the Induction and Perception of Immunogenic Cell Death.

Therapy-induced immunogenic cell death (ICD) can initiate both innate and adaptive immune responses for amplified anti-tumor efficacy. However, dying cell-released ICD signals are prone to being sequestered by the TIM-3 receptors on dendritic cell (DC) surfaces, preventing immune surveillance. Herein, dismantlable coronated nanoparticles (NPs) are fabricated as a type of spatiotemporally controlled nanocarriers for coupling tumor cell-mediated ICD induction to DC-mediated immune sensing. These NPs are loaded with an ICD inducer, mitoxantrone (MTO), and wrapped by a redox-labile anti-TIM-3 (αTIM-3) antibody corona, forming a separable core-shell structure. The antibody corona disintegrates under high levels of extracellular reactive oxygen species in the tumor microenvironment, exposing the MTO-loaded NP core for ICD induction and releasing functional αTIM-3 molecules for DC sensitization. Systemic administration of the coronated NPs augments DC maturation, promotes cytotoxic T cell recruitment, enhances tumor susceptibility to immune checkpoint blockade, and prevents the side effects of MTO. This study develops a promising nanoplatform to unleash the potential of host immunity in cancer therapy.

Targeted Delivery of Chemo-Sonodynamic Therapy via Brain Targeting, Glutathione-Consumable Polymeric Nanoparticles for Effective Brain Cancer Treatment.

Glioblastoma (GBM) is the most aggressive tumor of the central nervous system and remains universally lethal due to lack of effective treatment options and their inefficient delivery to the brain. Here the development of multifunctional polymeric nanoparticles (NPs) for effective treatment of GBM is reported. The NPs are synthesized using a novel glutathione (GSH)-reactive poly (2,2″-thiodiethylene 3,3″-dithiodipropionate) (PTD) polymer and engineered for brain penetration through neutrophil elastase-triggered shrinkability, iRGD-mediated targeted delivery, and lexiscan-induced autocatalysis. It is found that the resulting lexiscan-loaded, iRGD-conjugated, shrinkable PTD NPs, or LiPTD NPs, efficiently penetrate brain tumors with high specificity after intravenous administration. Furthermore, it is demonstrated that LiPTD NPs are capable of efficient encapsulation and delivery of chemotherapy doxorubicin and sonosensitizer chlorin e6 to achieve combined chemotherapy and sonodynamic therapy (SDT). It is demonstrated that the capability of GSH depletion of LiPTD NPs further augments the tumor cell killing effect triggered by SDT. As a result, treatment with LiPTD NPs effectively inhibits tumor growth and prolongs the survival of tumor-bearing mice. This study may suggest a potential new approach for effective GBM treatment.

Cellular Hypoxia Mitigation by Dandelion-like Nanoparticles for Synergistic Photodynamic Therapy of Oral Squamous Cell Carcinoma.

Hypoxia at the tumor site limits the therapeutic effects of photodynamic therapy (PDT) in oral squamous cell carcinoma (OSCC), which is an oxygen-consumption process. Inhibiting cellular oxygen consumption and reducing cellular ATP production are expected to enhance PDT. In this study, we designed and constructed dandelion-like size-shrinkable nanoparticles for tumor-targeted delivery of hypoxia regulator resveratrol (RES) and photodynamic agent chlorine e6 (CE6). Both drugs were co-encapsulated in small-sized micelles modified with EGFR targeting ligand GE11, which was further conjugated on hyaluronic nanogel (NG) to afford RC-GMN. After targeted accumulation in tumors mediated by GE11 and enhanced penetration and retention (EPR) effects, RC-GMN was degraded by hyaluronidase (HAase) and resulted in small-sized micelles, allowing for deep penetration and dual-receptor-mediated cellular internalization. Resveratrol inhibited cellular oxygen consumption and provided sufficient oxygen for PDT, which consequently activated PDT to produce reactive oxygen species (ROS). Notably, we found that autophagy was overactivated in PDT, which was further strengthened by the hypoxia regulator resveratrol, elevating autophagic cell death. The synergistic effects of resveratrol and CE6 promoted autophagic cell death and apoptosis in the enhanced PDT, resulting in stronger antitumor effects in the orthotopic OSCC model. Therefore, the facilitated delivery of hypoxia regulator enhanced PDT efficacy by elevating oxygen content in tumor cells and inducing autophagic cell death and apoptosis, which offers an alternative strategy for enhancing the PDT effects against OSCC.

A Near-Infrared Laser-Triggered Size-Shrinkable Nanosystem with In Situ Drug Release for Deep Tumor Penetration.

The development of smart size-tunable drug delivery nanoplatform enables the solving of the paradox of inconsistent size-dependence of high tumor accumulation and deep penetration during its delivery process, thus achieving superior cancer treatment efficacy. Herein, we report a size-shrinkable nanomicelle complex system with an initial size of 101 nm enabling effective retention around the tumor periphery and could destruct to ultrasmall nanomicelles triggered by a near-infrared (NIR) laser to realize the deep tumor penetration. The nanomicelle system is consisted of an upper critical solution temperature (UCST)-type block copolymer poly(acrylamide-acrylonitrile)-polyethylene glycol-lipoic acid (p(AAm-co-AN)-g-PEG-LA) encapsulating gold nanorods. Upon the irradiation of the NIR laser at the tumor site, gold nanorods could convert the light energy to heat energy, realizing the photothermal ablation of superficial tumor tissue. Concurrently, the large micelles split into a cascade of ultrasmall micelles (∼7 nm), which could easily penetrate into the deep site of the tumor and achieve the in situ "on-demand" release of the loaded drug to exert superior combined photothermal-chemotherapy of cancer. By the precise manipulation of laser, the micelle complex system realized the hierarchical killing from the superficial-to-deep tumor and achieved almost complete tumor growth inhibition on the established xenograft liver tumor mice model.

Size shrinkable drug delivery nanosystems and priming the tumor microenvironment for deep intratumoral penetration of nanoparticles.

The penetration of nanomedicine into solid tumor still constitutes a great challenge for cancer therapy, which lead to the failure of thorough clearance of tumor cells. Aiming at solving this issue, lots of encouraging progress has been made in the development of multistage nanoparticles triggered by various stimuli in the past few years. Besides, the therapeutical effects of nanoagents are also greatly impacted by the complex tumor microenvironment, and remodeling tumor microenvironment has become another important approach for promoting nanoparticles penetration. In this review, we summarize and analyze recent research progress and challenges in promoting nanoparticle penetration based on two kinds of different strategies, which include size shrinkable nanoparticles and priming tumor microenvironments. Especially, many recent reported multi-strategy approaches based on particle size reduction in conjugated with other therapeutic strategies are discussed. And we expect to provide some useful enlightenments and proposals on nanotechnology-based drug delivery systems for more effective therapy of solid tumors.

A dual strategy to improve the penetration and treatment of breast cancer by combining shrinking nanoparticles with collagen depletion by losartan.

Although development of nanomedicines has been a promising direction in tumor treatment, the therapeutic outcome of current nanomedicines is unsatisfying, partly because of the poor retention and penetration in tumors. Recently, a kind of tumor microenvironment sensitive size shrinkable nanoparticles (DOX-AuNPs-GNPs) has been developed by our lab, which could enhance the tumor penetration and retention depending on the size shrinking. However, the further enhancement is still restricted by dense collagen network in tumors. Thus in this study, we combined DOX-AuNPs-GNPs with losartan to deplete tumor collagen (constituted up to 90% of extracellular matrix) to further improve tumor penetration. In vitro, DOX-AuNPs-GNPs can shrink from over 117.8nm to less than 50.0nm and release DOX-AuNPs under the triggering of tumor overexpressed matrix metalloproteinases-2 (MMP-2). In vivo, pretreatment with losartan significantly decrease the collagen level and improve the tumor penetration. In combination, losartan combined with DOX-AuNPs-GNPs showed the best drug delivery efficiency, striking penetration efficiency and best 4T1 breast tumor inhibition effect. In conclusion, this study provided a promising synergetic strategy to improve the tumor treatment efficiency of nanomedicines. STATEMENT OF SIGNIFICANCE: We have developed a dual strategy for deep tumor penetration through combining size shrinkable DOX-AuNPs-GNPs with depleting tumor collagen by losartan. Additionally, we demonstrate therapeutic efficacy in breast tumor bearing mouse model. DOX-AuNPs-GNPs co-administration with losartan is a novel and highly attractive strategy for anti-tumor drug delivery with the potential for broad applications in clinic.