Afterglow/Photothermal Bifunctional Polymeric Nanoparticles for Precise Postbreast-Conserving Surgery Adjuvant Therapy and Early Recurrence Theranostic.

Adjuvant whole-breast radiotherapy is essential for breast cancer patients who adopted breast-conserving surgery (BCS) to reduce the risk of local recurrences, which however suffer from large-area and highly destructive ionizing radiation-induced adverse events. To tackle this issue, an afterglow/photothermal bifunctional polymeric nanoparticle (APPN) is developed that utilizes nonionizing light for precise afterglow imaging-guided post-BCS adjuvant second near-infrared (NIR-II) photothermal therapy. APPN consists of a tumor cell targeting afterglow agent, which is doped with a NIR dye as an afterglow initiator and a NIR-II light-absorbing semiconducting polymer as a photothermal transducer. Such a design realizes precise afterglow imaging-guided NIR-II photothermal ablation of minimal residual breast tumor foci after BCS, thus achieving complete inhibition of local recurrences. Moreover, APPN enables early diagnosis and treatment of local recurrence after BCS. This study thus provides a nonionizing modality for precision post-BCS adjuvant therapy and early recurrence theranostic.

Fluorination and Betaine Modification Augment the Blood-Brain Barrier-Crossing Ability of Cylindrical Polymer Brushes.

Blood-brain barrier (BBB)-crossing ability of drugs is of paramount importance for the treatments of central nervous system diseases. However, the known methods for drug transport across the BBB are generally complicated and inefficient, and exhibit serious side effects in some cases. Herein, we report an exciting finding that fluorination and betaine modification can significantly augment the BBB-crossing ability of cylindrical polymer brushes (CPBs), which was demonstrated by the comparison with the CPBs modified with alkyl and poly(ethylene glycol) chains, respectively. We surmise that fluorination enhances the BBB penetration of the CPBs by increasing the hydrophobicity and reducing the surface energy, and betaine medication achieves this function via a betaine transporter BGT1 expressed on brain capillaries. By means of an in vitro BBB model, we demonstrated that the CPBs penetrated the BBB through transendothelial transport. This work provides a novel strategy for enhancing the BBB-crossing ability of nanomaterials.

Phenylboronic Acid Modification Augments the Lysosome Escape and Antitumor Efficacy of a Cylindrical Polymer Brush-Based Prodrug.

Timely lysosome escape is of paramount importance for endocytosed nanomedicines to avoid premature degradation under the acidic and hydrolytic conditions in lysosomes. Herein, we report an exciting finding that phenylboronic acid (PBA) modification can greatly facilitate the lysosome escape of cylindrical polymer brushes (CPBs). On the basis of our experimental results, we speculate that the mechanism is associated with the specific interactions of the PBA groups with lysosomal membrane proteins and hot shock proteins. The featured advantage of the PBA modification over the known lysosome escape strategies is that it does not cause significant adverse effects on the properties of the CPBs; on the contrary, it enhances remarkably their tumor accumulation and penetration. Furthermore, doxorubicin was conjugated to the PBA-modified CPBs with a drug loading content larger than 20%. This CPBs-based prodrug could eradicate the tumors established in mice by multiple intravenous administrations. This work provides a novel strategy for facilitating the lysosome escape of nanomaterials and demonstrates that PBA modification is an effective way to improve the overall properties of nanomedicines including the tumor therapeutic efficacy.

Photoacoustic Imaging and Photothermal Therapy of Semiconducting Polymer Nanoparticles: Signal Amplification and Second Near-Infrared Construction.

Photoacoustic (PA) imaging and photothermal therapy (PTT) have attracted extensive attention in disease diagnosis and treatment. Although many exogenous contrast agents have been developed for PA imaging and PTT, the design guidelines to amplify their imaging and therapy performances remain challenging and are highly demanded. Semiconducting polymer nanoparticles (SPNs) composed of polymers with π-electron delocalized backbones can be designed to amplify their PA imaging and PTT performance, because of their clear structure-property relation and versatility in modifying their molecular structures to tune their photophysical properties. This review summarizes the recent advances in the photoacoustic imaging and photothermal therapy applications of semiconducting polymer nanoparticles with a focus on signal amplification and second near-infrared (NIR-II, 1000-1700 nm) construction. The strategies such as structure-property screening, fluorescence quenching, accelerated heat dissipation, and size-dependent heat dissipation are first discussed to amplify the PA brightness of SPNs for in vivo PA. The molecular approaches to shifting the absorption of SPNs for NIR-II PA imaging and PTT are then introduced so as to improve the tissue penetration depth for diagnosis and therapy. At last, current challenges and perspectives of SPNs in the field of imaging and therapy are discussed.

Translatable High Drug Loading Drug Delivery Systems Based on Biocompatible Polymer Nanocarriers.

Most nanocarriers possess low drug loading, resulting in frequently repeated administration and thereby high cost and increased side effects. Furthermore, the characteristics of nanocarrier materials, especially the drug loading capacity, plays a vital role in the drug delivery efficacy. In this review, we focus on the readily translatable polymeric drug delivery systems with high drug loading, which are comprised of biocompatible polymers such as poly(ethylene glycol), poly( N-vinylpyrrolidone), polyoxazoline, natural proteins like albumin and casein, non-natural proteins such as recombinant elastin-like polypeptides, as well as nucleic acids. At the end of this review, applications of these polymeric nanocarriers on the delivery of proteins and gene drugs are also briefly discussed.

Oligo(ethylene glycol)-based thermosensitive dendrimers and their tumor accumulation and penetration.

Dendrimers have several featured advantages over other nanomaterials as drug carriers, such as well-defined structure, specific low-nanometer size, and abundant peripheral derivable groups, etc. However, these advantages have not been fully exploited yet to optimize their biological performance, especially tumor penetration, which is a shortcoming of current nanomaterials. Here we show the syntheses of a new class of oligo(ethylene glycol) (OEG)-based thermosensitive dendrimers up to the fourth generation. Each dendrimer shows monodisperse structure. OEG/poly(ethylene glycol) (PEG) moieties with different precise lengths were introduced to the periphery of the fourth-generation dendrimer followed by an antitumor agent, gemcitabine (GEM). The biodistributions of the GEM-conjugated dendrimers were investigated by micro positron emission tomography and multispectral optoacoustic tomography imaging techniques and compared with that of GEM-conjugated poly(amidoamine) (PAMAM). The GEM-conjugated dendrimer with the longest peripheral PEG segments exhibited the most desirable tumor accumulation and penetration and thus had significantly higher antitumor activity than the GEM-conjugated PAMAM.

Enhancing the tumor penetration of multiarm polymers by collagenase modification.

Tumor penetration is a critical determinant of the therapy efficacy of nanomedicines. However, the dense extracellular matrix (ECM) in tumors significantly hampers the deep penetration of nanomedicines, resulting in large drug-untouchable areas and unsatisfactory therapy efficacy. Herein, we synthesized a third-generation PAMAM-cored multiarm copolymer and modified the polymer with collagenase to enhance its tumor penetration. Each arm of the copolymer was a diblock copolymer of poly(glutamic acid)-b-poly(carboxybetaine), in which the polyglutamic acid block with abundant side groups was used to link the anticancer agent doxorubicin through the pH-sensitive acylhydrazone linkage, and the zwitterionic poly(carboxybetaine) block provided desired water solubility and anti-biofouling capability. The collagenase was conjugated to the ends of the arms via the thiol-maleimide reaction. We demonstrated that the polymer-bound collagenase could effectively catalyze the degradation of the collagen in the tumor ECM, and consequently augmented the tumor penetration and antitumor efficacy of the drug-loaded polymers.

Advanced Biomaterials with Intrinsic Immunomodulation Effects for Cancer Immunotherapy.

In recent years, tumor immunotherapy has achieved significant success in tumor treatment based on immune checkpoint blockers and chimeric antigen receptor T-cell therapy. However, about 70-80% of patients with solid tumors do not respond to immunotherapy due to immune evasion. Recent studies found that some biomaterials have intrinsic immunoregulatory effects, except serve as carriers for immunoregulatory drugs. Moreover, these biomaterials have additional advantages such as easy functionalization, modification, and customization. In this review, the recent advances of these immunoregulatory biomaterials in cancer immunotherapy and their interaction with cancer cells, immune cells, and the immunosuppressive tumor microenvironment are summarized. Finally, the opportunities and challenges of immunoregulatory biomaterials used in the clinic and the prospect of their future in cancer immunotherapy are discussed.

Phenylboronic acid-modified nanoscale multi-arm polymers for tumor-targeted therapy.

Unimolecular polymer nanomaterials (UPNs) have well-defined structures, desirable stability and designable functional groups, and hence exhibit great application potential in drug delivery. However, the syntheses of UPNs are generally time-consuming and tedious, which greatly limit their applications. In this paper, we present the preparation of a ß-cyclodextrin-cored star-shaped polymer with 21 poly(tert-butyl acrylate) arms. This polymer was facilely synthesized by one-step atom transfer radical polymerization (ATRP). After cleaving the tert-butyl ester protecting groups, the abundant carboxylic acid side groups were used to incorporate doxorubicin (DOX), phenylboronic acid (PBA) groups and poly(ethylene glycol) (PEG) to achieve drug loading and tumor drug delivery. Due to the tumor-targeting ability of the PBA groups, this UPN-based nanomedicine showed high tumor accumulation, penetration and therapeutic efficacy.

Light-Driven Self-Recruitment of Biomimetic Semiconducting Polymer Nanoparticles for Precise Tumor Vascular Disruption.

Tumor vascular disrupting therapy has offered promising opportunities to treat cancer in clinical practice, whereas the overall therapeutic efficacy is notably limited due to the off-target effects and repeated dose toxicity of vascular disrupting agents (VDAs). To tackle this problem, a VDA-free biomimetic semiconducting polymer nanoparticle (SPNP ) is herein reported for precise tumor vascular disruption through two-stage light manipulation. SPNP consists of a semiconducting polymer nanoparticle as the photothermal agent camouflaged with platelet membranes that specifically target disrupted vasculature. Upon the first photoirradiation, SPNP administered in vivo generates mild hyperthermia to trigger tumor vascular hemorrhage, which activates the coagulation cascade and recruits more SPNP to injured blood vessels. Such enhanced tumor vascular targeting of photothermal agents enables intense hyperthermia to destroy the tumor vasculature during the second photoirradiation, leading to complete tumor eradication and efficient metastasis inhibition. Intriguingly, the mechanism study reveals that this vascular disruption strategy alleviates splenomegaly and reverses the immunosuppressive tumor microenvironment by reducing myeloid-derived suppressor cells. Therefore, this study not only illustrates a light-driven self-recruitment strategy to enhance tumor vascular disruption via a single dose of biomimetic therapeutics but also deciphers the immunotherapeutic role of vascular disruption therapy that is conducive to clinical studies.

Size Control and Biological Properties of PAMAM-Cored Multiarm Block Copolymers.

Size is one of the crucial factors influencing the biological properties of nanomedicines. However, the size control of nanomaterials is still very challenging, and the size effect on their biological properties is worth studying. Herein, we present the synthesis and size control of a series of multiarm block copolymers with the third-generation PAMAM (G3 PAMAM) as the core. The multiarm copolymers were synthesized by the ring-opening polymerization of N-carboxyanhydride of the l-glutamic acid-5-tert-butylester [Glu(OtBu)-NCA] monomer with the amine-terminated PAMAM as the initiator, followed by the synthesis of the poly(carboxybetaine) (PCB) block via the atom transfer radical polymerization of the 2-(dimethylamino)ethyl methacrylate monomer, the reaction with tert-butyl bromoacetate, and the deprotection of the tert-butyl ester groups. The polyglutamic acid (PGA) block provided abundant reactive groups for the functionalization of the multiarm block copolymers, and the PCB block imparted excellent water solubility and anti-protein adsorption capability. We synthesized three multiarm copolymers with diameters of 15, 24, and 41 nm, respectively, by tuning the polymerization degrees of the arms. Doxorubicin was coupled to the PGA block through the acylhydrazone linkage, which resulted in a pH-sensitive drug release and a drug loading of over 20%. We systematically investigated the size effects on their cellular uptake, cytotoxicity, endocytic pathway, biodistribution, tumor penetration, and antitumor activity. This work is helpful for the design of polymeric nano-drug carriers for tumor therapy.

Fluoropolymer-MOF Hybrids with Switchable Hydrophilicity for 19F MRI-Monitored Cancer Therapy.

Cancer theranostics that combines cancer diagnosis and therapy is a promising approach for personalized cancer treatment. However, current theranostic strategies suffer from low imaging sensitivity for visualization and an inability to target the diseased tissue site with high specificity, thus hindering their translation to the clinic. In this study, we have developed a tumor microenvironment-responsive hybrid theranostic agent by grafting water-soluble, low-fouling fluoropolymers to pH-responsive zeolitic imidazolate framework-8 (ZIF-8) nanoparticles by surface-initiated RAFT polymerization. The conjugation of the fluoropolymers to ZIF-8 nanoparticles not only allows sensitive in vivo visualization of the nanoparticles by 19F MRI but also significantly prolongs their circulation time in the bloodstream, resulting in improved delivery efficiency to tumor tissue. The ZIF-8-fluoropolymer nanoparticles can respond to the acidic tumor microenvironment, leading to progressive degradation of the nanoparticles and release of zinc ions as well as encapsulated anticancer drugs. The zinc ions released from the ZIF-8 can further coordinate to the fluoropolymers to switch the hydrophilicity and reverse the surface charge of the nanoparticles. This transition in hydrophilicity and surface charge of the polymeric coating can reduce the "stealth-like" nature of the agent and enhance specific uptake by cancer cells. Hence, these hybrid nanoparticles represent intelligent theranostics with highly sensitive imaging capability, significantly prolonged blood circulation time, greatly improved accumulation within the tumor tissue, and enhanced anticancer therapeutic efficiency.

Paclitaxel/tetrandrine coloaded nanoparticles effectively promote the apoptosis of gastric cancer cells based on "oxidation therapy".

Paclitaxel (Ptx) has demonstrated encouraging activity in the treatment of gastric cancer. Development of drug-containing biodegradable polymeric nanoparticles (np) becomes one of the solutions to relieve side effects of Ptx. However, Ptx-loaded nanoparticles prepared by the nanoprecipitation method are unstable in the aqueous phase. Here we report that tetrandrine (Tet) effectively increases the stability of Ptx-loaded nanoparticles when Tet is coencapsulated with Ptx into mPEG-PCL nanoparticles. The current study demonstrates the synergistic antitumor effect of Tet and Ptx against gastric cancer cells, which provides the basis of coadministration of Tet and Ptx by nanoparticles. It is reported that the cellular chemoresistance to Ptx correlates with intracellular antioxidant capacity and the depletion of cellular antioxidant capacity could enhance the cytotoxicity of Ptx. Tet effectively induces intracellular ROS production. Therefore, the present study provides a promising novel therapeutic strategy basing on "oxidation therapy" that it could amplify the antitumor effect of paclitaxel by employing Tet as a pro-oxidant. More intracellular Tet accumulation by endocytosis of Ptx/Tet-np than equivalent doses of free drug leads to more intracellular ROS induction, which could efficiently enhance the cytotoxicity of Ptx by sequential inhibition of ROS-dependent Akt pathway and activation of apoptotic pathways, all of which would mediate the superior cytotoxicity of Ptx/Tet-np over free drug. The present results suggest that the codelivery of Ptx and Tet by nanoparticles provides a novel therapeutic strategy basing on "oxidation therapy" against gastric cancer.

Superior antimetastatic effect of pemetrexed-loaded gelatinase-responsive nanoparticles in a mouse metastasis model.

Novel pemetrexed-loaded gelatinase-responsive nanoparticles were prepared as a targeted delivery system to determine its potential for clinical therapy of malignant melanoma. The pemetrexed-loaded poly(ethylene glycol)(PEG)-peptide-poly(ε-caprolactone) (PCL) nanoparticles included a gelatinase-cleavage peptide and a PEG-PCL-based structure. The pemetrexed-loaded PEG-peptide-PCL nanoparticles have shown the best antimetastatic effect in experimental lung metastasis models. The expressions of CD133 and thymidylate synthetase of metastatic tumors were also evaluated in our studies. Our results showed that pemetrexed-loaded gelatinase-responsive nanoparticles may represent a potent drug delivery system for inhibiting pulmonary metastasis and our preclinical results can provide new avenues for clinical therapy of malignant melanoma.

Semiconductor Polymer with Strong NIR-II Absorption for Photoacoustic Imaging and Photothermal Therapy.

Semiconductor polymers have several featured advantages, such as easily tunable optical properties, high light harvesting, good photostability, etc. However, semiconductor polymers with desirable NIR-II absorbance for the applications of both NIR-II photoacoustic (PA) imaging and photothermal therapy (PTT) are still lacking. Herein, we synthesized a donor-acceptor (D-A) type semiconductor polymer PTPTQ with thiophene (TP) as the electron donor and thiadiazoloquinoxaline (TQ) as the acceptor. PTPTQ had a brushlike topological structure with two poly(ethylene glycol) (PEG) chains (2000 Da) in each repeating unit. Such an intriguing structure endowed it with high hydrophilicity, good biocompatibility, and prominent passive tumor targeting ability. PTPTQ exhibited strong absorption in 600-1800 nm and good photostability. Its photothermal conversion efficiency was determined to be about 41.36%, which rendered it excellent properties in NIR-II PA imaging and PTT. By using PTPTQ as a PTT agent, the mouse tumor models can be eradicated. Taken together, the overall properties of PTPTQ make it promising as a tumor theranostic agent.

Effects of iRGD conjugation density on the in vitro and in vivo properties of cylindrical polymer brushes.

iRGD can significantly improve the tumor accumulation and tumor penetration of nanomaterials. However, it still remains unclear how far iRGD can enhance the properties of nanomaterials when its conjugation density is maximized. Herein, we synthesized three types of cylindrical polymer brushes (CPBs) with 0%, 50% and 100% of side chains terminated by iRGD, which were named CPBs-1, CPBs-2 and CPBs-3, respectively, and studied the effects of iRGD density on their cellular uptake, and tumor targeting ability and tumor permeability. It was demonstrated that compared with the iRGD-free CPBs-1, the cellular uptake of CPBs-3 was enhanced 5 times and their tumor accumulation was enhanced twice. The penetration depth of CPBs-3 in three-dimensional multicellular spheroids was larger than 100 µm. Our results provide useful information for the design of active tumor targeting nanomaterials as therapeutics or contrast agents.

Dendritic lipopeptide liposomes decorated with dual-targeted proteins.

Due to their homing effects, cell and cell membrane-derived nanocarriers have been widely used to enhance drug target delivery. Inspired by the protein-anchored cell membrane architecture, we here report a tumor-targeted liposome, dtDLP, which was constructed through the electrostatic interaction between dendritic lipopeptide liposomes and a dual-targeted recombinant protein, achieving superior tumor homing, cellular endocytotic and penetration abilities. The dual-targeted recombinant protein consists of an anti-epidermal growth factor receptor single domain antibody and a peptide ligand for the integrin αvß3. dtDLPs substantially reduced macrophage phagocytosis and increased drug internalization in both 4T1 cells and HeLa cells by providing more endocytic pathways. In addition, the dtDLPs showed great penetration ability in both multicellular spheroids and tumor tissues. Due to the improved cancer cellular uptake and tumor penetration, the dtDLPs exhibited a superior anticancer effect in both HeLa and 4T1 tumor-bearing mice. This work will be helpful for the design of cell-specific liposomes with admirable tumor targeting, endocytotic and penetration abilities.

Fluorination Effects on the Drug Delivery Property of Cylindrical Polymer Brushes.

Fluorination has been widely applied to improving the properties of small-molecule drugs. However, relatively little is known about the effects of fluorination on the drug delivery property of nanomaterials. In this paper, we synthesized a fluoroalkane-modified cylindrical polymer brush (CPB) BCPB-F and an alkane-modified analogue BCPB-H. Doxorubicin (DOX) was used as a model drug and was loaded onto the CPBs through a pH-responsive acylhydrazone linkage. High drug loading and good water solubility were achieved. The in vitro and in vivo experiments suggested that fluorination played an important role in improving the cellular uptake, blood circulation, tissue permeability, and tumor targeting ability of CPBs. Due to these superiorities, the DOX-loaded BCPB-F exhibited excellent antitumor efficacy and eradicated the tumors of mice after five-dose treatments. The well-defined structures of the drug-free and drug-loaded CPBs guaranteed the accuracy of the results. This work demonstrates that fluorination is a promising strategy to improve the overall properties of nanomedicines.

Enhancing Penetration Ability of Semiconducting Polymer Nanoparticles for Sonodynamic Therapy of Large Solid Tumor.

Sonodynamic therapy (SDT) holds growing promise in deep-seated or large solid tumor treatment owing to its high tissue penetration depth ability; however, its therapeutic efficacy is often compromised due to the hypopermeable and hypoxic characteristics in the tumor milieu. Herein, a semiconducting polymer nanoparticle (SPNC) that synergistically enhances tumor penetration and alleviates tumor hypoxia is reported for sonodynamic therapy of large solid tumors. SPNC comprises a semiconducting polymer nanoparticle core as a sonodynamic converter coated with a poly (ethylene glycol) corona. An oxygen-modulating enzyme, catalase, is efficiently conjugated to the surface of nanoparticles via the coupling reaction. Superior to its counterpart SPNCs (SPNC2 (84 nm) and SPNC3 (134 nm)), SPNC with the smallest size (SPNC1 (35 nm)) can efficiently penetrate throughout the tumor interstitium to alleviate whole tumor hypoxia in a large solid tumor model. Upon ultrasound (US) irradiation, SPNC1 can remotely generate sufficient singlet oxygen to eradicate tumor cells at a deep-tissue depth. Such a single treatment of SPNC1-medicated sonodynamic therapy effectively inhibits tumor growth in a large solid tumor mouse model. Therefore, this study provides a generalized strategy to synergistically overcome both poor penetration and hypoxia of large tumors for enhanced cancer treatment.

A facile strategy for constructing boron-rich polymer nanoparticles via a boronic acid-related reaction.

We present here a facile strategy for constructing Dextran-poly(3-acrylamidophenylboronic acid) (Dextran-PAPBA) nanoparticles (NPs) through a radical polymerization of the monomer 3-acrylamidophenylboronic acid (APBA) bound by dextran via a boronic acid-diol reaction in aqueous solution. The synthesized Dextran-PAPBA NPs are stable in a wide pH range. Their size and composition are tunable by varying the feeding molar ratio of the glucopyranoside unit in dextran to APBA. Additionally, the NPs have good biocompatibility and cell membrane penetrability, as demonstrated by in vitro experiments. Doxorubicin was encapsulated in the NPs and exhibited a sustained and strongly pH-dependent release profile that would greatly favor the in vivo drug delivery performance of the NPs. The facility of this strategy together with the tunable boron content and outstanding drug release and cellular membrane crossing performance of the produced NPs should greatly boost their applications in boron neutron capture therapy (BNCT) and chemotherapy for cancer treatment.