Sonodynamic-chemotherapy synergy with chlorin e6-based carrier-free nanoparticles for non-small cell lung cancer.

Sonodynamic therapy (SDT), an emerging cancer treatment with significant potential, offers the advantages of non-invasiveness and deep tissue penetrability. The method involves activating sonosensitizers with ultrasound to generate reactive oxygen species (ROS) capable of eradicating cancer cells, addressing the challenge faced by photodynamic therapy (PDT) where conventional light sources struggle to penetrate deep tissues, impacting treatment efficacy. This study addresses prevalent challenges in numerous nanodiagnostic and therapeutic agents, such as intricate synthesis, poor repeatability, low stability, and high cost, by introducing a streamlined one-step assembly method for nanoparticle preparation. Specifically, the sonosensitizer Chlorin e6 (Ce6) and the chemotherapy drug erlotinib are effortlessly combined and self-assembled under sonication, yielding carrier-free nanoparticles (EC-NPs) for non-small cell lung cancer (NSCLC) treatment. The resulting EC-NPs exhibit optimal drug loading capacity, a simplified preparation process, and robust stability both in vitro and in vivo, owing to their carrier-free characteristics. Under the synergistic treatment of sonodynamic therapy and chemotherapy, EC-NPs induce an excess of reactive oxygen in tumor tissue, prompting apoptosis of cancer cells and reducing their proliferative capacity. Both in vitro and in vivo experiments demonstrate superior therapeutic effects of EC-NPs under ultrasound conditions compared to free Ce6. In summary, our research findings highlight that the innovatively designed carrier-free sonosensitizer EC-NPs present a therapeutic option with commendable efficacy and minimal side effects.

A Novel Redox-Sensitive Drug Delivery System Based on Trimethyl-Locked Polycarbonate.

Stimuli-responsive polymer nanocarriers, capable of exploiting subtle changes in the tumor microenvironment for controlled drug release, have gained significant attention in cancer therapy. Notably, NAD(P)H: quinone oxidoreductase 1 (NQO1), found to be upregulated in various solid tumors, represents a promising therapeutic target due to its effective capability to enzymatically reduce trimethyl-locked (TML) benzoquinone structures in a physiological condition. In this study, a novel redox-sensitive carbonate monomer, MTC, was synthesized, and its amphiphilic block copolymers were prepared through ring-opening polymerization. By successfully self-assembling poly(ethylene glycol)-b-PMTC micelles, the model drug doxorubicin (DOX) was encapsulated with high efficiency. The micelles exhibited redox-responsive behavior, leading to rapid drug release. In vitro assessments confirmed their excellent biocompatibility and hemocompatibility. Furthermore, the inhibition of the NQO1 enzyme reduced drug release in NQO1-overexpressed cells but not in control cells, resulting in decreased cytotoxicity in the presence of NQO1 enzyme inhibitors. Overall, this study showcases the potential of MTC-based polycarbonate micelles to achieve targeted and specific drug release in the NQO1 enzyme-mediated tumor microenvironment. Therefore, the self-assembly of MTC-based polymers into nanomicelles holds immense promise as intelligent nanocarriers in drug delivery applications.

Nanoparticle-Mediated Delivery of Satraplatin to Overcome Cisplatin Drug Resistance.

Drug resistance and cancer metastasis are the major obstacles for widely used platinum-based chemotherapy. It is acknowledgement that the decreasing intracellular accumulation of anticancer drugs and increasing sulfur-binding detoxification are two major mechanisms related to drug resistance. Herein, we developed a practical and straightforward method for formulating the clinically used anticancer drug satraplatin (JM-216) with D-α-tocopheryl polyethylene glycol succinate (TPGS)-based polymers to create satraplatin-loaded nanoparticles (SatPt-NPs). The experimental results demonstrate that SatPt-NPs exhibited comparable efficacy to A2780 in treating the A2780 cisplatin-resistant ovarian cancer cell line (A2780DDP), indicating their significant potential in overcoming drug resistance. Additionally, buthionine sulfoximine (BSO) is capable of depleting intracellular glutathione (GSH), resulting in reduced detoxification. After BSO treatment, the IC50 value of SatPt-NPs changed from 0.178 to 0.133 µM, which remained relatively unchanged compared to cisplatin. This suggests that SatPt-NPs can overcome drug resistance by evading GSH detoxification. Therefore, SatPt-NPs have the ability to inhibit drug resistance in tumor cells and hold tremendous potential in cancer treatment.

A Novel NQO1 Enzyme-Responsive Polyurethane Nanocarrier for Redox-Triggered Intracellular Drug Release.

The design of nano-drug delivery vehicles responsive to tumor microenvironment stimuli has become a crucial aspect in developing cancer therapy in recent years. Among them, the enzyme-responsive nano-drug delivery system is particularly effective, as it utilizes tumor-specific and highly expressed enzymes as precise targets, leading to increased drug release at the target sites, reduced nonspecific release, and improved efficacy while minimizing toxic side effects on normal tissues. NAD(P)H:quinone oxidoreductase 1 (NQO1) is an important reductase associated with cancer and is overexpressed in some cancer cells, particularly in lung and breast cancer. Thus, the design of nanocarriers with high selectivity and responsiveness to NQO1 is of great significance for tumor diagnosis and treatment. It has been reported that under physiological conditions, NQO1 can specifically reduce the trimethyl-locked benzoquinone structure through a two-electron reduction, resulting in rapid lactonization via an enzymatic reaction. Based on this, a novel reduction-sensitive polyurethane (PEG-PTU-PEG) block copolymer was designed and synthesized by copolymerizing diisocyanate, a reduction-sensitive monomer (TMBQ), and poly(ethylene glycol). The successful synthesis of monomers and polymers was verified by nuclear magnetic resonance (1H NMR) and gel permeation chromatography (GPC). Then, the PEG-PTU-PEG micelles were successfully prepared by self-assembly, and their reductive dissociation behavior in the presence of Na2S2O4 was verified by dynamic light scattering (DLS), 1H NMR, and GPC. Next, the model drug doxorubicin (DOX) was encapsulated into the hydrophobic core of this polyurethane micelles by microemulsion method. It was observed that the drug-loaded micelles could also achieve a redox response and rapidly release the encapsulated substances. In vitro cell experiments demonstrated that PEG-PTU-PEG micelles had good biocompatibility and a low hemolysis rate (<5%). Furthermore, in the presence of an NQO1 enzyme inhibitor (dicoumarol), lower drug release from micelles was observed in A549 and 4T1 cells by both fluorescence microscopy and flow cytometry assays, but not in NIH-3T3 control cells. Predictably, DOX-loaded micelles also showed lower cytotoxicity in 4T1 cells in the presence of NQO1 enzyme inhibitors. These results indicate that drug-loaded polyurethane micelles could accomplish specific drug release in the reducing environment in the presence of NQO1 enzymes. Therefore, this study provides a new option for the construction of polyurethane nanocarriers for precise targeting and reductive release, which could benefit the intracellular drug-specific release and precision therapy of tumors.

Novel Donor-Acceptor Conjugated Polymer-Based Nanomicelles for Photothermal Therapy in the NIR Window.

In this study, a novel donor-acceptor conjugated polymer PDPPDTP was designed and synthesized by D-A polymerization using 2,6-di(trimethyltin)-N-dithieno[3,2-b:20,30-d]pyrrole as the electron-donating (D) unit and 3,6-bis(5-bromothiophen-2-yl)-2,5-dihexadecylpyrrolo[3,4-c]pyrrole-1,4-dione as the electron-accepting (A) unit. The prepared polymer has strong absorption in the near-infrared (NIR) range of 700-900 nm. Moreover, it shows excellent photothermal performance under irradiation at 808 nm. Next, the biodegradable amphiphilic polymer polyethylene glycol-polycaprolactone was used to encapsulate the new conjugated polymer into nanomicelles by the microemulsion method. The obtained PDPPDTP-loaded micelles exhibited a regular spherical structure, and their hydrodynamic diameter was about 78 nm, characterized by transmission electron microscopy and dynamic light scattering. Notably, the micelles exhibited good stability, and the encapsulation efficiency of the conjugated polymer in the micelles was ∼80%. In vitro cell experiments demonstrated that the nanomicelles not only showed good biocompatibility and low toxicity but also could effectively inhibit the proliferation of breast cancer cells 4T1 under the NIR light irradiation of 808 nm. Furthermore, in vivo studies of photothermal therapy (PTT) efficacy showed that the PDPPDTP-loaded micelles exhibited a remarkable tumor growth inhibition in a syngeneic murine tumor model, indicating that the nanomicelles loaded with this novel conjugated polymer could be further explored as a new type of theranostic agent and applied in the PTT of tumors.

Recent progress of nanomedicine in secreted phospholipase A2 as a potential therapeutic target.

Overexpressed secretory phospholipase A2 (sPLA2) is found in many inflammatory diseases and various types of cancer. sPLA2 can catalyze the hydrolysis of phospholipid sn-2 ester bonds to lysophosphatidylcholine and free fatty acids, and its catalytic substrate and downstream products mediate a series of cascade reactions and inflammatory responses. Furthermore, different subtypes of sPLA2 can participate in different physiological processes by driving unique lipid pathways. Recently, many diseases have not been treated by appropriate chemotherapy methods due to low bioavailability and severe side effects of clinically available small-molecule drugs. Therefore, they have great development prospects of revealing the therapeutic mechanism of sPLA2 and use sPLA2 as a potential therapeutic target for designing and exploring new drugs and their delivery systems. Notably, the emergence of nanomedicines in recent years provides a practical and innovative means for overcoming the challenges associated with chemotherapy. With these considerations in mind, this paper systematically reviews recent studies on nanomedicines targeting sPLA2 overexpression in various diseases during the past few years.

Rapid, site-specific labeling of "off-the-shelf" and native serum autoantibodies with T cell-redirecting domains.

Extensive antibody engineering and cloning is typically required to generate new bispecific antibodies. Made-to-order genes, advanced expression systems, and high-efficiency cloning can simplify and accelerate this process, but it still can take months before a functional product is realized. We developed a simple method to site-specifically and covalently attach a T cell-redirecting domain to any off-the-shelf, human immunoglobulin G (IgG) or native IgG isolated from serum. No antibody engineering, cloning, or knowledge of the antibody sequence is required. Bispecific antibodies are generated in just hours. By labeling antibodies isolated from tumor-bearing mice, including two syngeneic models, we generated T cell-redirecting autoantibodies (TRAAbs) that act as an effective therapeutic. TRAAbs preferentially bind tumor tissue over healthy tissue, indicating a previously unexplored therapeutic window. The use of autoantibodies to direct the tumor targeting of bispecific antibodies represents a new paradigm in personalized medicine that eliminates the need to identify tumor biomarkers.

3D Printed Personalized Nerve Guide Conduits for Precision Repair of Peripheral Nerve Defects.

The treatment of peripheral nerve defects has always been one of the most challenging clinical practices in neurosurgery. Currently, nerve autograft is the preferred treatment modality for peripheral nerve defects, while the therapy is constantly plagued by the limited donor, loss of donor function, formation of neuroma, nerve distortion or dislocation, and nerve diameter mismatch. To address these clinical issues, the emerged nerve guide conduits (NGCs) are expected to offer effective platforms to repair peripheral nerve defects, especially those with large or complex topological structures. Up to now, numerous technologies are developed for preparing diverse NGCs, such as solvent casting, gas foaming, phase separation, freeze-drying, melt molding, electrospinning, and three-dimensional (3D) printing. 3D printing shows great potential and advantages because it can quickly and accurately manufacture the required NGCs from various natural and synthetic materials. This review introduces the application of personalized 3D printed NGCs for the precision repair of peripheral nerve defects and predicts their future directions.

Oriented nanofibrous P(MMD-co-LA)/Deferoxamine nerve scaffold facilitates peripheral nerve regeneration by regulating macrophage phenotype and revascularization.

Delayed injured nerve regeneration remains a clinical problem, partly ascribing to the lack of regulation of regenerative microenvironment, topographical cues, and blood nourishment. Functional electrospun conduits have been established as an efficacious strategy to facilitate nerve regeneration by providing structural guidance, regulating the regenerative immune microenvironment, and improving vascular regeneration. However, the synthetic polymers conventionally used to fabricate electrospinning scaffolds, such as poly(L-lactic acid), poly(glycolic acid), and poly(lactic-co-glycolic acid), can cause aseptic inflammation due to acidic degradation products. Therefore, a poly[3(S)-methyl-morpholine-2,5-dione-co-lactic] [P(MMD-co-LA)] containing alanine units with good mechanical properties and reduced acid degradation products, was obtained by melt ring-opening polymerization (ROP). Here, we aimed to explore the effect of oriented nanofiber/Deferoxamine (DFO, a hydrophilic angiogenic drug) scaffold in the rapid construction of a favorable regenerative microenvironment, including cell bridge, polarized vascular system, and immune microenvironment. In vitro studies have shown that the scaffold can sustainably release DFO, which accelerates the migration and tube formation of human umbilical vein endothelial cells (HUVECs), as well as the expression of genes related to angiogenesis. The physical clues provided by the arranged nanofibers can regulate the polarization of macrophages and reduce the expression of inflammatory factors. Furthermore, the in vivo results demonstrated a higher M2 polarization level of the oriented nanofibrous scaffold treatment group with reducedinflammation reaction in the injured nerve. Moreover, the in-situ release of DFO up-regulated the expression of HIF1-α and SDF-1α genes, as well as the expression of HIF1-α's target gene VEGF, further promoting revascularization and enhancing nerve regeneration at the defect site. The obtained results provide essential insights on accelerating the creation of the nerve regeneration microenvironment by combining the physiological processes of nerve regeneration with topographical cues and chemical signal induction.

Targeting cartilage EGFR pathway for osteoarthritis treatment.

Osteoarthritis (OA) is a widespread joint disease for which there are no disease-modifying treatments. Previously, we found that mice with cartilage-specific epidermal growth factor receptor (EGFR) deficiency developed accelerated knee OA. To test whether the EGFR pathway can be targeted as a potential OA therapy, we constructed two cartilage-specific EGFR overactivation models in mice by overexpressing heparin binding EGF-like growth factor (HBEGF), an EGFR ligand. Compared to wild type, Col2-Cre HBEGF-overexpressing mice had persistently enlarged articular cartilage from adolescence, due to an expanded pool of chondroprogenitors with elevated proliferation ability, survival rate, and lubricant production. Adult Col2-Cre HBEGF-overexpressing mice and Aggrecan-CreER HBEGF-overexpressing mice were resistant to cartilage degeneration and other signs of OA after surgical destabilization of the medial meniscus (DMM). Treating mice with gefitinib, an EGFR inhibitor, abolished the protective action against OA in HBEGF-overexpressing mice. Polymeric micellar nanoparticles (NPs) conjugated with transforming growth factor-α (TGFα), a potent EGFR ligand, were stable and nontoxic and had long joint retention, high cartilage uptake, and penetration capabilities. Intra-articular delivery of TGFα-NPs effectively attenuated surgery-induced OA cartilage degeneration, subchondral bone plate sclerosis, and joint pain. Genetic or pharmacologic activation of EGFR revealed no obvious side effects in knee joints and major vital organs in mice. Together, our studies demonstrate the feasibility of using nanotechnology to target EGFR signaling for OA treatment.

Enhanced proliferation and differentiation of neural stem cells by peptide-containing temperature-sensitive hydrogel scaffold.

Hydrogel has attracted great attention in the past few years as a widely used material for repairing central nerve damage. However, conventional hydrogel bio-scaffold, such as chitosan, gelatin, and sodium alginate, lack sufficient biological activity and have limited nerve repair capabilities. Therefore, to explore biologically active and intelligent hydrogel materials is particularly important and necessary for central nerve repair. Herein, we developed a temperature-sensitive hydrogel grafted with a bioactive peptide IKVAV (Ile-Lys-Val-Ala-Val, IKVAV). The hydrogel was prepared by copolymerization of N-propan-2-ylprop-2-enamide (NIPAM) and AC-PEG-IKVAV copolymers via reversible addition-fracture chain transfer (RAFT) polymerization, using polyethylene glycol (PEGDA) and N, N'-Methylenebisacrylamide (BISAM) as cross-linking agents. The prepared hydrogel scaffold demonstrates a series of excellent properties such as rapid (de)swelling performance, good biocompatibility, regular three-dimensional porous structure, and in particular good biological activity, which can guide cell fate and mediate neuron's differentiation. Therefore, the developed peptide hydrogel scaffold provides a new strategy for designing biomaterials that are widely used in tissue engineering for central nervous system injury.

Indocyanine Green-Coated Polycaprolactone Micelles for Fluorescence Imaging of Tumors.

Recently, near-infrared (NIR) fluorescent dyes such as indocyanine green (ICG) have received tremendous interest as contrast agents for use in fluorescence-guided, intraoperative cancer resection surgery. However, despite showing great promise, ICG has many shortcomings such as rapid clearance and poor tumor accumulation. To improve the selective accumulation of ICG within tumors, numerous groups have formulated ICG into nanoparticles, but these approaches can suffer from rapid leakage of ICG, use of materials that exhibit poor or incomplete excretion, or complex chemistries that are not easily amenable to scale up for clinical use. Here, we developed a simple one-step method to prepare ICG-based fluorescent micelles that are composed solely of unmodified ICG and polycaprolactone (PCL), two clinically used materials with well-characterized safety profiles. The ICG-PCL micelles are prepared via oil-in-water emulsions, and the resulting micelles exhibit a uniform size, good reproducibility, and high loading efficiency. In vivo fluorescence imaging demonstrated that the ICG-PCL micelles led to a significant improvement in the accumulation and retention of ICG, in four different tumor models, compared with free dye, making them an attractive option for image-guided surgery.

Use of Oppositely Polarized External Magnets To Improve the Accumulation and Penetration of Magnetic Nanocarriers into Solid Tumors.

Drug delivery to solid tumors is hindered by hydrostatic and physical barriers that limit the penetration of nanocarriers into tumor tissue. When exploiting the enhanced permeability and retention (EPR) effect for passive targeting of nanocarriers, the increased interstitial fluid pressure and dense extracellular matrix in tumors limits the distribution of the nanocarriers to perivascular regions. Previous strategies have shown that magnetophoresis enhances accumulation and penetration of nanoparticles into solid tumors. However, because magnetic fields fall off rapidly with distance from the magnet, these methods have been limited to use in superficial tumors. To overcome this problem, we have developed a system comprising two oppositely polarized magnets that enables the penetration of magnetic nanocarriers into more deeply seeded tumors. Using this method, we demonstrate a 5-fold increase in the penetration and a 3-fold increase in the accumulation of magnetic nanoparticles within solid tumors compared to EPR.

Dextran-Benzoporphyrin Derivative (BPD) Coated Superparamagnetic Iron Oxide Nanoparticle (SPION) Micelles for T2-Weighted Magnetic Resonance Imaging and Photodynamic Therapy.

Photodynamic therapy (PDT) has attracted extensive attention in recent years as a noninvasive and locally targeted cancer treatment approach. Nanoparticles have been used to improve the solubility and pharmacokinetics of the photosensitizers required for PDT; however, nanoparticles also suffer from many shortcomings including uncontrolled drug release and low tumor accumulation. Herein, we describe a novel biodegradable nanoplatform for the delivery of the clinically used PDT photosensitizer benzoporphyrin derivative monoacid ring A (BPD-MA) to tumors. Specifically, the hydrophobic photosensitizer BPD was covalently conjugated to the amine groups of a dextran-b-oligo (amidoamine) (dOA) dendron copolymer, forming amphiphilic dextran-BPD conjugates that can self-assemble into nanometer-sized micelles in water. To impart additional imaging capabilities to these micelles, superparamagnetic iron oxide nanoparticles (SPIONs) were encapsulated within the hydrophobic core to serve as a magnetic resonance imaging (MRI) contrast agent. The use of a photosensitizer as a hydrophobic building block enabled facile and reproducible synthesis and high drug loading capacity (∼30%, w/w). Furthermore, covalent conjugation of BPD to dextran prevents the premature release of drug during systemic circulation. In vivo studies show that the intravenous administration of dextran-BPD coated SPION nanoparticles results in significant MR contrast enhancement within tumors 24 h postinjection and PDT led to a significant reduction in the tumor growth rate.

Chlorin e6-Coated Superparamagnetic Iron Oxide Nanoparticle (SPION) Nanoclusters as a Theranostic Agent for Dual-Mode Imaging and Photodynamic Therapy.

Photodynamic therapy (PDT) is an approved modality for the treatment of various types of maligancies and diseased states. However, most of the available photosensitizers (PS) are highly hydrophobic, which limits their solubility and dispersion in biological fluids and can lead to self-quenching and sub-optimal therapeutic efficacy. In this study, chlorin e6 (Ce6)-coated superparamagnetic iron oxide nanoparticle (SPION) nanoclusters (Ce6-SCs) were prepared via an oil-in-water emulsion. The physical-chemical properties of the Ce6-SCs were systematically evaluated. Dual-mode imaging and PDT was subsequently performed in tumor-bearing mice. Chlorin e6 is capable of solubilizing hydrophobic SPION into stable, water-soluble nanoclusters without the use of any additional amphiphiles or carriers. The method is reproducible and the Ce6-SCs are highly stable under physiological conditions. The Ce6-SCs have an average diameter of 92 nm and low polydispersity (average PDI < 0.2). Encapsulation efficiency of both Ce6 and SPION is ≈100%, and the total Ce6 payload can be as high as 56% of the total weight (Ce6 + Fe). The Ce6-SCs localize within tumors via enhanced permeability and retention and are detectable by magnetic resonance (MR) and optical imaging. With PDT, Ce6-SCs demonstrate high singlet oxygen generation and produce a significant delay in tumor growth in mice.

Protoporphyrin IX (PpIX)-Coated Superparamagnetic Iron Oxide Nanoparticle (SPION) Nanoclusters for Magnetic Resonance Imaging and Photodynamic Therapy.

The ability to produce nanotherapeutics at large-scale with high drug loading efficiency, high drug loading capacity, high stability, and high potency is critical for clinical translation. However, many nanoparticle-based therapeutics under investigation suffer from complicated synthesis, poor reproducibility, low stability, and high cost. In this work, a simple method for preparing multifunctional nanoparticles is utilized that act as both a contrast agent for magnetic resonance imaging and a photosensitizer for photodynamic therapy for the treatment of cancer. In particular, the photosensitizer protoporphyrin IX (PpIX) is used to solubilize small nanoclusters of superparamagnetic iron oxide nanoparticles (SPIONs) without the use of any additional carrier materials. These nanoclusters are characterized with a high PpIX loading efficiency; a high loading capacity, stable behavior; high potency; and a synthetic approach that is amenable to large-scale production. In vivo studies of photodynamic therapy (PDT) efficacy show that the PpIX-coated SPION nanoclusters lead to a significant reduction in the growth rate of tumors in a syngeneic murine tumor model compared to both free PpIX and PpIX-loaded poly(ethylene glycol)-polycaprolactone micelles, even when injected at 1/8th the dose. These results suggest that the nanoclusters developed in this work can be a promising nanotherapeutic for clinical translation.

The Development of a Nano-based Approach to Alleviate Cisplatin-Induced Ototoxicity.

Cisplatin-induced hearing loss is experienced by a high percentage of patients with squamous cell carcinoma undergoing cisplatin chemotherapy. A novel nano-construct capable of sequestering extracellular cisplatin was developed to combat this problem. The nano-construct consisted of superparamagnetic iron oxide nanoparticles (SPIONs) entrapped within polymeric micelles, which were formed from a glutathione diethyl ester-conjugated amphiphilic diblock copolymer. The glutathione-micelles were analyzed at the cellular level and in an organotypic study for safety evaluation. All utilized methods indicated that the micelles do not cause cellular toxicity or organ damage. The micelles' ability to reduce cisplatin-induced cytotoxicity was then probed in an in vitro model. Cisplatin was pre-treated with the novel nano-construct before being added to growing cells. When compared to cells that were exposed to untreated cisplatin, cells in the pre-treated cisplatin group showed a significant increase in cell viability. This clearly demonstrates that the construct is able to protect the cells from cisplatin cytotoxicity and makes it highly likely that the novel nano-construct will be able to play a role in the protection of the inner ear from cisplatin-induced ototoxicity.

A Versatile Method to Prepare Protein Nanoclusters for Drug Delivery.

Nanocarriers based on natural biomaterials such as peptides and proteins have shown great advantages in the field of nanomedicine. However, the complicated preparation process and possible denaturation of proteins may limit their further applications. Herein, a novel method is developed to prepare protein nanocluster drug delivery system based on the self-aggregated property of proteins under the isoelectric point condition. The crosslinked protein nanoclusters, prepared by adding modified natural crosslinking agent polysaccharide, exhibit excellent stability and autofluorescent property in physiological conditions. Hemoglobin, a model protein, is chosen for preparation of drug-loaded nanoclusters. The as-prepared nanoclusters demonstrate a pH-responsive drug release behavior and can successfully deliver drugs into cancer cells. Moreover, this approach can be extended to various proteins, exemplifying the universal applicability of our new preparation method for protein-based nanoparticles.

Photoacoustic-Guided Surgery with Indocyanine Green-Coated Superparamagnetic Iron Oxide Nanoparticle Clusters.

A common cause of local tumor recurrence in brain tumor surgery results from incomplete surgical resection. Adjunctive technologies meant to facilitate gross total resection have had limited efficacy to date. Contrast agents used to delineate tumors preoperatively cannot be easily or accurately used in the real-time operative setting. Although multimodal imaging contrast agents are developed to help the surgeon discern tumor from normal tissue in the operating room, these contrast agents are not readily translatable. This study has developed a novel contrast agent comprised solely of two Food and Drug Administration approved components, indocyanine green (ICG) and superparamagnetic iron oxide (SPIO) nanoparticles-with no additional amphiphiles or carrier materials, to enable preoperative detection by magnetic resonance (MR) imaging and intraoperative photoacoustic (PA) imaging. The encapsulation efficiency of both ICG and SPIO within the formulated clusters is ≈100%, and the total ICG payload is 20-30% of the total weight (ICG + SPIO). The ICG-SPIO clusters are stable in physiologic conditions; can be taken up within tumors by enhanced permeability and retention; and are detectable by MR. In a preclinical surgical resection model in mice, following injection of ICG-SPIO clusters, animals undergoing PA-guided surgery demonstrate increased progression-free survival compared to animals undergoing microscopic surgery.

Improved Photodynamic Therapy Efficacy of Protoporphyrin IX-Loaded Polymeric Micelles Using Erlotinib Pretreatment.

Photodynamic therapy (PDT) has attracted widespread attention in recent years as a noninvasive and highly selective approach for cancer treatment. We have previously reported a significant increase in the 90-day complete response rate when tumor-bearing mice are treated with the epidermal growth factor receptor (EGFR) inhibitor erlotinib prior to PDT with the photosensitizer benzoporphyrin-derivative monoacid ring A (BPD-MA) compared to treatment with PDT alone. To further explore this strategy for anticancer therapy and clinical practice, we tested whether pretreatment with erlotinib also exhibited a synergistic therapeutic effect with a nanocarrier containing the clinically relevant photosensitizer protoporphyrin IX (PpIX). The PpIX was encapsulated within biodegradable polymeric micelles formed from the amphiphilic block copolymer poly(ethylene glycol)-polycaprolactone (PEG-PCL). The obtained micelles were characterized systematically in vitro. Further, an in vitro cytotoxicity study showed that PDT with PpIX loaded micelles did exhibit a synergistic effect when combined with erlotinib pretreatment. Considering the distinct advantages of polymeric nanocarriers in vivo, this study offers a promising new approach for the improved treatment of localized tumors. The strategy developed here has the potential to be extended to other photosensitizers currently used in the clinic for photodynamic therapy.