Polymer Prodrug Nanoparticles Research Articles

Thermosensitive polymer prodrug nanoparticles prepared by an all-aqueous nanoprecipitation process and application to combination therapy

Despite their great versatility and ease of functionalization, most polymer-based nanocarriers intended for use in drug delivery often face serious limitations that can prevent their clinical translation, such as uncontrolled drug release and off-target toxicity, which mainly originate from the burst release phenomenon. In addition, residual solvents from the formulation process can induce toxicity, alter the physico-chemical and biological properties and can strongly impair further pharmaceutical development. To address these issues, we report polymer prodrug nanoparticles, which are prepared without organic solvents via an all-aqueous formulation process, and provide sustained drug release. This was achieved by the “drug-initiated” synthesis of well-defined copolymer prodrugs exhibiting a lower critical solution temperature (LCST) and based on the anticancer drug gemcitabine (Gem). After screening for different structural parameters, prodrugs based on amphiphilic diblock copolymers were formulated into stable nanoparticles by all-aqueous nanoprecipitation, with rather narrow particle size distribution and average diameters in the 50–80 nm range. They exhibited sustained Gem release in human serum and acetate buffer, rapid cellular uptake and significant cytotoxicity on A549 and Mia PaCa-2 cancer cells. We also demonstrated the versatility of this approach by formulating Gem-based polymer prodrug nanoparticles loaded with doxorubicin (Dox) for combination therapy. The dual-drug nanoparticles exhibited sustained release of Gem in human serum and acidic release of Dox under accelerated pathophysiological conditions. Importantly, they also induced a synergistic effect on triple-negative breast cancer line MDA-MB-231, which is a relevant cell line to this combination.

Tumor-targeted and stimulus-responsive polymeric prodrug nanoparticles to enhance the anticancer therapeutic efficacy of doxorubicin

Polymeric prodrug nanoparticles have gained increasing attention in the field of anticancer drug delivery because of their dual functions as a drug carrier and a therapeutic agent. Doxorubicin (DOX) is a highly effective chemotherapeutic agent for various cancers but causes cardiotoxicity. In this work, we developed polymeric prodrug (pHU) nanoparticles that serve as both a drug carrier of DOX and a therapeutic agent. The composition of pHU includes antiangiogenic hydroxybenzyl alcohol (HBA) and ursodeoxycholic acid (UDCA), covalently incorporated through hydrogen peroxide (H2O2)-responsive peroxalate. To enhance cancer cell specificity, pHU nanoparticles were surface decorated with taurodeoxycholic acid (TUDCA) to facilitate p-selectin-mediated cancer targeting. TUDCA-coated and DOX-loaded pHU nanoparticles (t-pHUDs) exhibited controlled release of DOX triggered by H2O2, characteristic of the tumor microenvironment. t-pHUDs also effectively suppressed cancer cell migration and vascular endothelial growth factor (VEGF) expression in response to H2O2. In animal studies, t-pHUDs exhibited highly potent anticancer activity. Notably, t-pHUDs, with their ability to accumulate preferentially in tumors due to the p-selectin targeting, surpassed the therapeutic efficacy of equivalent DOX and pHU nanoparticles alone. What is more, t-pHUDs significantly suppressed VEGF expression in tumors and mitigated hepato- and cardiotoxicity of DOX. Given their cancer targeting ability, enhanced therapeutic efficacy and minimized off-target toxicity, t-pHUDs present an innovative and targeted approach with great translational potential as an anticancer therapeutic agent.

Coarse‐Grained Model‐Assisted Design of Polymer Prodrug Nanoparticles with Enhanced Cytotoxicity: A Combined Theoretical and Experimental Study

AbstractTo achieve drug release from polymer prodrug nanoparticles, the drug‐polymer linker must be accessible for cleavage to release the drug, which can occur under certain physiological conditions (e.g., presence of specific enzymes). Supramolecular organization of polymer prodrug nanoparticles is crucial as it greatly affects the location of the linker, its surface exposure/solvation and thus its cleavage to release the drug. Since experimental access to these data is not straightforward, new methodologies are critically needed to access this information and to accelerate the development of more effective polymer prodrug nanoparticles, and replace the time‐consuming and resource‐intensive traditional trial‐and‐error strategy. In this context, we reported here the use of a coarse‐grained model to assist the design of polymer prodrug nanoparticles with enhanced cytotoxicity. By choosing the solvent accessible surface area as the critical parameter for predicting drug release and hence cytotoxicity of polymer prodrug nanoparticles, we developed an optimized polymer‐drug linker with enhanced hydrophilicity and solvation. Our hypothesis was then experimentally validated by the synthesis of the corresponding polymer prodrugs based on two different drugs (gemcitabine and paclitaxel), which demonstrated greater performances in terms of drug release and cytotoxicity on two cancer cell lines. Interestingly, our methodology can be easily applied to other polymer prodrug structures, which would contribute to the development of more efficient drug delivery systems via in silico screening.

Coarse-Grained Model-Assisted Design of Polymer Prodrug Nanoparticles with Enhanced Cytotoxicity: A Combined Theoretical and Experimental Study.

To achieve drug release from polymer prodrug nanoparticles, the drug-polymer linker must be accessible for cleavage to release the drug, which can occur under certain physiological conditions (e.g., presence of specific enzymes). Supramolecular organization of polymer prodrug nanoparticles is crucial as it greatly affects the location of the linker, its surface exposure/solvation and thus its cleavage to release the drug. Since experimental access to these data is not straightforward, new methodologies are critically needed to access this information and to accelerate the development of more effective polymer prodrug nanoparticles, and replace the time-consuming and resource-intensive traditional trial-and-error strategy. In this context, we reported here the use of a coarse-grained model to assist the design of polymer prodrug nanoparticles with enhanced cytotoxicity. By choosing the solvent accessible surface area as the critical parameter for predicting drug release and hence cytotoxicity of polymer prodrug nanoparticles, we developed an optimized polymer-drug linker with enhanced hydrophilicity and solvation. Our hypothesis was then experimentally validated by the synthesis of the corresponding polymer prodrugs based on two different drugs (gemcitabine and paclitaxel), which demonstrated greater performances in terms of drug release and cytotoxicity on two cancer cell lines. Interestingly, our methodology can be easily applied to other polymer prodrug structures, which would contribute to the development of more efficient drug delivery systems via in silico screening.

Reactive Oxygen Species‐Responsive Polymeric Prodrug Nanoparticles for Selective and Effective Treatment of Inflammatory Diseases (Adv. Healthcare Mater. 29/2023)

Reactive Oxygen Species‐Responsive Polymeric Prodrug Nanoparticles for Selective and Effective Treatment of Inflammatory Diseases (Adv. Healthcare Mater. 29/2023)

Targeted echogenic and anti-inflammatory polymeric prodrug nanoparticles for the management of renal ischemia/reperfusion injury

Ischemia/reperfusion (IR) injury is an inevitable pathological event occurring when blood is resupplied to the tissues after a period of ischemia. One of major causes of IR injury is the overproduction of reactive oxygen species (ROS) including hydrogen peroxide (H2O2), which mediates the expression of various inflammatory cytokines to exacerbate tissue damages. The overproduced H2O2 could therefore serve as a diagnostic and therapeutic biomarker of IR injury. In this study, poly(boronated methacrylate) (pBMA) nanoparticles were developed as nanotheranostic agents for renal IR injury, which not only generate CO2 bubbles to enhance the ultrasound contrast but also provide potent preventive effects in a H2O2-triggered manner. The surface of pBMA nanoparticles was decorated with taurodeoxycholic acid (TUDCA) that binds P-selectin overexpressed in inflamed tissues. In the mouse model of renal IR injury, TUDCA-coated pBMA (T-pBMA) nanoparticles preferentially accumulated in the injured kidney and markedly enhanced the ultrasound contrast. T-pBMA nanoparticles also effectively prevented renal IR injury by scavenging H2O2 and suppressing the expression of inflammatory cytokines. Treatment progress of IR injury could be also monitored by echogenic T-pBMA nanoparticles. Given their targeting ability, excellent H2O2-responsiveness, anti-inflammatory activity and H2O2-triggered echogenicity, T-pBMA nanoparticles have excellent translational potential for the management of various H2O2-related diseases including IR injury.

Reactive Oxygen Species-Responsive Polymeric Prodrug Nanoparticles for Selective and Effective Treatment of Inflammatory Diseases.

It is challenging to manage inflammatory diseases using traditional anti-inflammatory drugs due to their limited efficacy and systemic side effects, which are a result of their lack of selectivity, poor stability, and low solubility. Herein, it reports the development of a novel nanoparticle system, called ROS-CA-NPs, which is formed using polymer-cinnamaldehyde (CA) conjugates and is responsive to reactive oxygen species (ROS). ROS-CA-NPs exhibit excellent drug stability, tissue selectivity, and controlled drug release upon oxidative stress activation. Using mouse models of chronic rheumatoid arthritis and acute ulcerative colitis, this study demonstrates that the systemic administration of ROS-CA-NPs results in their accumulation at inflamed lesions and leads to greater therapeutic efficacy compared to traditional drugs. Furthermore, ROS-CA-NPs present excellent biocompatibility. The findings suggest that ROS-CA-NPs have the potential to be developed as safe and effective nanotherapeutic agents for a broad range of inflammatory diseases.

H2O2-responsive polymer prodrug nanoparticles with glutathione scavenger for enhanced chemo-photodynamic synergistic cancer therapy

The combination of chemotherapy and photodynamic therapy (PDT) based on nanoparticles (NPs) has been extensively developed to improve the therapeutic effect and decrease the systemic toxicity of current treatments. However, overexpressed glutathione (GSH) in tumor cells efficiently scavenges singlet oxygens (1O2) generated from photosensitizers and results in the unsatisfactory efficacy of PDT. To address this obstacle, here we design H2O2-responsive polymer prodrug NPs with GSH-scavenger (Ce6@P(EG-a-CPBE) NPs) for chemo-photodynamic synergistic cancer therapy. They are constructed by the co-self-assembly of photosensitizer chlorin e6 (Ce6) and amphiphilic polymer prodrug P(EG-a-CPBE), which is synthesized from a hydrophilic alternating copolymer P(EG-a-PD) by conjugating hydrophobic anticancer drug chlorambucil (CB) via an H2O2-cleavable linker 4-(hydroxymethyl)phenylboronic acid (PBA). Ce6@P(EG-a-CPBE) NPs can efficiently prevent premature drug leakage in blood circulation because of the high stability of the PBA linker under the physiological environment and facilitate the delivery of Ce6 and CB to the tumor site after intravenous injection. Upon internalization of Ce6@P(EG-a-CPBE) NPs by tumor cells, PBA is cleaved rapidly triggered by endogenous H2O2 to release CB and Ce6. Ce6 can effectively generate abundant 1O2 under 660nm light irradiation to synergistically kill cancer cells with CB. Concurrently, PBA can be transformed into a GSH-scavenger (quinine methide, QM) under intracellular H2O2 and prevent the depletion of 1O2, which induces the cooperatively strong oxidative stress and enhanced cancer cell apoptosis. Collectively, such H2O2-responsive polymer prodrug NPs loaded with photosensitizer provide a feasible approach to enhance chemo-photodynamic synergistic cancer treatment.

CD163 Monoclonal Antibody Modified Polymer Prodrug Nanoparticles for Targeting Tumor-Associated Macrophages (TAMs) to Enhance Anti-Tumor Effects.

Tumor-associated macrophages (TAMs)-based immunotherapy is a promising strategy. Since TAMs are mainly composed of M2-type macrophages, they have a promoting effect on tumor growth, invasion, and metastasis. M2-type macrophages contain a specific receptor CD163 on their surface, providing a prerequisite for active targeting to TAMs. In this study, we prepared CD163 monoclonal antibody modified doxorubicin-polymer prodrug nanoparticles (abbreviated as mAb-CD163-PDNPs) with pH responsiveness and targeted delivery. First, DOX was bonded with the aldehyde group of a copolymer by Schiff base reaction to form an amphiphilic polymer prodrug, which could self-assemble into nanoparticles in the aqueous solution. Then, mAb-CD163-PDNPs were generated through a "Click" reaction between the azide group on the surface of the prodrug nanoparticles and dibenzocyclocytyl-coupled CD163 monoclonal antibody (mAb-CD163-DBCO). The structure and assembly morphology of the prodrug and nanoparticles were characterized by 1H NMR, MALDI-TOF MS, FT-IR UV-vis spectroscopy, and dynamic light scattering (DLS). In vitro drug release behavior, cytotoxicity, and cell uptake were also investigated. The results show that the prodrug nanoparticles have regular morphology and stable structure, especially mAb-CD163-PDNPs, which can actively target TAMs at tumor sites, respond to the acidic environment in tumor cells, and release drugs. While depleting TAMs, mAb-CD163-PDNPs can actively enrich drugs at the tumor site and have a strong inhibitory effect on TAMs and tumor cells. The result of the in vivo test also shows a good therapeutic effect, with a tumor inhibition rate of 81%. This strategy of delivering anticancer drugs in TAMs provides a new way to develop targeted drugs for immunotherapy of malignant tumors.

Degradable polyisoprene by radical ring-opening polymerization and application to polymer prodrug nanoparticles.

Radical ring-opening polymerization (rROP) has received renewed attention to incorporate cleavable linkages into the backbones of vinyl polymers, especially from cyclic ketene acetals (CKAs). Among the monomers that hardly copolymerize with CKAs are (1,3)-dienes such as isoprene (I). This is unfortunate since synthetic polyisoprene (PI) and its derivatives are the materials of choice for many applications, in particular as elastomers in the automotive, sport, footwear, and medical industries, but also in nanomedicine. Thionolactones have been recently proposed as a new class of rROP-compatible monomers for insertion of thioester units in the main chain. Herein, we report the synthesis of degradable PI by rROP via the copolymerization of I and dibenzo[c,e]oxepane-5-thione (DOT). Free-radical polymerization as well as two reversible deactivation radical polymerization techniques were successfully used for the synthesis of (well-defined) P(I-co-DOT) copolymers with adjustable molecular weights and DOT contents (2.7-9.7 mol%). Reactivity ratios of r DOT = 4.29 and r I = 0.14 were determined, suggesting preferential incorporation of DOT in comparison to I. The resulting P(I-co-DOT) copolymers were successfully degraded (from -47% to -84% decrease in M n) under basic conditions. As a proof of concept, the P(I-co-DOT) copolymers were formulated into stable and narrowly dispersed nanoparticles, showing similar cytocompatibility on J774.A1 and HUVEC cells compared to their PI counterparts. Furthermore, Gem-P(I-co-DOT) prodrug nanoparticles were synthesized by the "drug-initiated" method and exhibited significant cytotoxicity on A549 cancer cells. P(I-co-DOT) and Gem-P(I-co-DOT) nanoparticles were degraded under basic/oxidative conditions by bleach and under physiological conditions in the presence of cysteine or glutathione.

Pro-drug Nanoparticle Loaded Supramolecular Hydrogels for Drug Delivery to IDH1 Wild-Type Glioblastoma

Abstract AIMS A hyaluronic acid-based hydrogel with mechanical properties comparable to human brain tissue is being investigated as an implantable drug-delivery vehicle for post-surgical treatment of IDH1 wild-type glioblastoma (GBM). Hydrogels are to be loaded with polymeric pro-drug nanoparticles to enable controlled drug release and increased drug penetration through brain parenchyma for enhanced treatment of residual disease within and beyond the invasive margin. METHOD A panel of patient-derived glioblastoma cell lines resected from tumour core and invasive margin, have been used to generate tumour spheroids. Chemotherapeutic drug screening has been performed to select lead compounds for formulation and gel loading. Synergies of drug combinations have been studied for potential combination loading. Upcoming work will investigate nanoparticle internalisation, spheroid penetration and prodrug nanoparticle potency. Nanoparticle loaded hydrogels are then to be studied for validation of effective in vitro application. RESULTS Current results demonstrate that patient-derived cell lines can generate robust, reproducible tumour spheroids with diameters approx. 350-400 µm. Patient-to-patient differences in drug potencies were observed, with differences also noted between counterpart core and marginal cells from the same patients, illustrating the importance of using patient-derived cells and distinct regional cells to study heterogenous disease such as GBM. Drug combination experiments indicated synergy of topoisomerase I inhibitor (Irinotecan) with PARP inhibitor (Ola-parib). Interestingly, combination of PARP inhibition with topoisomerase II inhibitors (Doxorubicin, Etoposide) was found not synergistic. CONCLUSION Together, data gathered on single drug and drug-drug combinations will inform upcoming formulation and in vitro application of hydrogels planned, with eventual translation to pre-clinical in vivo models.

NIR and Reduction Dual-Sensitive Polymeric Prodrug Nanoparticles for Bioimaging and Combined Chemo-Phototherapy.

The combination of chemotherapy, photothermal therapy (PTT) and photodynamic therapy (PDT) based on a single nanosystem is highly desirable for cancer treatment. In this study, we developed a versatile Pt(IV) prodrug-based nanodrug, PVPt@Cy NPs, to realize synchronous chemotherapy, PDT and PTT and integrate cancer treatment with bioimaging. To construct PVPt@Cy NPs, the amphiphilic Pt(IV)-based polymeric prodrug PVPt was synthesized by a facile one-pot coupling reaction, and then it was used to encapsulate an optotheranostic agent (HOCyOH, Cy) via hydrophobic interaction-induced self-assembly. These NPs would disaggregate under acidic, reductive conditions and NIR irradiation, which are accompanied by photothermal conversion and reactive oxygen species (ROS) generation. Moreover, the PVPt@Cy NPs exhibited an enhanced in vitro anticancer efficiency with 808-nm light irradiation. Furthermore, the PVPt@Cy NPs showed strong NIR fluorescence and photothermal imaging in H22 tumor-bearing mice, allowing the detection of the tumor site and monitoring of the drug biodistribution. Therefore, PVPt@Cy NPs displayed an enormous potential in combined chemo-phototherapy.

Passerini chemistries for synthesis of polymer pro-drug and polymersome drug delivery nanoparticles.

New materials chemistries are urgently needed to overcome the limitations of existing biomedical materials in terms of preparation, functionality and versatility, and also in regards to their compatibility with biological environments. Here, we show that Passerini reactions are especially suited for the preparation of drug delivery materials, as with relatively few steps, polymers can be synthesized with functionality installed enabling drug conjugation and encapsulation, self-assembly into micellar or vesicular architectures, and with facile attachment triggerable chemistries. The polymers can be made with a variety of building blocks and assemble into nanoparticles, which are rapidly internalized in triple negative breast cancer (TNBC) cells. In addition, the polymers transport drug molecules efficiently through 3D cell cultures, and when designed with chemistries allowing pH-mediated release, exhibit greater efficacy against TNBC cells compared to the parent drug.

Supramolecular Organization of Polymer Prodrug Nanoparticles Revealed by Coarse-Grained Simulations.

Drug-polymer conjugates that can self-assemble into nanoparticles are promising drug delivery systems that improve the drug bioavailability and allow their controlled release. However, despite the possibility of reaching high drug loadings, the efficiency of the drug release, mediated by cleavage of the drug-polymer linker, is a key parameter to obtain significant anticancer activity. To overcome the limitations of experimental characterizations and to gain a better understanding of such systems, we conducted a coarse-grained molecular dynamics simulation study on four representative drug-polymer conjugates obtained by the "drug-initiated" method and studied their supramolecular organization upon self-assembly. The prodrugs were composed of either a gemcitabine or a paclitaxel anticancer drug, either a propanoate or a diglycolate linker, and a polyisoprene chain. Our simulations gave crucial information concerning the spatial organization of the different components (e.g., drug, linker, polymer, etc.) into the nanoparticles and revealed that the linkers are not fully accessible to the solvent. Notably, some cleavage sites were either poorly hydrated or partially solvated. These observations might account for the low efficiency of drug release from the nanoparticles, particularly when the linker is too short and/or not hydrophilic/solvated enough. We believe that our theoretical study could be adapted to other types of polymer prodrugs and could guide the design of new polymer prodrug nanoparticles with improved drug release efficiency.

CD147 Monoclonal Antibody Targeted Reduction-Responsive Camptothecin Polyphosphoester Nanomedicine for Drug Delivery in Hepatocellular Carcinoma Cells.

In the treatment of tumor-targeted small-molecule anti-cancer drugs, antibody-mediated therapies, especially for antibody-drug conjugates (ADCs), have revealed great latent force. However, the therapeutic drugs provided by ADCs possess limitation. Considering that the combination of antibodies and nano-drugs can broaden their applicability in the field of tumor treatment, herein, we developed an antibody conjugated polymeric prodrug nanoparticles SAE-PEG-b-PBYP-ss-CPT for targeted camptothecin (CPT) delivery to liver tumor cells. The diblock copolymer was composed of PEG and biodegradable polyphosphoester (PBYP) containing alkynyl groups in the side chain. A derivative of CPT (CPT-ss-N3) was bonded to the PBYP via "click" reaction. The diethyl squarate (SAE) in the terminal of PEG chain was used as a functional group to bond with CD147 monoclonal antibody (CD147 mAb). The particle size and size distribution of the both nanoparticles, with antibody binding (namely CD147-CPT NPs) and without antibody (abbreviated as CPT-loaded NPs), were measured by dynamic light scattering (DLS). The morphologies of both two kinds of nanoparticles were observed by transmission electron microscope (TEM). The results of X-ray photoelectron spectroscopy (XPS) showed that CD147 mAb had been coupled to the surface of CPT-loaded NPs. Endocytosis test indicated that CD147-CPT NPs had higher uptake rate and accumulation in HepG2 cells than those of CPT-loaded NPs without antibodies, due to CD147 mAb can specifically bind to CD147 protein overexpressed in HepG2 cells. We establish a method to bond monoclonal antibodies to anti-cancer polymeric prodrugs, and endow biodegradable polymeric prodrugs with precise targeting functions to liver cancer cells.

Polymer Pro-Drug Nanoparticles for Sustained Release of Cytotoxic Drugs Evaluated in Patient-Derived Glioblastoma Cell Lines and In Situ Gelling Formulations.

Glioblastoma (GBM) is the most common, malignant and aggressive brain tumour in adults. Despite the use of multimodal treatments, involving surgery, followed by concomitant radiotherapy and chemotherapy, the median survival for patients remains less than 15 months from diagnosis. Low penetration of drugs across the blood-brain barrier (BBB) is a dose-limiting factor for systemic GBM therapies, and as a result, post-surgical intracranial drug delivery strategies are being developed to ensure local delivery of drugs within the brain. Here we describe the effects of PEGylated poly(lactide)-poly(carbonate)-doxorubicin (DOX) nanoparticles (NPs) on the metabolic activity of primary cancer cell lines derived from adult patients following neurosurgical resection, and the commercially available GBM cell line, U87. The results showed that non-drug-loaded NPs were well tolerated at concentrations of up to 100 µg/mL while tumour cell-killing effects were observed for the DOX-NPs at the same concentrations. Further experiments evaluated the release of DOX from polymer-DOX conjugate NPs when incorporated in a thermosensitive in situ gelling poly(DL-lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA/PEG) matrix paste, in order to simulate the clinical setting of a locally injected formulation for GBM following surgical tumour resection. These assays demonstrated drug release from the polymer pro-drugs, when in PLGA/PEG matrices of two formulations, over clinically relevant time scales. These findings encourage future in vivo assessment of the potential capability of polymer–drug conjugate NPs to penetrate brain parenchyma efficaciously, when released from existing interstitial delivery systems.

Reduction-responsive sulfur dioxide polymer prodrug nanoparticles loaded with irinotecan for combination osteosarcoma therapy

Combination therapy can boost the therapeutic effectiveness of monotherapies by achieving synergy between therapeutic agents. Herein, a reduction-responsive sulfur dioxide (SO2) polymer prodrug was synthesized as a nanocarrier to load irinotecan (IRN) to be used in combination osteosarcoma therapy. The SO2 prodrug (denoted as mPEG-PLG (DNs)) was synthesized by coupling a small-molecule SO2 donor, N-(3-azidopropyl)-2,4-dinitrobenzenesulfonamide (AP-DNs), to the side chains of methoxy poly (ethylene glycol)-block-poly (γ-propargyl-L-glutamate) block copolymer. The mPEG-PLG (DNs) had the ability to self-assemble into micelles while simultaneously encapsulating IRN in aqueous media. The formed micelles led to enhanced SO2 and IRN release in reductive conditions. Using nile red as a model drug, the loaded micelles were efficiently internalized by cancer cells, demonstrated by confocal laser scanning microscopy and flow cytometry. The release of SO2 within nanoparticles (NPs) in tumor cells led to enhanced intracellular reactive oxygen species amounts together with induced oxidative destruction to cancer cells. Furthermore, the IRN-loaded SO2 polymer prodrug NPs mediated synergistic therapeutic effects against osteosarcoma cells, leading to improved biodistribution and enhanced tumor growth inhibition over control groups in a murine osteosarcoma model. Taken together, this work highlights the potential of SO2 polymer prodrugs as reduction-responsive nanocarriers to load chemotherapeutics for effective combination osteosarcoma therapy.

PH-responsive intramolecular FRET-based self-tracking polymer prodrug nanoparticles for real-time tumor intracellular drug release monitoring and imaging.

An intramolecular fluorescence resonance energy transfer (FRET)-based macromolecular theranostic prodrug was designed by directly conjugating Doxorubicin (DOX) as the FRET acceptor onto the naphthalimide side groups in the fluorescent copolymer PPEGMA20-PNAP8 as the FRET energy donor via an acid-labile imine bond, without a fluorogenic linker. The proposed PPEGMA20-PNAP8-DOX theranostic prodrug showed a high DOX content of 24.3% owing to a conjugation efficiency of>93% under mild conjugation conditions. It could easily self-assemble into unique theranostic nanoparticles with a Dh of 71nm. The theranostic nanoparticles showed excellent pH-triggered DOX release performance with very low premature drug leakage of 6.3% in normal physiological medium over 129h, while>91% of the conjugated DOX was released in the acidic tumor intracellular microenvironment. MTT assays indicated the enhanced antitumor efficacy of the proposed theranostic nanoparticles compared with free DOX. Furthermore, because drug release was triggered by pH, orange fluorescence was restored to the blue fluorescence of the backbone copolymer. Such self-tracking pH-responsive colorful fluorescence variations during intracellular drug delivery and release are expected to allow real-time tumor intracellular drug release monitoring and imaging diagnosis.

Redox-Sensitive Hyaluronic Acid Polymer Prodrug Nanoparticles for Enhancing Intracellular Drug Self-Delivery and Targeted Cancer Therapy.

Currently, available nanoscale anticancer drug delivery systems have low targeting and release efficiency, limiting their therapeutic effects. Thus, tumor-targeting nanocarriers for self-assembly of amphiphilic polymer-drug conjugates are urgently needed to improve drug targeting and treatment efficacy. Here, we report the construction of a stable, reduction-sensitive prodrug conjugate based on hyaluronic acid-grafted pH-sensitive doxorubicin (DOX). The amphiphilic prodrug copolymer self-assembled into spherical nanoparticles in aqueous solution and exhibited an average diameter of 150 nm. Prodrug micelles were stable in a normal physiological environment and achieve selective and rapid release under acidic pH and/or high reduction conditions. Cell Counting Kit-8, flow cytometry, and live cell imaging assays showed that the prodrug had high targeting and antitumor activity against CD44 receptors. Moreover, in vivo pharmacokinetics and biodistribution studies showed that the prodrug had a longer circulation time in BALB/c mice and higher accumulation in 4T1 tumors. Interestingly, the prodrug could effectively treat tumors with few side effects. These results showed that the DOX prodrug micelles developed in this study may have great potential in targeted therapy.

EXTH-69. NANOTHERAPEUTICS FOR NEUROSURGICALLY-APPLIED DRUG DELIVERY

Abstract Despite multimodal treatment, the median survival of Glioblastoma multiforme (GBM) patients remains less than 15 months, in considerable part due to diffusely infiltrative disease. Better treatment methods are necessary to eradicate residual tumour burden remaining beyond the resection cavity boundary. It is hypothesised that incorporating drug-loaded polymer pro-drug nanoparticles into a biodegradable microparticulate paste will lead to efficacious local delivery. We report the formulation of numerous self-assembling cytocompatible nanoparticles, based on different linear and branched polymeric architectures, amenable for localised intra-cavity delivery post-surgery. The polymers were synthesised by ring-opening polymerisation with organic catalysts, leading to controlled reaction kinetics and greater potential biomedical applicability. A simple nanoprecipitation technique was employed to gain nanoparticles with the size range of 60–130 nm, depending on the initial monomer ratios and polymeric architectures. Successful biocompatibility studies of the self-assembling nanoparticles have been carried out in vitro on the U87 glioma cell line. We demonstrated that copolymerisation of a monomer with functional capability enabled the successful conjugation of doxorubicin to the polymer chain. We will discuss strategies to incorporate pH-sensitive linkers to the polymeric backbone, which would allow controlled drug release in acidic microenvironments. Based on an increasing understanding of GBM intra-tumour heterogeneity, the capability to deliver multiple therapeutic moieties from single formulations is clinically-relevant. Thus, we hypothesised that polymers with a greater degree of branching over traditional linear structures would lead to greater drug loading, and successfully tested this hypothesis through the encapsulation of olaparib. Future work will assess the efficacy of the polymer pro-drug nanoparticles against both commercial and primary cell lines, and safety/efficacy of intra-cavity delivery using orthotopic syngeneic allografts, thus giving a more therapeutically-relevant insight into the activity of the formulations. This is the first study incorporating polymer pro-drugs of this type into an existing localised micro-scale delivery system for GBM therapies.