Delivery Of Nanodrugs Research Articles

Advancements in the Controlled Delivery of Nanodrugs to the Central Nervous System: Challenges and Innovations.

About 1 million of the 6.8 million deaths attributed to disorders of the central nervous system (CNS) each year are caused by neurodegenerative diseases, which include Parkinson’s disease, Alzheimer’s disease, tumors, and ischemic stroke. Because of the complexity of the brain, CNS issues are a major concern. To address issues with toxicity, specificity, and delivery, several drugs are available to treat illnesses of the central nervous system (CNS). Therapeutic drugs are challenged by barriers such as the blood-brain barrier (BBB), which prevents them from reaching their intended target. Scholars have been investigating pathways for pharmaceuticals to cross the blood-brain barrier and reach their intended targets. These issues show how different cellular processes must be changed or manipulated by nanotechnology to obtain the required properties. Nanoparticles are an efficient replacement for drug delivery and other methods because of their nano size, which allows them to cross the blood-brain barrier. Effective drug transfer and enhanced CNS disease treatment and diagnosis are possible using nanotechnology. Drugs could be altered via nanoengineering to carry out tasks like transferring across the blood-brain barrier, modifying signaling pathways, focusing on certain cells, facilitating efficient gene transfer, and encouraging nerve cell regeneration and preservation.

Transcytosis-Based Renal Tubular Reabsorption of Luminescent Gold Nanoparticles for Enhanced Tumor Imaging.

Transcytosis-based tubular reabsorption of endogenous proteins is a well-known energy-saving pathway that prevents nutrient loss. However, utilization of this well-known reabsorption pathway for the delivery of exogenous nanodrugs remains a challenge. In this study, using the surface mimic strategy of a specific PEPT1/2-targeted Gly-Sar peptide as a ligand, renal-clearable luminescent gold nanoparticles (P-AuNPs) were developed as protein mimics to investigate the transcytosis-based tubular reabsorption of exogenous substances. By regulating the influential factors (H+ content in tubular lumens and PEPT1/2 transporter counts in tubular cells) of Gly-Sar-mediated transcytosis, the specific and efficient interaction between P-AuNPs and renal tubular cells was demonstrated both in vitro and in vivo. Efficient transcellular transportation significantly guided the reabsorption of P-AuNPs back into the bloodstream, which enhanced the blood concentration and bioavailability of nanoparticles, contributing to high-contrast tumor imaging.

Transcytosis‐Based Renal Tubular Reabsorption of Luminescent Gold Nanoparticles for Enhanced Tumor Imaging

AbstractTranscytosis‐based tubular reabsorption of endogenous proteins is a well‐known energy‐saving pathway that prevents nutrient loss. However, utilization of this well‐known reabsorption pathway for the delivery of exogenous nanodrugs remains a challenge. In this study, using the surface mimic strategy of a specific PEPT1/2‐targeted Gly−Sar peptide as a ligand, renal‐clearable luminescent gold nanoparticles (P−AuNPs) were developed as protein mimics to investigate the transcytosis‐based tubular reabsorption of exogenous substances. By regulating the influential factors (H+ content in tubular lumens and PEPT1/2 transporter counts in tubular cells) of Gly−Sar‐mediated transcytosis, the specific and efficient interaction between P−AuNPs and renal tubular cells was demonstrated both in vitro and in vivo. Efficient transcellular transportation significantly guided the reabsorption of P−AuNPs back into the bloodstream, which enhanced the blood concentration and bioavailability of nanoparticles, contributing to high‐contrast tumor imaging.

Study of Drug Delivery Using Purely Organic Macrocyclic Containers-Cucurbit[7]uril and Pillararene.

An impaired immune system is the root of various human ailments provoking the urge to find vehicle-mediated quick delivery of small drug molecules and other vital metabolites to specific tissues and organs. Thus, drug delivery strategies are in need of improvement in therapeutic efficacy. It can be achieved only by increasing the drug-loading capacity, increasing the sustained release of a drug to its target site, easy relocation of drug molecules associated with facile complexation-induced properties of molecular vehicles, and high stimuli-responsive drug administration. Supramolecular drug delivery systems (SDDS) provide a much needed robust yet facile platform for fabricating innovative drug nanocarriers assembled by thermodynamically noncovalent interaction with the tunable framework and above-mentioned properties. Measures of cytotoxicity and biocompatibility are the two main criteria that lie at the root of any promising medicinal applications. This Review features significant advancements in (i) supramolecular host-guest complexation using cucurbit[7]uril (CB[7]), (ii) encapsulation of the drug and its delivery application tailored for CB[7], (iii) self-assembly of supramolecular amphiphiles, (iv) supramolecular guest relay using host-protein nanocavities, (v) pillararene (a unique macrocyclic host)-mediated SDDS for the delivery of smart nanodrugs for siRNA, fluorescent molecules, and insulin for juvenile diabetes. Furthermore, fundamental questions and future hurdles related to smart SDDS based on CB[7] and pillararenes and their future promising breakthrough implementations are also distinctly outlined in this Review.

Fully Active Delivery of Nanodrugs In Vivo via Remote Optical Manipulation.

The active delivery of nanodrugs has been a bottleneck problem in nanomedicine. While modification of nanodrugs with targeting agents can enhance their retention at the lesion location, the transportation of nanodrugs in the circulation system is still a passive process. The navigation of nanodrugs with external forces such as magnetic field has been shown to be effective for active delivery, but the existing techniques are limited to specific materials like magnetic nanoparticles. In this study, an alternative actuation method is proposed based on optical manipulation for remote navigation of nanodrugs in vivo, which is compatible with most of the common drug carriers and exhibits significantly higher manipulation precision. By the programmable scanning of the laser beam, the motion trajectory and velocity of the nanodrugs can be precisely controlled in real time, making it possible for intelligent drug delivery, such as inverse-flow transportation, selective entry into specific vascular branch, and dynamic circumvention across obstacles. In addition, the controlled mass delivery of nanodrugs can be realized through indirect actuation by the microflow field. The developed optical manipulation method provides a new solution for the active delivery of nanodrugs, with promising potential for the treatment of blood diseases such as leukemia and thrombosis.

Enhancing Efficacy of Albumin-Bound Paclitaxel for Human Lung and Colorectal Cancers through Autophagy Receptor Sequestosome 1 (SQSTM1)/p62-Mediated Nanodrug Delivery and Cancer therapy.

Selective autophagy is a defense mechanism by which foreign pathogens and abnormal substances are processed to maintain cellular homeostasis. Sequestosome 1 (SQSTM1)/p62, a vital selective autophagy receptor, recruits ubiquitinated cargo to form autophagosomes for lysosomal degradation. Nab-PTX is an albumin-bound paclitaxel nanoparticle used in clinical cancer therapy. However, the role of SQSTM1 in regulating the delivery and efficacy of nanodrugs remains unclear. Here we showed that SQSTM1 plays a crucial role in Nab-PTX drug delivery and efficacy in human lung and colorectal cancers. Nab-PTX induces SQSTM1 phosphorylation at Ser403, which facilitates its incorporation into the selective autophagy of nanoparticles, known as nanoparticulophagy. Nab-PTX increased LC3-II protein expression, which triggered autophagosome formation. SQSTM1 enhanced Nab-PTX recognition to form autophagosomes, which were delivered to lysosomes for albumin degradation, thereby releasing PTX to induce mitotic catastrophe and apoptosis. Knockout of SQSTM1 downregulated Nab-PTX-induced mitotic catastrophe, apoptosis, and tumor inhibition in vitro and in vivo and inhibited Nab-PTX-induced caspase 3 activation via a p53-independent pathway. Ectopic expression of SQSTM1 by transfection of an SQSTM1-GFP vector restored the drug efficacy of Nab-PTX. Importantly, SQSTM1 is highly expressed in advanced lung and colorectal tumors and is associated with poor overall survival in clinical patients. Targeting SQSTM1 may provide an important strategy to improve nanodrug efficacy in clinical cancer therapy. This study demonstrates the enhanced efficacy of Nab-PTX for human lung and colorectal cancers via SQSTM1-mediated nanodrug delivery.

NIR-activated acid-response “four-in-one” nanomotor for photothermal therapy, chemodynamic therapy and hypoxic-activated chemotherapy

The dense extracellular matrix (ECM) and internal fluid pressure (IFP) seriously alter the effective delivery of nanodrugs in tumour tissue. In order to solve this problem, a photothermal driven nanomotor was designed (PB@ZIF-8@TPZ, PZT), performing the function of “four in one” on the premise of minimum composition. The nanomotor can simultaneously realise PTT/CDT/hypoxia-activation-CT, GSH consumption and photothermal-driven, among which prussian blue (PB) was first found to be able to simultaneously realise photothermal-driven, GSH consumption and PTT/CDT’s “four in one” function. Nanomotor has the advantages of good stability, low cost, easy synthesis, excellent ability for deep puncture and a high anti-tumour effect.

Photothermally driven degradable nanomissile for single-wavelength phototherapy and hypoxia-activated chemotherapy

Viscous tumour tissue seriously affects the effective delivery of nanodrugs and reduces their anti-tumour effect. In order to solve this problem, a nanomotor (Cy7@ZIF-8@TPZ) for penetrating tumour tissue was synthesized. A new amphiphilic molecule Cy7 was designed and synthesized to wrap ZIF-8 loaded with TPZ to obtain the final nanomotor. The synthesized Cy7 can not only realize photodynamic therapy (PDT) and photothermal therapy (PTT) simultaneously under single-wavelength illumination, but also promote the movement of nanoparticles through thermal drive. Through the targeting ability of Cy7 and the enhanced permeability and retention (EPR) effect, the nanomotor can conduct directional deep puncture under illumination. The oxygen continuously consumed by PDT further activates hypoxia-activated chemotherapy, and the combined PTT/PDT/hypoxia-activated CT therapy greatly enhances the anti-tumour efficacy of Cy7@ZIF-8@TPZ. In addition, light-degradable Cy7, acid-degraded ZIF-8 and hypoxia-activated TPZ greatly reduce the side effects of nanomotors.

Hsp70-Targeting and Size-Tunable Nanoparticles Combine with PD-1 Checkpoint Blockade to Treat Glioma.

Invasive glioma usually disrupts the integrity of the blood-brain barrier (BBB), making the delivery of nanodrugs across the BBB possible, but sufficient targeting ability is still avidly needed to improve drug accumulation in glioma. Membrane-bound heat shock protein 70 (Hsp70) is expressed on the membrane of glioma cells rather than adjacent normal cells, therefore it can serve as a specific glioma target. Meanwhile, prolonging the retention in tumors is important for active-targeting nanoparticles to overcome receptor-binding barriers. Herein, the Hsp70-targeting and acid-triggered self-assembled gold nanoparticles (D-A-DA/TPP) are proposed to realize selective delivery of doxorubicin (DOX) to glioma. In the weakly acidic glioma matrix, D-A-DA/TPP formed aggregates to prolong retention, improve receptor-binding efficiency and facilitate acid-responsive DOX release. DOX accumulation in glioma induced immunogenic cell death (ICD) to promote antigen presentation. Meanwhile, combination with the PD-1 checkpoint blockade further activate T cells and provokes robust anti-tumor immunity. The results showed that D-A-DA/TPP can induce more glioma apoptosis. Furthermore, in vivo studies indicated D-A-DA/TPP plus PD-1 checkpoint blockade significantly improved median survival time. This study offeres a potential nanocarrier combining size-tunable strategy with active targeting ability to increase drug enrichment in glioma and synergizes with PD-1 checkpoint blockade to achieve chemo-immunotherapy.

CAR-neutrophil mediated delivery of tumor-microenvironment responsive nanodrugs for glioblastoma chemo-immunotherapy

Glioblastoma (GBM) is one of the most aggressive and lethal solid tumors in human. While efficacious therapeutics, such as emerging chimeric antigen receptor (CAR)-T cells and chemotherapeutics, have been developed to treat various cancers, their effectiveness in GBM treatment has been hindered largely by the blood-brain barrier and blood-brain-tumor barriers. Human neutrophils effectively cross physiological barriers and display effector immunity against pathogens but the short lifespan and resistance to genome editing of primary neutrophils have limited their broad application in immunotherapy. Here we genetically engineer human pluripotent stem cells with CRISPR/Cas9-mediated gene knock-in to express various anti-GBM CAR constructs with T-specific CD3ζ or neutrophil-specific γ-signaling domains. CAR-neutrophils with the best anti-tumor activity are produced to specifically and noninvasively deliver and release tumor microenvironment-responsive nanodrugs to target GBM without the need to induce additional inflammation at the tumor sites. This combinatory chemo-immunotherapy exhibits superior and specific anti-GBM activities, reduces off-target drug delivery and prolongs lifespan in female tumor-bearing mice. Together, this biomimetic CAR-neutrophil drug delivery system is a safe, potent and versatile platform for treating GBM and possibly other devastating diseases.

Phased array ultrasound enhanced delivery of nano drugs for tendon adhesion treatment

IntroductionOver the decades, tendon adhesion has become a major health problem threatening the rehabilitation of patients after tendon surgery. Injury of the flexor tendon leads to rupture of the synovial sheath, which causes tendon exposure and adhesion with subcutaneous tissue. Current conservative therapies can promote chronic healing of tendon adhesion but have mixed success rates. ObjectivesTo reduce the degree of tendon adhesion, the need for a new non-invasive and accurate treatment method is substantial. MethodsA concave spherical ultrasonic phased array was fabricated by a fast 3D printing method. We generated a set of delayed square wave pulse sequences by Field Programmable Gate Arrays (FPGA) to excite the ultrasonic array, creating an ultrasonic focal area. Then we put flexor tendon phantoms, which were constructed by chitosan hydrogel and fibrous membrane using electrospinning, into the preset focal region and injected nano drugs in them. Finally, we measured the pulling force of tendon phantoms with a tensile tester. ResultsThe pulling force of three experimental groups were measured by a tensile tester. Compared to the “untreated group” (0.96 N), the phantom pulling force of the “ultrasound + drug group” is 0.15 N, which is reduced by 85%. Furthermore, with the driving voltage increased from 5 V to 20 V, the pulling force can be reduced by 60%; with the duty ratio increased from 20% to 60%, the pulling force can be reduced by 50%; with treatment time increased from 1 min to 5 min, the pulling force can be reduced by 64%. ConclusionUtilizing an ultrasonic array combined with nano drugs, our phase compensation control method can reduce the degree of tendon adhesion and hold a great implication for applications of rehabilitation treatment for postoperative patients.

Selective Enhancing Blood Flow in Solid Tumor Tissue Is the Key for Achieving Satisfactory Delivery and Therapeutic Outcome of Nanodrugs via the EPR Effect

The enhanced permeability and retention effect (EPR effect) is a crucial phenomenon for understanding the pathophysiological characteristics of blood vasculature and microenvironments in solid tumors. It is also an essential concept for designing anticancer drugs that can be selectively delivered into tumor tissue via the unique extravasation and retention mechanism for macromolecular drugs. As tumor vasculature is highly heterogeneous, the intensities of the EPR effect vary according to the types and locations of solid tumors in different species. However, the EPR effect is universally observed in a broad spectrum of solid tumors in human cancer as well as experimental animal tumor models. The matter is how to utilize the EPR effect for drug design and clinical application. Many hypotheses were proposed and tested to enhance the EPR effect in solid tumors in order to increase the efficacy of drug delivery. However, we should focus on increasing the blood flow in tumors so that more drugs can be perfused and accumulated inside tumor tissue and execute anticancer activities. Angiotensin II co-administration and the approach of intratumor arterial infusion should be considered to achieve selective tumor tissue perfusion for nanodrugs.

Large-Volume Focused-Ultrasound Mild Hyperthermia for Improving Blood-Brain Tumor Barrier Permeability Application.

Mild hyperthermia can locally enhance permeability of the blood-tumor barrier in brain tumors, improving delivery of antitumor nanodrugs. However, a clinical transcranial focused ultrasound (FUS) system does not provide this modality yet. The study aimed at the development of the transcranial FUS technique dedicated for large-volume mild hyperthermia in the brain. Acoustic pressure, multiple-foci, temperature and thermal dose induced by FUS were simulated in the brain through the skull. A 1-MHz, 114-element, spherical helmet transducer was fabricated to verify large-volume hyperthermia in the phantom. The simulated results showed that two foci were simultaneously formed at (2, 0, 0) and (−2, 0, 0) and at (0, 2, 0) and (0, −2, 0), using the phases of focusing pattern 1 and the phases of focusing pattern 2, respectively. Switching two focusing patterns at 5 Hz produced a hyperthermic zone with an ellipsoid of 7 mm × 6 mm × 11 mm in the brain and the temperature was 41–45 °C in the ellipsoid as the maximum intensity was 150 W/cm2 and sonication time was 3 min. The phased array driven by switching two mode phases generated a 41 °C-contour region of 10 ± 1 mm × 8 ± 2 mm × 13 ± 2 mm in the phantom after 3-min sonication. Therefore, we have demonstrated our developed FUS technique for large-volume mild hyperthermia.

Cancer cells targeting with genetically engineered constructs based on a pH-dependent membrane insertion peptide and fluorescent protein

The targeted delivery of nanodrugs to malignant neoplasm is one of the most pressing challenges in the development of modern medicine. It was reported earlier that a bacteriorhodopsin-derived pH low insertion peptide (pHLIP) targets acidic tumors and has the ability to translocate low molecular weight cargoes across the cancer cell membrane. Here, to better understand the potential of pHLIP-related technologies, we used genetically engineered fluorescent protein (EGFP) as a model protein cargo and examined targeting efficiencies of EGFP-pHLIP hybrid constructs in vitro with the HeLa cell line at different pHs. By two independent monitoring methods we observed an increased binding affinity of EGFP-pHLIP fusions to HeLa cells at pH below 6.8. Confocal images of EGFP-pHLIP-treated cells showed bright fluorescence associated with the cell membrane and fluorescent dots localized inside the cell, that became brighter with time. To elucidate the pHLIP-mediated EGFP cell entry mechanisms, we performed a series of experiments with specific inhibitors of endocytosis. Our results imply that EGFP-pHLIP internalization is realized by endocytosis of various types.

Using Intralipid to Improve Delivery of Anti-Cancer Nanodrugs: Effects on RES Clearance and Toxi city, EPR, and Immune Modulation

Encapsulation of therapeutic molecules (e.g., small molecule inhibitors, mRNA, siRNA, aptamers, etc.) into nanomaterials can improve the solubility and blood circulation of the drugs, alter their biodistribution, decrease their toxicities, overcome drug resistance, and facilitate their entry into target cells [1]. The development of anti-cancer nanodrugs has been the focus of intense study for decades. Several anti-cancer nanodrugs have been approved for clinical use all over the world [2]. These have contributed greatly to a lower death rate from some cancers, and thus are widely used. However, an extensive analysis of anti-cancer nanodrugs found an extremely low efficiency of delivery to the tumor, i.e., less than 1% [2]. This is obviously very wasteful and contributes greatly to the increasing cost of health care [1]. To date, most nanodrugs have been focused on cancer research, but the techniques have been translated for many other applications, e.g., vaccines, cardiovascular disease, and neuropathy disease [3-6].

Preparation and Cytotoxic Effect of Pterocarpus santalinus Selenium Based Mouthwash

Introduction: A mouthwash or rinse cannot replace the regular oral hygiene routine of twice-daily tooth brushing and daily flossing.A mouthwash or rinse freshen breath, and control the bad breath.A mouthwash is a medicated liquid which is held in the mouth and swished by the action of perioral musculature to eliminate the oral pathogens.The medicinal plants have their application in pharmaceutical, cosmetic, agricultural and food industries.Medicinal plants act as a natural source for bioactive medicinal compounds.Selenium is a vita micronutrient that has excellent antimicrobial, anti cancerous, antidiabetic, and anti-inflammatory properties.The biological method of synthesis of Selenium nanoparticles has extensive application in the field of biomedicine due to low toxicity, targeted delivery of Nano drugs and stability.
 Materials and Methods: Pterocarpus santalinus plant extract and mouthwash was prepared and cytotoxicity activity was performed.
 Results: On day 1 all the 10 nauplii were alive in all the concentrations. On day 2 when the concentration was 5, 10, 20, 40,80, control the number of live nauplii was 10,8,8,8,7,10 respectively.Results were tabulated and graphically analyzed in SPSS software. Correlation analysis was done using SPSS software.
 Conclusion: Increased concentration of selenium nanoparticles was not toxic to living nauplii as it did not cause the death of it.But the Pterocarpus santalinus extraction based selenium nanoparticles have less to no cytotoxicity.This study shows that mouth rinses from medicinal plants as a source of an excellent alternative with less common side-effects to chemical-based oral antimicrobial products.

Improving Pulmonary Nanotherapeutics Using Helical Aerosol Streams: An In Silico Study.

The increasing prevalence of pulmonary ailments including asthma, chronic obstructive pulmonary disorder, lung tuberculosis, and lung cancer, coupled with the success of pulmonary therapy, has led to a plethora of scientific research focusing on improving the efficacy of pulmonary drug delivery systems. Recent advances in nanoscience and nano-engineering help achieve this by developing stable, potent, inhalable nanosize drug formulations that potentially increase dosages at target sites with significant therapeutic effects. In this study, we numerically analyze a novel methodology of incorporating helical air-nanoparticle streams for pulmonary nanotherapeutics, using a customized version of the open-source computational fluid dynamics (CFD) toolbox openfoam. As nanoparticles predominantly follow streamlines, helical airflow transports them in a centralized core along the human upper respiratory tract, thereby minimizing deposition and hence waste on the oropharyngeal walls, potentially also reducing the risk of drug-induced toxicity in healthy tissues. Advancing our previous study on micron-particle dynamics, helical streams are shown to improve the delivery of nanodrugs, to deeper lung regions when compared to a purely axial fluid-particle jet. For example, an optimal helical stream featuring a volumetric flow rate of 30 L/min, increased the delivery of 300-nm particles to regions beyond generation 3 by 5%, in comparison to a conventional axial jet. Results from regional deposition studies are presented to demonstrate the robustness of helical flows in pulmonary drug delivery, thus paving the way toward successful implementation of the novel methodology in nanotherapeutics.

Mesenchymal stromal cells mediated delivery of photoactive nanoparticles inhibits osteosarcoma growth in vitro and in a murine in vivo ectopic model

BackgroundOsteosarcoma (OS) is an aggressive malignant neoplasm that still suffers from poor prognosis in the case of distal metastases or occurrence of multi-drug resistance. It is therefore crucial to find novel therapeutic options able to go beyond these limitations and improve patients’ survival. The objective of this study is to exploit the intrinsic properties of mesenchymal stromal cells (MSCs) to migrate and infiltrate the tumor stroma to specifically deliver therapeutic agents directly to cancer cells. In particular, we aimed to test the efficacy of the photoactivation of MSCs loaded with nanoparticles in vitro and in a murine in vivo ectopic osteosarcoma model.MethodsAlPcS4@FNPs were produced by adding tetra-sulfonated aluminum phthalocyanine (AlPcS4) to an aqueous solution of positively charged poly-methyl methacrylate core-shell fluorescent nanoparticles (FNPs). The photodynamic therapy (PDT) effect is achieved by activation of the photosensitizer AlPcS4 in the near-infrared light with an LED source. Human MSCs were isolated from the bone marrow of five donors to account for inter-patients variability and used in this study after being evaluated for their clonogenicity, multipotency and immunophenotypic profile. MSC lines were then tested for the ability to internalize and retain the nanoparticles, along with their migratory properties in vitro. Photoactivation effect was evaluated both in a monolayer (2D) co-culture of AlPcS4@FNPs loaded MSCs with human OS cells (SaOS-2) and in tridimensional (3D) multicellular spheroids (AlPcS4@FNPs loaded MSCs with human OS cells, MG-63). Cell death was assessed by AnnexinV/PI and Live&Dead CalceinAM/EthD staining in 2D, while in the 3D co-culture, the cell killing effect was measured through ATP content, CalceinAM/EthD staining and TEM imaging. We also evaluated the effectiveness of AlPcS4@FNPs loaded MSCs as delivery systems and the ability of the photodynamic treatment to kill cancer cells in a subcutaneous mouse model of OS by bioluminescence imaging (BLI) and histology.ResultsMSCs internalized AlPcS4@FNPs without losing or altering their motility and viability in vitro. Photoactivation of AlPcS4@FNPs loaded MSCs induced high level of OS cells death in the 2D co-culture. Similarly, in the 3D co-culture (MSCs:OS ratios 1:1 or 1:3), a substantial decrease of both MSCs and OS cells viability was observed. Notably, when increasing the MSCs:OS ratio to 1:7, photoactivation still caused more than 40% cells death. When tested in an in vivo ectopic OS model, AlPcS4@FNPs loaded MSCs were able to decrease OS growth by 68% after two cycles of photoactivation.ConclusionsOur findings demonstrate that MSCs can deliver functional photosensitizer-decorated nanoparticles in vitro and in vivo and inhibit OS tumor growth. MSCs may be an effective platform for the targeted delivery of therapeutic nanodrugs in a clinical scenario, alone or in combination with other osteosarcoma treatment modalities.

Co-Administration Of iRGD Enhances Tumor-Targeted Delivery And Anti-Tumor Effects Of Paclitaxel-Loaded PLGA Nanoparticles For Colorectal Cancer Treatment.

BackgroundNanoparticles exhibit great promise for improving the solubility and tissue-specific distribution of chemotherapeutic agents; however, the passive and highly variable enhanced permeability and retention (EPR) effects observed in tumors frequently leads to insufficient delivery of nanodrugs into tumors. The tumor-penetrating peptide iRGD can actively enhance tumor-selective delivery of nanoparticles into tumors by binding to integrin and interacting with tissue-penetrating receptor neuropilin-1.Materials and methodsTo improve colorectal cancer treatment, in this study, we prepared a paclitaxel (PTX)-loaded PLGA nanoparticle (PLGA-PTX) and evaluated its tumor-targeting and antitumor activity by co-administration with iRGD.ResultsCompared to free PTX, encapsulated PTX retained preferential cytotoxicity toward various colorectal cancer cells while effectively sparing healthy cells. PLGA-PTX treatment resulted in cell cycle arrest at the G2/M phase and apoptosis, leading to inhibition of cancer cell migration and invasion. PLGA-PTX combined with iRGD displayed little enhancement of cytotoxicity in vitro. Despite this, iRGD receptors integrin and neuropilin-1 were found to be primarily overexpressed on abundant tumor vessels in mice bearing colorectal tumors. Consequently, co-administration of nanoparticles with iRGD promoted the selective delivery of nanoparticles into tumor tissues in vivo. Additionally, the combined regimen enhanced the antitumor effects compared to those of each individual reagent.ConclusionOur findings suggest that PLGA nanoparticles combined with the iRGD peptide provide a promising drug delivery strategy for facilitating active drug accumulation into tumors, given that iRGD receptors are overexpressed on tumor vessels. This co-administration system lacking covalent conjugation provides a more convenient means to combine various therapeutic agents with iRGD to achieve personalized nanotherapy.

Augmentation of EPR Effect and Efficacy of Anticancer Nanomedicine by Carbon Monoxide Generating Agents.

One obstacle to the successful delivery of nanodrugs into solid tumors is the heterogeneity of an enhanced permeability and retention (EPR) effect as a result of occluded or embolized tumor blood vessels. Therefore, the augmentation of the EPR effect is critical for satisfactory anticancer nanomedicine. In this study, we focused on one vascular mediator involved in the EPR effect, carbon monoxide (CO), and utilized two CO generating agents, one is an extrinsic CO donor (SMA/CORM2 micelle) and another is an inducer of endogenous CO generation via heme oxygenase-1 (HO-1) induction that is carried out using pegylated hemin. Both agents generated CO selectively in solid tumors, which resulted in an enhanced EPR effect and a two- to three-folds increased tumor accumulation of nanodrugs. An increase in drug accumulation in the normal tissue did not occur with the treatment of CO generators. In vivo imaging also clearly indicated a more intensified fluorescence of macromolecular nanoprobe in solid tumors when combined with these CO generators. Consequently, the combination of CO generators with anticancer nanodrugs resulted in an increased anticancer effect in the different transplanted solid tumor models. These findings strongly warrant the potential application of these CO generators as EPR enhancers in order to enhance tumor detection and therapy using nanodrugs.