Blood Circulation Time Research Articles

Immune-stealth VP28-conjugated heparin nanoparticles for enhanced and reversible anticoagulation

Heparins are a family of sulfated linear negatively charged polysaccharides that have been widely used for their anticoagulant, antithrombotic, antitumor, anti-inflammatory, and antiviral properties. Additionally, it has been used for acute cerebral infarction relief as well as other pharmacological actions. However, heparin’s self-aggregated macrocomplex may reduce blood circulation time and induce life-threatening thrombocytopenia (HIT) complicating the use of heparins. Nonetheless, the conjugation of heparin to immuno-stealth biomolecules may overcome these obstacles. An immunostealth recombinant viral capsid protein (VP28) was expressed and conjugated with heparin to form a novel nanoparticle (VP28-heparin). VP28-heparin was characterized and tested to determine its immunogenicity, anticoagulation properties, effects on total platelet count, and risk of inducing HIT in animal models. The synthesized VP28-heparin trimeric nanoparticle was non-immunogenic, possessed an average hydrodynamic size (8.81 ± 0.58 nm) optimal for the evasion renal filtration and reticuloendothelial system uptake (hence prolonging circulating half-life). Additionally, VP28-heparin did not induce mouse death or reduce blood platelet count when administered at a high dose in vivo (hence reducing HIT risks). The VP28-heparin nanoparticle also exhibited superior anticoagulation properties (2.2× higher prothrombin time) and comparable activated partial thromboplastin time, but longer anticoagulation period when compared to unfractionated heparin. The anticoagulative effects of the VP28-heparin can also be reversed using protamine sulfate. Thus, VP28-heparin may be an effective and safe heparin derivative for therapeutic use.

Metal organic framework-based variable-size nanoparticles for tumor microenvironment-responsive drug delivery.

Nanoparticles (NPs) have been designed for the treatment of tumors increasingly. However, the drawbacks of single-size NPs are still worth noting, as their circulation and metabolism in the blood are negatively correlated with their accumulation at the tumor site. If the size of single-size NPs is too small, it will be quickly cleared in the blood circulation, while, the size is too large, the distribution of NPs in the tumor site will be reduced, and the widespread distribution of NPs throughout the body will cause systemic toxicity. Therefore, a class of variable-size NPs with metal organic frameworks (MOFs) as the main carrier, and size conversion in compliance with the characteristics of the tumor microenvironment (TME), was designed. MOF-based variable-size NPs can simultaneously extend the time of blood circulation and metabolism, then enhance the targeting ability of the tumor site. In this review, MOF NPs are categorized and exemplified from a new perspective of NP size variation; the advantages, mechanisms, and significance of MOF-based variable-size NPs were summarized, and the potential and challenges in delivering anti-tumor drugs and multimodal combination therapy were discussed.

Curcumin-conjugated Nanoparticles: An Approach to Target Mitochondria

Background: Unconjugated nanoparticles used in the treatment of cancer and various metabolic and neurodegenerative disorders exhibit extended blood circulation time, inhibition of enzymatic degradation, and increased chemical stability of the encapsulated therapeutic molecules. However, the unconjugated nanoparticles often show off-target effects and lack of specificity, which limit their applications in the healthcare system. Objective: Curcumin, a polyphenolic compound known for its proficiency to scavenge reactive oxygen species attributed to antioxidant activity and anticancer effects associated with mitochondrial dysfunction, is one of the most effective therapeutic agents. Therefore, with respect to chemotherapeutic strategies, the development of mitochondrial targeting curcumin nanoparticles for target-specific drug delivery has been extensively studied. Conclusion: The present review has focused on diverse curcumin-loaded nanoparticles targeting mitochondria along with their improved delivery potential, enhanced localization and biodistribution profile.

A Biomimetic Multifunctional Nanoframework for Symptom Relief and Restorative Treatment of Acute Liver Failure.

Acute liver failure (ALF) is a rare and serious condition characterized by major hepatocyte death and liver dysfunction. Owing to the limited therapeutic options, this disease generally has a poor prognosis and a high mortality rate. When ALF cannot be reversed by medications, liver transplantation is often needed. However, transplant rejection and the shortage of donor organs still remain major challenges. Most recently, stem cell therapy has emerged as a promising alternative for the treatment of liver diseases. However, the limited cell delivery routes and poor stability of live cell products have greatly hindered the feasibility and therapeutic efficacy of stem cell therapy. Inspired by the functions of mesenchymal stem cells (MSCs) primarily through the secretion of several factors, we developed an MSC-inspired biomimetic multifunctional nanoframework (MBN) that encapsulates the growth-promoting factors secreted by MSCs via combination with hydrophilic or hydrophobic drugs. The red blood cell (RBC) membrane was coated with the MBN to enhance its immunological tolerance and prolong its circulation time in blood. Importantly, the MBN can respond to the oxidative microenvironment, where it accumulates and degrades to release the payload. In this work, two biomimetic nanoparticles, namely, rhein-encapsulated MBN (RMBN) and N-acetylcysteine (NAC)-encapsulated MBN (NMBN), were designed and synthesized. In lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced and acetaminophen (APAP)-induced ALF mouse models, RMBN and NMBN could effectively target liver lesions, relieve the acute symptoms of ALF, and promote liver cell regeneration by virtue of their strong antioxidative, anti-inflammatory, and regenerative activities. This study demonstrated the feasibility of the use of an MSC-inspired biomimetic nanoframework for treating ALF.

Enzyme-Responsive Modular Peptides Enhance Tumor Penetration of Quantum Dots via Charge Reversal Strategy.

Quantum dots (QDs) are colloidal semiconductor nanoparticles acting as fluorescent probes for detection, disease diagnosis, and photothermal and photodynamic therapy. However, their performance in cancer treatment is limited by inadequate tumor accumulation and penetration due to the larger size of nanoparticles compared to small molecules. To address this challenge, charge reversal nanoparticles offer an effective strategy to prolong blood circulation time and achieve enhanced endocytosis and tumor penetration. In this study, we leveraged the overexpressed γ-glutamyl transpeptidase (GGT) in many human tumors and developed a library of modular peptides to serve as water-soluble surface ligands of QDs. We successfully transferred the QDs from the organic phase to the aqueous phase within 5 min. And through systematic tuning of the peptide sequence, we optimized the fluorescent stability of QDs and their charge reversal behavior in response to GGT. The resulting optimal peptide stabilized QDs in aqueous solution with a high fluorescent retention rate of 93% after three months and realized the surface charge reversal of QDs triggered by GGT in vitro. The binding between the peptide and QD surface was investigated by using saturation transfer differential nuclear magnetic resonance (STD NMR). Thanks to its charge reversal ability, the GGT-responsive QDs exhibited enhanced cellular uptake in GGT-expressing cancer cells and deeper penetration in the 3D multicellular spheroids. This enzyme-responsive modular peptide can lead to specific tumor targeting and deeper tumor penetration, holding great promise to enhance the treatment efficacy of QD-based theranostics.

Twins‐like nanodrugs synchronously transport in blood and coalesce inside tumors for sensitive ultrasound imaging and triggerable penetrative drug delivery

AbstractNanodrugs capable of aggregating in the tumor microenvironment (TME) have demonstrated great efficiency in improving the therapeutic outcome. Among various approaches, the strategy utilizing electrostatic interaction as a driving force to achieve intratumor aggregation of nanodrugs has attracted great attention. However, the great difference between the two nanodrugs with varied physicochemical properties makes their synchronous transport in blood circulation and equal‐opportunity tumor uptake impossible, which significantly detracts from the beneficial effects of nanodrug aggregation inside tumors. We herein propose a new strategy to construct a pair of extremely similar nanodrugs, referred to as “twins‐like nanodrugs (TLNs)”, which have identical physicochemical properties including the same morphology, size, and electroneutrality to render them the same blood circulation time and tumor entrance. The 1:1 mixture of TLNs (TLNs‐Mix) intravenously injected into a mouse model efficiently accumulates in tumor sites and then transfers to oppositely charged nanodrugs for electrostatic interaction‐driven coalescence via responding to matrix metalloproteinase‐2 (MMP‐2) enriched in tumor. In addition to enhanced tumor retention, the thus‐formed micron‐sized aggregates show high echo intensity essential for ultrasound imaging as well as ultrasound‐triggered penetrative drug delivery. Owing to their distinctive features, the TLNs‐Mix carrying sonosensitizer, immune adjuvant, and ultrasound contrast agent exert potent sonodynamic immunotherapy against hypovascular hepatoma, demonstrating their great potential in treating solid malignancies.

VISUALIZATION OF NANOPOROUS SILICA NANOPARTICLE DISTRIBUTION FOR IMPLANT-DIRECTED MAGNETIC DRUG TARGETING BY 68GA-LABELING AND PET/CT

In orthopedic surgery, implant infections are a serious issue and difficult to treat. The aim of this study was to use superparamagnetic nanoporous silica nanoparticles (MNPSNP) as candidates for directed drug delivery. Currently, short blood circulation half-life due to interactions with the host's immune system hinder nanoparticles in general from being clinically used. PEGylation is an approach to reduce these interactions and to enhance blood circulation time. The effect of PEGylation of the used 68Ga-labelled MNPSNP on the distribution and implant accumulation was examined by PET/CT imaging and gamma counting in an implant mouse model.Female Balb/c mice (n=24) received a magnetic implant subcutaneously on the left and a titanium implant on the right hind leg. On day one, 12 of these mice received an additional clodronate®-injection for macrophage depletion. On the second postoperative day, mice were anaesthetized and MNPSNP (native or PEGylated) injected intravenously, followed by a dynamic PET-scan over 60 minutes, a CT- and a static PET-scan at 120 min. As control, 12 mice received only 68Ga-MNPSNP (native or PEGylated). Gamma counting of inner organs, urine, blood and implant area was performed as further final analysis. Although PEGylation of the nanoparticles already resulted in lower liver uptakes, both variants of 68Ga-labeled MNPSNP accumulated in liver and spleen. Combination of PEGylation with clodronate®-injection led to a highly significant effect whereas clodronate®-injection alone could not reveal significant differences. In gamma counting, a significantly higher %I.D./g was found for the tissue surrounding the magnetic implants compared to the titanium control, although in a low range. PEGylation and/or clodronate®-injection revealed no significant differences regarding nanoparticle accumulation at the implantation site. PEGylation increases circulation time, but MNPSNP accumulation at the implant site was still insufficient for treatment of infections. Additional efforts have to further increase circulation time and local accumulation.Acknowledgements: This work is funded by the German Research Foundation (DFG, project number 280642759).

Carriers for hydrophobic drug molecules: lipid-coated hollow mesoporous silica particles, and the influence of shape and size on encapsulation efficiency.

Hydrophobic drugs, while designed to interact with specific receptors or enzymes located in lipid-rich cell membranes, often face challenges of limited bioavailability and insufficient circulation time due to their insolubility in aqueous environments. One plausible pathway to increase their blood circulation time is to load these drugs into biocompatible and hydrophilic carriers to enhance their uptake. In this study, mesoporous silica (mSiO2) nanocarriers of various morphologies (including cubes, capsules, and spheres) were synthesized. These nanocarriers were then surface-functionalized with alkyl chain hydrocarbons, specifically octadecyl-trimethoxysilane, (OCH3)3Si(CH2)17CH3, to render them hydrophobic. The resulting nanocarriers (((OCH3)3Si(CH2)17CH3)@mSiO2) showed up to 80% uptake for hydrophobic drugs. However, a significant drawback was observed as most of the drugs were prone to uncontrollable release within 6 h. This challenge of premature drug release was successfully mitigated by effectively sealing the drug-loaded nanocarriers with a pH-sensitive lipid overlayer. The lipid-coated nanocarriers prolonged drug containment and sustained release up to 72 h, compared to 6 h for uncoated nanocarriers, thereby facilitating longer blood circulation times. Moreover, the shape and size of nanocarriers were found to influence both drug entrapment capacity and release behavior with cubic forms exhibiting superior loading capacity due to higher surface area and porosity. Additionally, it was observed that the molecular weight and chemical structure of the drug molecules played a crucial role in determining their uptake and release profiles. Furthermore, the influence of different morphologies of nanocarriers on cell uptake and cytotoxicity in immune cells was elucidated. These findings underscore the importance of nanocarrier morphology and drug properties to enhance loading capacities and controlled release profiles, for designing drug delivery systems tailored for hydrophobic drugs.

Ultrasmall catechol-PEG-anchored ferrite nanoparticles for highly sensitive magnetic resonance angiography.

Highly sensitive iron oxide nanoparticles with stable, safe and efficient surface functionalization, as potential substitutes for gadolinium-based contrast agents (GBCAs) with increasing biosafety concerns, exhibit great potential for high-performance magnetic resonance angiography (MRA). Herein, we developed ultrasmall catechol-PEG-anchored ferrite nanoparticles (PEG-UMFNPs) for highly sensitive MRA. The obtained nanoprobe has a high T1 relaxivity value (7.2 mM-1 s-1) due to its ultrasmall size and Mn doping. It has a suitable hydrodynamic size of 20 nm, which prevents rapid vascular extravasation and renal clearance and prolongs its blood circulation time. In vivo MRA at 3.0 T using the nanoprobe shows that the arteries and veins of rats, even blood vessels as small as 0.32 mm, are distinctly visible, and the contrast enhancement can last for at least 1 h. In addition, due to the outstanding contrast enhancement and long circulation time, the stenosis and recanalization process of the rat's carotid artery can be continuously monitored with a single injection of the nanoprobe. Our study indicates that PEG-UMFNPs are outstanding MR imaging nanoprobes that can be used to diagnose vascular diseases without the biosafety issues of GBCAs.

Introduction of a fatty acid chain modification to prolong circulatory half-life of a radioligand towards glucose-dependent insulinotropic polypeptide receptor

BackgroundThe beneficial role of glucose-dependent insulinotropic polypeptide receptor (GIPR) in weight control and maintaining glucose levels has led to the development of several multi-agonistic peptide drug candidates, targeting GIPR and glucagon like peptide 1 receptor (GLP1R) and/or the glucagon receptor (GCGR). The in vivo quantification of target occupancy by these drugs would accelerate the development of new drug candidates. The aim of this study was to evaluate a novel peptide (GIP1234), based on previously reported ligand DOTA-GIP-C803, modified with a fatty acid moiety to prolong its blood circulation. It would allow higher target tissue exposure and consequently improved peptide uptake as well as in vivo PET imaging and quantification of GIPR occupancy by novel drugs of interest. MethodA 40 amino acid residue peptide (GIP1234) was synthesized based on DOTA-GIP-C803, in turn based on the sequences of endogenous GIP and Exendin-4 with specific amino acid modifications to obtain GIPR selectivity. A palmitoyl fatty acid chain was furthermore added at Lys14 via a glutamic acid linker to prolong its blood circulation time by the interaction with albumin. GIP1234 was conjugated with a DOTA chelator at the C-terminal cysteine residue to achieve 68Ga radiolabeling. The resulting PET probe, [68Ga]Ga-DOTA-GIP1234 was evaluated for receptor binding specificity and selectivity using HEK293 cells transfected with human GIPR, GLP1R, or GCGR. Blocking experiments with tirzepatide (2 μM) were conducted using huGIPR HEK293 cells to investigate binding specificity. Ex vivo and in vivo organ distribution of [68Ga]Ga-DOTA-GIP1234 was studied in rats and a pig in comparison to [68Ga]Ga-DOTA-C803-GIP. Binding of [68Ga]Ga-DOTA-GIP1234 to albumin was assessed in situ using polyacrylamide gel electrophoresis (PAGE). The stability was tested in formulation buffer and rat blood plasma. Results[68Ga]Ga-DOTA-GIP1234 was synthesized with non-decay corrected radiochemical yield of 88 ± 3.7 % and radiochemical purity of 97.8 ± 0.8 %. The molar activity for the radiotracer was 8.1 ± 1.1 MBq/nmol. [68Ga]Ga-DOTA-GIP1234 was stable and maintained affinity to huGIPR HEK293 cells (dissociation constant (Kd) = 40 ± 12.5 nM). The binding of [68Ga]Ga-DOTA-GIP1234 to huGCGR and huGLP1R cells was insignificant. Pre-incubation of huGIPR HEK293 cell sections with tirzepatide resulted in the decrease of [68Ga]Ga-DOTA-GIP1234 binding by close to 90 %. [68Ga]Ga-DOTA-GIP1234 displayed slow blood clearance in pigs with SUV = 3.5 after 60 min. Blood retention of the tracer in rat was 2-fold higher than that of [68Ga]Ga-DOTA-C803-GIP. [68Ga]Ga-DOTA-GIP1234 also demonstrated strong liver uptake in both pig and rat combined with decreased renal excretion. The concentration dependent binding of [68Ga]Ga-DOTA-GIP1234 to albumin was confirmed in situ by PAGE. Conclusion[68Ga]Ga-DOTA-GIP1234 demonstrated nanomolar affinity and selectivity for huGIPR in vitro. Addition of a fatty acid moiety prolonged blood circulation time and tissue exposure in both rat and pig in vivo. However, the liver uptake was also increased which may make PET imaging of abdominal tissues such as pancreas challenging. The investigation of the influence of fatty acid moiety on the biological performance of the peptide ligand paved the way for further rational design of GIPR ligand analogues with improved characteristics.

Choice of Nanoparticles for Theranostics Engineering: Surface Coating to Nanovalves Approach.

Surface engineered nanoparticles (metallic and nonmetallic) have gained tremendous attention for precise imaging and therapeutics of cell/tumors at molecular and anatomic levels. These tiny agents have shown their specific physicochemical properties for early-stage disease diagnosis and cancer theranostics applications (imaging and therapeutics by a single system). For example, gold nanorods (AuNRs) demonstrate better photothermal response and radiodensity for theranostics applications. However, upon near infrared light exposure these AuNRs lose their optical property which is characteristic of phototherapy of cancer. To overcome this issue, silica coating is a safe choice for nanorods which not only stabilizes them but also provides extra space for cargo loading and makes them multifunctional in cancer theranostics applications. On the other hand, various small molecules have been coated on the surface of nanoparticles (organic, inorganic, and biological) which improve their biocompatibility, blood circulation time, specific biodistribution and tumor binding ability. A few of them have been reached in clinical trials, but, struggling with FDA approval due to engineering and biological barriers. Moreover, nanoparticles also face various challenges of reliability, reproducibility, degradation, tumor entry and exit in translational research. On the other hand, cargo carrier nanoparticles have been facing critical issues of premature leakage of loaded cargo either anticancer drug or imaging probes. Hence, various gate keepers (quantum dots to supramolecules) known nanovalves have been engineered on the pore opening of the cargo systems. Here, a review on the evolution of nanoparticles and their choice for diagnostics and therapeutics applications has been discussed. In this context, basic requirements of multifunctional theranostics design for targeted imaging and therapy have been highlighted and with several challenges. Major hurdles experienced in the surface engineering routes (coating to nanovalves approach) and limitations of the designed theranostics such as poor biocompatibility, low photostability, non-specific targeting, low cargo capacity, poor biodegradation and lower theranostics efficiency are discussed in-depth. The current scenario of theranostics systems and their multifunctional applications have been presented in this article.

Progress in ultrasmall ferrite nanoparticles enhanced T1 magnetic resonance angiography.

Contrast-enhanced magnetic resonance angiography (CE-MRA) plays a critical role in diagnosing and monitoring various vascular diseases. Achieving high-sensitivity detection of vascular abnormalities in CE-MRA depends on the properties of contrast agents. In contrast to clinically used gadolinium-based contrast agents (GBCAs), the new generation of ultrasmall ferrite nanoparticles-based contrast agents have high relaxivity, long blood circulation time, easy surface functionalization, and high biocompatibility, hence showing promising prospects in CE-MRA. This review aims to comprehensively summarize the advancements in ultrasmall ferrite nanoparticles-enhanced MRA for detecting vascular diseases. Additionally, this review also discusses the future clinical translational potential of ultrasmall ferrite nanoparticles-based contrast agents for vascular imaging. By investigating the current status of research and clinical applications, this review attempts to outline the progress, challenges, and future directions of using ultrasmall ferrite nanoparticles to drive the field of CE-MRA into a new frontier of accuracy and diagnostic efficacy.

Recent Progress of Bioinspired Cell Membrane in Cancer Immunotherapy.

By modifying immune cells, immunotherapy can activate immune response to establish long-term immune memory and prevent tumor recurrence. However, their effectiveness is largely constricted by the poor immunogenicity, immune escape, and immune tolerance of the tumor. This is related to the characteristics of the tumor itself, such as genome instability and mutation. The combination of various nanocarriers with tumor immunotherapy is beneficial for overcoming the shortcomings of traditional immunotherapy. Nanocarriers coated by cell membranes can extend blood circulation time, improve ability to evade immune clearance, and enhance targeting, thus significantly enhancing the efficacy of immunotherapy and showing great potential in tumor immunotherapy. This article reviews the application research progress of different types of cell membrane-modified nanocarriers in tumor immunotherapy, immunotherapy combination therapy, and tumor vaccines, and provides prospects for future research.

Dual stimuli-responsive biotinylated polymer-drug conjugate for dual drug delivery.

Stimuli-responsive nanoscale polymer-drug conjugates are one of the most promising alternatives in the realm of advanced therapeutics, rendering several characteristics such as spatio-temporal control over drug release, reduced off-target toxicity, enhanced bioavailability, and longer blood circulation time of the drug. Fostered by the aforementioned conceptualization, our quest to develop an ideal polymer-drug conjugate has originated the present investigation of developing a reactive oxygen species (ROS) and esterase-responsive self-assembled polymer-drug (chlorambucil, CBL) conjugate with biotin pendants (DP2) for cancer cell targeting, surrogating another antineoplastic drug, doxorubicin (DOX) via physical encapsulation (DP2@DOX). The ROS and esterase trigger not only released the covalently stitched CBL but also resulted in DOX release by dismantling the amphiphilic balance of the nanoaggregates. Biotinylation-mediated enhancement of cellular uptake of DP2@DOX was reflected in the synergistic anticancer activity of both the drugs (CBL and DOX) in HeLa cells (biotin receptor-positive cells) compared to HEK 293T cells (biotin receptor-negative cells). Furthermore, the selective internalization of the fluorophore-tagged DOX-loaded polymer (DP4@DOX) in HeLa cells compared to HEK 293T cells was confirmed by confocal microscopy and flow cytometry. In summary, the present investigation demonstrates a state-of-the-art self-assembled polymer-drug conjugate as a next-generation dual stimuli-responsive drug delivery vehicle.

Cell Membrane-Coated Nanoparticles for Dental, Oral, and Craniofacial Diseases.

Dental, oral, and craniofacial diseases can substantially impact the quality of human life, thereby posing a serious public health concern. Although conventional therapies such as surgery have solved these problems largely, the prognosis of patients is not always satisfactory. Cell membrane-coated nanoparticles (CMCNPs) carry nanodrugs with the help of natural cell membranes, therefore utilizing their remarkable ability to interface and interact with their surrounding environment. These nanoparticles have demonstrated substantial advantages in drug targeting, prolonging blood circulation time, penetrating biofilms, and immune escape. With the assistance of CMCNPs, the therapeutic effects of dental, oral, and craniofacial diseases can reach a higher level. CMCNPs have been applied for dental, oral, and craniofacial diseases for various conditions such as head and neck cancer, periodontal disease, and oral biosignal detection. For the therapies of head and neck cancer, CMCNPs have been widely utilized as a tool of chemotherapy, phototherapy, and immunotherapy, while yet to be exploited in imaging technique. In the end, we summarized the challenges and prospectives of CMCNPs for dental, oral, and craniofacial diseases: large-scale production with uniform standards and high quantity, extensive application directions in dental, oral, and craniofacial regions (implant, endodontics), and the promotion of its clinical application.

Microfluidic development and biological evaluation of targeted therapy-loaded biomimetic nano system to improve the metastatic melanoma treatment

Optimizing current therapies is among next steps in metastatic melanoma (MM) treatment landscape. The innovation of this study is the design of production process by microfluidics of cell membrane (CM)-modified nanoparticles (NPs), as an emerging biomimetic platform that allows for reduced immune clearance, long blood circulation time and improved specific tumor targeting. To achieve melanoma selectivity, direct membrane fusion between synthetic liposomes and CMs extracted from MM cell line was performed by microfluidic sonication approach, then the hybrid liposomes were loaded with cobimetinib (Cob) or lenvatinib (Lenva) targeting agents and challenged against MM cell lines and liver cancer cell line to evaluate homotypic targeting and antitumor efficacy. Characterization studies demonstrated the effective fusion of CM with liposome and the high encapsulation efficiency of both drugs, showing the proficiency of microfluidic-based production. By studying the targeting of melanoma cells by hybrid liposomes versus liposomes, we found that both NPs entered cells through endocytosis, whereas the former showed higher selectivity for MM cells from which CM was extracted, with 8-fold higher cellular uptake than liposomes. Hybrid liposome formulation of Cob and Lenva reduced melanoma cells viability to a greater extent than liposomes and free drug and, notably, showed negligible toxicity as demonstrated by bona fide haemolysis test. The CM-modified NPs presented here have the potential to broaden the choice of therapeutic options in MM treatment.

Innovative applications of electrospun nanofibers in cancer research

Cancer, a leading cause of global mortality, has ignited substantial interest in the advancement of chemotherapy drugs. Nonetheless, challenges such as limited blood circulation time, drug instability, and severe side effects have curtailed the effectiveness of conventional treatments. In recent times, the groundbreaking electrospinning technique has ushered in the era of nanofibers imbued with a diverse array of chemotherapeutic agents. This innovation harnesses the potential of natural, synthetic polymers, and composite materials. The resulting nanofibers exhibit a customizable interplay of mechanical, physical, and chemical attributes, thereby facilitating controlled drug release and targeted drug delivery. This, in turn, augments the therapeutic efficacy. This article undertakes a comprehensive journey through the recent strides achieved in the domain of cancer therapy, specifically concerning the utilisation of electrospinning. It delves into a myriad of electrospinning techniques, delving into the materials employed in the creation of nanofibers and the multifaceted properties they exhibit. Furthermore, this review encompasses an expansive exploration of the manifold applications of these nanofibers as potent drug delivery systems within the realm of cancer therapy. These applications span a wide spectrum, ranging from localized chemotherapy to the integration of multiple anticancer drugs, facilitating combinatorial therapies. Additionally, these nanofibers play an instrumental role in cancer cell detection, capture, and isolation, as well as the nuanced manipulation of cancer cell behavior. Furthermore, they are instrumental in constructing intricate cancer models, enabling in-depth studies of metastasis.

Abstract A032: Cell membrane coated- Biomimetic biodegradable nanoparticles for tumor targeted delivery of THP-doxorubicin using polylactic acid based redox responsive polymer

Abstract Chemotherapy is a widely used systemic treatment modality for cancer treatment as it kills the rapidly dividing cells. However, the administered chemo-drugs cause systemic toxicity, have fast degradation rate at physiological conditions hence low bioavailability and poor tumor accumulation. These shortcomings can be mitigated by the use of tumor targeting drug delivery systems. The nanoparticles can further be tailor made according to physiological conditions of the tumor microenvironment. Herein, the redox responsive polymer has been synthesized by introducing the disulphide linkage in the polymer. The drug release profile indicated the release of the drug is more efficient in presence of 10mM Dithiothreitol(reducing agent for disulphide linkage) when compared to 0mM dithiothreitol. In this context, this study investigates the therapeutic efficacy of THP-doxorubicin encapsulated in polylactic acid based redox responsive nanoparticle(NP) whose surface have been modified with tumor (4T1) and macrophage (J774) cell membranes. The coated cell membrane provides advantages such as immune escape, long blood circulation time, specific molecular recognition and cell targeting. The prepared nanoparticles have a hydrodynamic size of 210±10 nm with zeta potential of -30±3 mV. The cellular internalization studies of free drug vs the cell membrane coated NPs (CMNPs) were done and it was confirmed that CMNPs were internalized more efficiently in one hour drug incubation study. The same was confirmed when cancer cell proliferation inhibition assay was done, and half maximal inhibitory concentration of free drug, uncoated NPs and CMNPs were 0.31µM , 0.463µM and 0.137µM respectively. This study provides the synthesis and characterization of redox responsive polymer, preparation of cell membrane coated nanoparticles and in-vitro studies for the same. This study has a future scope in the field of personalized medicine at much cheaper price when compared to active targeting methods by antibodies, CART, proteins etc. Citation Format: Harshdeep Kaur, Harpal Singh, Neetu Singh. Cell membrane coated- Biomimetic biodegradable nanoparticles for tumor targeted delivery of THP-doxorubicin using polylactic acid based redox responsive polymer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A032.

PEGylation Strategy for Improving the Pharmacokinetic and Antitumoral Activity of the IL-2 No-alpha Mutein.

In a previous work, an IL-2Rβγ biased mutant derived from human IL-2 and called IL-2noα, was designed and developed. Greater antitumor effects and lower toxicity were observed compared to native IL-2. Nevertheless, mutein has some disadvantages, such as a very short half-life of about 9-12 min, propensity for aggregation, and solubility problems. In this study, PEGylation was employed to improve the pharmacokinetic and antitumoral properties of the novel protein. Pegylated IL-2noα was characterized by polyacrylamide gel electrophoresis, size exclusion chromatography, in vitro cell proliferation and in vivo cell expansion bioassays, and pharmacokinetic and antitumor studies. IL-2noα-conjugates with polyethylene glycol (PEG) of 1.2 kDa, 20 kDa, and 40 kDa were obtained by classical acylation. No significant changes in the secondary and tertiary structures of the modified protein were detected. A decrease in biological activity in vitro and a significant improvement in half-life were observed, especially for IL-2noα-PEG20K. PEGylation of IL-2noα with PEG20K did not affect the capacity of the mutant to induce preferential expansion of T effector cells over Treg cells. This pegylated IL-2noα exhibited a higher antimetastatic effect compared to unmodified IL-2noα in the B16F0 experimental metastases model, even when administered at lower doses and less frequently. PEG20K was selected as the best modification strategy, to improve the blood circulation time of the IL-2noα with a superior antimetastatic effect achieved with lower doses.

The Influence of PEG Chain Length on the in vivo Tumor Accumulation of Self-assembled Amphiphilic Drug-PEG Polymeric Micelles

The integration of a drug and polyethylene glycol (PEG) into an amphiphilic polymer to form self-assembled micelles with high drug loading for self-delivery to tumors is recently reported, which has showed high clinical availability. However, the effect of PEG chain length on cell internalization efficiency and tumor targeting efficiency in this PEG-drug conjugate micelle self-delivery system has yet to be studied. Herein, pyropheophorbide-a (PhA) was used as a model drug and a fluorescent tracer to synthesize amphiphilic polymers with varying PEG chain lengths, which self-assembled into PhA-PEG2000 NPs and PhA-PEG5000 NPs with high drug loading (21.2% and 9.7%, respectively, according to calculation). The results showed that PhA-PEG2000 NPs had higher cell internalization in vitro than PhA-PEG5000 NPs, but much lower tumor accumulation in vivo than PhA-PEG5000 NPs. This was attributed to the longer in vivo blood circulation time of the latter. Furthermore, the in vitro and in vivo examinations revealed negligible side effects, indicating the intrinsic safety of the micelles. This study provides insight into the influence of PEG chain length on biodistribution of organs and tumor accumulation after intravenous administration of PEG-drug conjugate micelle and guides the design of drug incorporated amphiphilic polymer-based micelles.