A Smart Core-Crosslinked Supramolecular Drug Delivery System (SDDS) Enabled by Pendant Cyclodextrins Encapsulation of Drug Dimers via Host-Guest Interaction.

Owing to poor aqueous solubility and low delivery efficiency, most of anti-cancer chemodrugs depend on various smart drug delivery platforms to enhance the treatment efficacy. Herein, a stimuli-responsive supramolecular drug delivery system (SDDS) is developed based on polymeric cyclodextrins (PCD) which crosslinked by stimuli-cleavable drug dimers via host-guest interaction. PEGylated PCD was precisely controlled synthesized by ring-opening polymerization and azide-alkyne click chemistry, and two doxorubicins (DOX) were linked with a disulfide bond to form a drug dimer (ss-DOX). They then co-assembled into supramolecular micelles. Drug dimers were utilized as cross-linkers to stabilize the micelles. The drug loading efficiency was very high that could be up to 98%. The size and morphology were measured by DLS and TEM. Owing to the disulfide bonds of drug dimers, these supramolecular micelles were dissociated by treating with dithiothreitol (DTT). In the meanwhile, the free DOXs were recovered and released from cavities of cyclodextrins because of dynamic equilibrium and hydrophilicity changes. The release profile was studied under mimic physiological conditions. Furthermore, in vitro cytotoxicity study showed excellent anti-cancer efficacy of reduced-responsive supramolecular polymeric micelles. Therefore, it can be served as a safe and stimuli-responsive SDDS for cancer therapy.

Ultrasmall Zwitterionic Polypeptide-Coordinated Nanohybrids for Highly Efficient Cancer Photothermal Ferrotherapy.

Ferroptosis therapy (FT) based on the Fenton reaction of ferrous nanoparticles has been becoming a unique strategy for cancer treatment; however, current ferrous nanoparticles suffer from slower Fenton reaction kinetics, lower ferroptosis efficacy, and long-term toxicity, so it is urgent to construct biocompatible ferrous nanomaterials with highly efficient Fenton reaction activity for cancer FT. Inspired by single-atom catalysis and size-determined tumor penetration, we conceived an innovative strategy for constructing ultrasmall zwitterionic polypeptide-coordinated nanohybrids of PCGA@FeNP with about 6 nm by utilizing thiol/hydroxyl-iron cooperative coordination chemistry. The ultrasmall size, unsaturated ferrous coordination, and intracellular acidic pH could accelerate the Fenton reaction, thus boosting the efficacy of ferroptosis. Moreover, those coordinated nanohybrids exhibited prominent photothermia with 59.5% conversion efficiency, further accelerating the Fenton reaction and inducing a synergistic effect between FT and photothermal therapy (PTT). In vitro and in vivo GPX-4 expression ascertained that PCGA@FeNP indeed induced effective FT and synergistic FT-PTT. Remarkably, in vivo FT-PTT completely ablated 4T1 solid tumors by one treatment, presenting outstanding and synergistic antitumor efficacy via the photothermia-boosted ferroptosis and apoptosis pathways. This work supplies a practicable strategy to fabricate ultrasmall zwitterionic coordination nanohybrids for highly efficient cancer FT and FT-PTT theranostics with potential clinical transitions.

A zwitterionic polypeptide nanocomposite with unique NIR-I/II photoacoustic imaging for NIR-I/II cancer photothermal therapy.

The second near infrared photoacoustic imaging (NIR-II PAI) and photothermal therapy (NIR-II PTT) have attracted wide interest in cancer theranostics because of maximum permission exposure (MPE), deep penetration, and lower scattering and background noise compared to NIR-I counterparts; however, it is imperative to develop biocompatible nanomaterials having NIR-II response. By utilizing multivalent Au-S coordination bonds, we constructed a zwitterionic polypeptide nanocomposite of PMC@AuNP with a suitable size of 48 ± 2 nm, which possessed a strong and broad absorbance at 650-1100 nm and an excellent photothermal conversion efficiency of 49.5%. In vitro biological studies demonstrated that NIR-II PTT within MPE was more effective than NIR-I PTT beyond MPE. Along with X-ray computed tomography and photothermal imaging functions, PMC@AuNP in vivo presented unique NIR-I/II PAI with 2.6-5.9 times signal enhancement compared to the contrast. By single dose and NIR-II irradiation (1064 nm, 1 W cm-2, 10 min), NIR-II PTT within MPE completely eradicated MCF-7 tumors without tissue damage and tumor recurrence within 24 days, inducing a better antitumor efficacy than NIR-I PTT beyond MPE. Importantly, this study provides an innovative method for the fabrication of biocompatible zwitterionic polypeptide nanocomposites with unique NIR-I/II PAI and NIR-II PTT attributes, thus holding great potential for precise cancer theranostics and further clinical transitions.

Hydroxyapatite-Bovine Serum Albumin-Paclitaxel Nanoparticles for Locoregional Treatment of Osteosarcoma.

Osteosarcoma is the most primary type of bone tumor occurring in the pediatric and adolescent age groups. In order to obtain the most appropriate prognosis, both tumor recurrence inhibition and bone repair promotion are required. In this study, a ternary nanoscale biomaterial/antitumor drug complex including hydroxyapatite (HA), bovine serum albumin (BSA) and paclitaxel (PTX) is prepared for post-surgical cancer treatment of osteosarcoma in situ. The HA-BSA-PTX nanoparticles, about 55 nm in diameter with drug loading efficiency (32.17 wt%), have sustained release properties of PTX and calcium ions (Ca2+ ) and low cytotoxicity to human fetal osteoblastic (hFOB 1.19) cells in vitro. However, for osteosarcoma (143B) cells, the proliferation, migration, and invasion ability are significantly inhibited. The in situ osteosarcoma model studies demonstrate that HA-BSA-PTX nanoparticles have significant anticancer effects and can effectively inhibit tumor metastasis. Meanwhile, the detection of alkaline phosphatase activity, calcium deposition, and reverse transcription-polymerase chain reaction proves that the HA-BSA-PTX nanoparticles can promote the osteogenic differentiation. Therefore, the HA-BSA-PTX nanodrug delivery system combined with sustained drug release, antitumor, and osteogenesis effects is a promising agent for osteosarcoma adjuvant therapy.

A pure molecular drug hydrogel for post-surgical cancer treatment.

Local drug delivery systems, especially hydrogels, show superior strengths in postoperative recurrence prevention. Despite great advances, clinical translation of the hydrogels has been largely restricted as these drug delivery systems generally require chemical modification or additional carrier molecules to form hydrogels, which results in side effects correlative with local inflammation and systemic toxicity. Here, we developed a pure molecular anticancer drug hydrogel that reduced post-surgical tumor recurrence. The macroscopic pure molecular hydrogel was generated via ultrasonication of anticancer drug raltitrexed in aqueous solution, which was facile and environmentally friendly without involving chemical synthesis. Molecular dynamics simulations confirmed that raltitrexed self-assembled into a nanofibrous hydrogel through hydrogen bond and π-π interaction. Delivered as a hydrogel, raltitrexed could effectively decrease tumor recurrence rate and promote the inhibition of tumor growth in vivo. This raltitrexed self-delivery hydrogel has the potential to serve as a powerful auxiliary implement for preventing postoperative local tumor recurrence.

Nanobody-guided targeted delivery of microRNA via nucleic acid nanogel to inhibit the tumor growth.

MicroRNAs (miRNAs) play crucial roles in maintaining normal physiological processes by regulating gene expression network and thus the tumor-suppressive miRNA has emerged as a promising antitumor agent for cancer treatment. However, targeted delivery of miRNA remains a challenge owing to its intrinsic macromolecular and negatively-charged features. Herein, we first employ the miRNA as crosslinker to construct a nucleic acid nanogel, in which miRNA is embedded and protected inside the three-dimensional (3D) nanostructure. Thereafter, nanobody (Nb) conjugated DNA (Nb-DNA) strands are further loaded on nanogel surface through nucleic acid hybridization, to form a Nb-functionalized nanogel (Nb-nanogel) for tumor-targeted miRNA delivery and antitumor treatment. Both in vitro and in vivo experiments show that nanogel equipped with Nb targeting moieties can greatly promote the miRNA accumulation at the tumor site and cellular uptake efficiency, resulting in significant improvement of the miRNA-mediated antitumor efficacy. This research provides a new approach for targeted miRNA delivery and may pave a new avenue to realize efficient miRNA replacement therapy for cancer treatment.

Polydopamine-coated nucleic acid nanogel for siRNA-mediated low-temperature photothermal therapy.

Photothermal therapy (PTT) normally requires to maintain the temperature of tumor lesions above 50 °C, which potentially induces local inflammation and tumor metastasis. To avoid these side effects, it is vital to achieve effective antitumor efficacy at relatively low temperature (42-45 °C) during the PTT treatment. Herein, we design a polydopamine (PDA)-coated nucleic acid nanogel as a therapeutic complex for siRNA-mediated low-temperature PTT. First, siRNAs that target the heat-shock-protein 70 (Hsp70) serve as crosslinkers to guide the DNA-grafted polycaprolactone (DNA-g-PCL) assemble into nanosized hydrogel particles through nucleic acid hybridization. Thereafter, the obtained siRNA-embedded nanogels are further coated with a thin layer of polydopamine, which not only protects the nanogels against enzymatic degradation but also endows the nanogels with excellent photothermal conversion capacity under near infrared (NIR) light irradiation. After surface PEGylation, this triple shield siRNA delivery complex shows the capability of effective ablating the tumor under relatively mild condition.

Chlorin e6 and polydopamine modified gold nanoflowers for combined photothermal and photodynamic therapy.

Combinational photo-based approaches with enhanced efficacy for cancer therapy have garnered increasing attention in recent years. In this work, a multifunctional system for synergistic photothermal and photodynamic cancer therapy was successfully prepared. The system consists of gold nanoflowers (AuNFs) conjugated with Chlorin e6 (Ce6), and then coated with a polydopamine (PDA) layer. AuNFs with diameters around 80 nm and a broad absorbance in the visible-near infrared (Vis-NIR) range of 500 to 800 nm, were successfully synthesized by a two-step process at 0 °C, using HAuCl4, ascorbic acid (AA), and hydroxylamine hydrochloride (NH2OH·HCl) as the reactants. Glutathione (GSH) molecules chemically anchored to the gold surfaces were used to provide addressable sites for Ce6 conjugated to GSH-AuNFs through an amidation reaction. A PDA layer was then wrapped outside the Ce6-GSH-AuNFs via self-polymerization of dopamine, which provided additional chemical modification and functionalization. Finally, the multifunctional PDA-Ce6-GSH-AuNFs were obtained. The content of Ce6 incorporated into the AuNFs was 14.0 wt%, and the singlet oxygen yield of PDA-Ce6-GSH-AuNFs was approximately 91.0% of that of free Ce6. PDA-Ce6-GSH-AuNFs showed better photothermal conversion efficiency (η = 23.6%), lower cytotoxicity, and faster cell internalization. Both in vitro and in vivo investigation of the combined treatment with a near-infrared (NIR) laser (660 nm for photodynamic therapy, and 808 nm for photothermal therapy) demonstrated that PDA-Ce6-GSH-AuNFs had excellent phototoxicity and synergistic effects of killing cancer cells. Hence, PDA-Ce6-GSH-AuNFs are a dual phototherapeutic agent that exhibits photodynamic and photothermal therapeutic effects and has potential application in enhanced cancer therapy.

Methotrexate-Mn2+ based nanoscale coordination polymers as a theranostic nanoplatform for MRI guided chemotherapy.

Theranostic nanoplatforms based on magnetic resonance imaging (MRI) technology have drawn much attention due to their inherent advantages such as non-invasiveness and high spatial resolution, but their construction is usually complicated and the compositions are uncontrollable. Herein, a simple and controllable theranostic nanoplatform by replacing a chelating agent with a chemotherapeutic drug directly was proposed. In detail, we elaborately synthesized Mn2+ and methotrexate (MTX) based nanoscale coordination polymers (NCPs) coated with poly(ethylene glycol) (PEG), MTX-Mn@PEG, in which Mn2+ ions served as MRI contrast agents (CAs), MTX was used as a chemotherapy drug and PEG provided a stable environment for nanoparticles, respectively. The obtained MTX-Mn@PEG NCPs showed a relatively uniform size, a pH-responsive feature and long blood circulation to enrich in the tumor location through the enhanced permeability and retention (EPR) effect. We determined the composition and coordination mechanism of MTX-Mn@PEG through thermogravimetric analysis (TGA), Fourier transform infrared (FI-TR) spectroscopy, powder X-ray diffraction (XRD) and so on. We determined the composition and coordination mechanism of MTX-Mn@PEG with the molar ratio of MTX to Mn2+ as 1 : 1. Then we confirmed that the antitumor ability was mediated by MTX through MTT and cell apoptosis assay in vitro. In vivo MR imaging and antitumor assays demonstrated the excellent effect of the NCPs in diagnosis and therapy of tumors. Overall, these novel MTX-Mn@PEG NCPs provide a theranostic nanoplatform for cancer treatment.

A Paclitaxel-Based Mucoadhesive Nanogel with Multivalent Interactions for Cervical Cancer Therapy.

Cervical cancer treatment is subject to limited drug access to locally diseased targets and generally resistant to chemotherapy, thus it is essential to develop a local drug delivery system to overcome these problems, premised on guaranteeing drug efficacy. With this goal in mind, a multivalent interactions-based mucoadhesive nanogel for vaginal delivery is proposed. Briefly, the nanogel is constructed with mucoadhesive poly(acrylic acid) as the backbone and multiple inclusions between ß-cyclodextrin and paclitaxel as the crosslinking points. The in vitro experiments demonstrate that nanogel exerts high cytotoxicity to cancer cells, reverses multidrug resistance effectively, and successfully promotes the permeation of drugs. More to the point, as proved in the in vivo experiments, the retention time in the vagina is prolonged and the tumor growth is effectively suppressed by the nanogel without any side effects in the orthotopic cervical cancer model. As mentioned above, this novel mucoadhesive nanogel is believed to be a useful tool toward designing drug delivery systems for cervical cancer treatment.

Dual drug-paired polyprodrug nanotheranostics reverse multidrug resistant cancers via mild photothermal-cocktail chemotherapy.

Combating multidrug resistance (MDR) of tumors is still challenging for clinical chemotherapy, cocktail chemotherapy (CCT), and currently widely-studied nanodrug-based treatments. Inspired by different MDR-overcoming and antitumor mechanisms of CCT and photothermal therapy (PT), a dual drug-paired polyprodrug nanoparticle (PDCN25-CDDP) was constructed to achieve the combination therapy PT-CCT for reversing MDR and combating multidrug resistant cancers. The PT-CCT treatment can greatly downregulate the P-gp expression level and achieve utmost MDR-reversal and antitumor efficacy by both a cocktail effect of CCT and a synergistic effect of CCT with PT; meanwhile, PT can inhibit the expression of heat shock protein 90 and enhance the thermosensitivity of cancer cells. Upon NIR irradiation, PDCN25-CDDPin vivo produced a selective tumor accumulation effect and relatively deep tumor penetration, as evidenced by fluorescent and photoacoustic imaging and CLSM. The mild PT-CCT treatment completely eradicated MCF-7/ADR and OVCAR-3/DDP tumors without skin damage or tumor recurrence for 30 days, exhibiting synergistic MDR-reversal and superior antitumor efficacy in vivo. Importantly, this work provides an innovative strategy for reversing MDR and combating DOX-resistant breast and CDDP-resistant ovarian cancers.

NIR-Responsive Polypeptide Nanocomposite Generates NO Gas, Mild Photothermia, and Chemotherapy to Reverse Multidrug-Resistant Cancer.

Multidrug resistance (MDR) of cancers that results from overexpression of a P-glycoprotein (P-gp) transporter mainly causes chemotherapy (CT) failure and hinders clinical transitions of current polypeptide nanomedicines. Herein, a novel polypeptide nanocomposite PNOC-PDA that integrates heat-sensitive NO gas delivery and photothermal conversion attributes can overcome MDR and maximize CT; meanwhile the optimized CT and intracellular high-concentration NO gas can assist a mild photothermal therapy (PTT) to eradicate cancer cells. The triple therapies produced a superior and synergistic effect on MDR-reversal and killing MCF-7/ADR in vitro, and the P-gp expression level was downregulated to 46%, as confirmed by means of MTT, Western blot, flow cytometry, and confocal laser scanning microscopy. Significantly, by using one intravenous injection of PNOC-PDA/DOX and a single near-infrared irradiation, the triple therapies of mild PTT, NO gas therapy, and CT achieved complete MCF-7/ADR tumor ablation without skin damage, scarring, and tumor recurrence within 30 days. This work provides a versatile method for the fabrication of NIR-responsive polypeptide nanocomposite with intrinsic photothermal conversion and NO-releasing attributes, opening up a new avenue for reversing MDR in tumors.

Achieving traceless ablation of solid tumors without recurrence by mild photothermal-chemotherapy of triple stimuli-responsive polymer-drug conjugate nanoparticles.

Although photothermal therapy (PT) and photothermal-chemotherapy (PT-CT) treatments have been used to achieve complete ablation of solid tumors, they are often implemented at more than 50 °C under high intensity and using a high dose of NIR irradiation, concomitantly inducing heavy skin burning, tissue damage, and ugly scarring. Moreover, the residual tumor cells at the treated site cannot be completely eradicated, resulting in tumor recurrence and metathesis. These key obstacles have prohibited PT and PT-CT treatments from transitioning to clinical use, therefore achieving traceless ablation of solid tumors without recurrence is still a challenge for real applications. To balance hyperthermia and a high drug-loading capacity in polyprodrugs to achieve mild PT-CT, we rationally designed a novel type of intracellular pH and reduction-cleavable chlorambucil prodrug and synthesized high drug-loading polydopamine-chlorambucil conjugate nanoparticles (PDCBs). The PDCBs show good photothermal properties and demonstrate intracellular pH-, reduction-cleavable, and external near infrared (NIR)-triggered drug release profiles. Polydopamine-chlorambucil conjugate nanoparticles with 40 wt% CB (PDCB40) and mild NIR irradiation could facilitate cellular internalization and subcellular trafficking, generating an excellent and synergistic antitumor effect in vitro. Pharmacokinetics and small animal fluorescent and photoacoustic imaging demonstrate that PDCB40 has a 3.6-fold longer blood circulation time compared to free CB and attained selective tumor accumulation, simultaneously inducing a 4.1-fold stronger photoacoustic signal than the control. By using one intravenous injection of PDCB40 and a single dose of mild NIR irradiation, this simple and mild PT-CT treatment achieved a non-discerned tumor on the sixth day, and traceless and complete ablation of a solid MCF-7 tumor without recurrence within 50 days, opening up a new avenue for precise cancer therapy with the potential for real applications.

Platinum(IV) complex-based two-in-one polyprodrug for a combinatorial chemo-photodynamic therapy.

A combinatorial therapy that utilizes two or more therapeutic modalities is more effective in overcoming the limitations than each individual method used alone. Despite great advances have been achieved, the combination of chemotherapy and photodynamic therapy (PDT) still cannot satisfy the clinic requirements as the antitumor efficacy could be severely affected by tumor-associated hypoxia. Herein, for the first time, we reported a platinum(IV) complex-based polyprodrug that can in situ generate the highly toxic platinum(II) species as chemotherapeutics and simultaneously induce a high level of reactive oxygen species (ROS) in a PDT-like process without the use of photosensitizer and consumption of oxygen. By in situ polymerizing the platinum(IV) complex-based prodrug monomer (PPM) and 2-methacryloyloxy ethyl phosphorylcholine (MPC), nanosized hydrogel-like polyprodrug could be synthesized. Upon being exposed to light, Pt(IV) moieties in this photoactivable polyprodrug were reduced to generate Pt(II) species. At the meantime, a high level of ROS was generated without the presence of endogenous oxygen, which was confirmed by electron spin resonance (ESR) and fluorescence probes. With the unique nanosized architecture and photoresponsive feature, the as-synthesized polyprodrug exhibited the advantages of sustained drug release, long-term circulation, preferable tumor accumulation, and reversing drug resistance by downregulating the expression of multidrug resistance-associated protein 1 (MRP1) in the anticancer treatment.

Biopolymer-Drug Conjugate Nanotheranostics for Multimodal Imaging-Guided Synergistic Cancer Photothermal-Chemotherapy.

Some of the biomedical polymer-drug conjugates are being translated into clinical trials; however, they intrinsically lack photothermal and multi-imaging capabilities, hindering them from imaging-guided precision cancer therapy and complete tumor regression. We introduce a new concept of all-in-one biopolymer-drug conjugate nanotheranostics and prepare a kind of intracellular pH-sensitive polydopamine-doxorubicin (DOX) conjugate nanoparticles (PDCNs) under mild conditions. Significantly, this strategy integrates polymeric prodrug-induced chemotherapy (CT), near-infrared (NIR) light-mediated photothermal therapy (PT), and triple modalities including DOX self-fluorescence, photothermal, and photoacoustic (PA) imaging into one conjugate nanoparticle. The PDCNs present excellent photothermal property, dual stimuli-triggered drug release behavior, and about 12.4-fold blood circulation time compared to free DOX. Small animal fluorescent imaging technique confirms that PDCNs have preferential tumor accumulation effect in vivo, giving a 12.8-fold DOX higher than the control at 12 h postinjection. Upon NIR laser irradiation (5 min, 808 nm, and 2 W·cm-2), the PDCN-mediated photothermal effect can quickly elevate the tumor over 50 °C, exhibiting good photothermal and PA imaging functions, of which the PA amplitude is 3.6-fold greater than the control. In vitro and in vivo assays persuasively verify that intravenous photothermal-CT of PDCNs produces synergistic antitumor activity compared to single PT or CT, achieving complete tumor ablation during the evaluation period.

Construction of a Supramolecular Drug-Drug Delivery System for Non-Small-Cell Lung Cancer Therapy.

Nanoscale drug delivery systems (DDSs) are generally considered to be an effective alternative to small molecular chemotherapeutics due to improved accumulation in the tumor site and enhanced retention in blood. Nevertheless, most DDSs have low loading efficiency or even pose a high threat to normal organs from severe side effects. Ideally, a supramolecular drug-drug delivery system (SDDDS) composed of pure drugs via supramolecular interaction provides a hopeful approach for cancer treatment. Herein we propose a facile method to construct SDDDS via coassembly of gefitinib (GEF) and tripeptide tyroservatide (YSV), two kinds of chemotherapeutic pharmaceuticals for non-small-cell lung cancer (NSCLC) via multiple intermolecular interactions, including hydrogen bonding and π-π stacking. As shown through transmission electron microscopy (TEM) and dynamic light scattering (DLS), GEF and YSV self-assemble into nanoparticles with regular morphology and uniform size, which facilitates the delivery of both drugs. In vitro studies demonstrate that the SDDDS is much more efficient in entering cancer cells and inhibiting the proliferation of cancer cells compared with single GEF, YSV, or GEF/YSV drug mixture. In vivo experiments show that the SDDDS can selectively accumulate in tumor tissue, resulting in much better drug efficacy without evident side effects. Considering the advantages of the SDDDS, we believe this strategy provides a promising route for enhanced anticancer therapy in nanomedicine.