Increased Tumor Accumulation Research Articles

Overcoming drug resistance with a docetaxel and disulfiram loaded pH-sensitive nanoparticle.

Previous studies have demonstrated that breast cancer cells deploy a myriad array of strategies to thwart the activity of anticancer drugs like docetaxel (DTX), including acquired drug resistance due to overexpression of drug-efflux pumps like P-glycoprotein (P-gp) and innate drug resistance by cancer stem cells (CSCs). As disulfiram (DSF) can inhibit both P-gp and CSCs, we hypothesized that co-treatment of DTX and DSF could sensitize the drug-resistant breast cancer cells. To deliver a fixed dose ratio of DTX and DSF targeted to the tumor, a tumor extracellular pH-responsive nanoparticle (NP) was developed using a histidine-conjugated star-shaped PLGA with TPGS surface decoration ([DD]NpH-T). By releasing the encapsulated drugs in the tumor microenvironment, pH-sensitive NPs can overcome the tumor stroma-based resistance against nanomedicines. In in-vitro studies, [DD]NpH-T exhibited increased drug release at pH 6.4, improved penetration in a 3D tumor spheroid, reduced serum protein adsorption, and enhanced cytotoxic efficacy against both innate and acquired DTX-resistant breast cancer cells. In in-vivo studies, a significant increase in plasma AUC and tumor drug delivery was observed with [DD]NpH-T, which resulted in an enhanced in-vivo anti-tumor efficacy against a mouse orthotopic breast cancer, with a significantly increased intratumoral ROS and apoptosis, while decreasing P-gp expression and prevention of lung metastasis. Altogether, the current study demonstrated that the DTX and DSF combination could effectively target multiple drug-resistance pathways in-vitro, and the in-vivo delivery of this drug combination using TPGS-decorated pH-sensitive NPs could increase tumor accumulation, resulting in improved anti-tumor efficacy.

Bone tumor-homing nanotherapeutics for prolonged retention in tumor microenvironment and facilitated apoptotic process via mevalonate pathway inhibition.

Bone malignancy features a mineralized extracellular matrix primarily composed of hydroxyapatite, which interferes with the distribution and activity of antineoplastic agents. Herein, we report bone tumor-homing polymeric nanotherapeutics consisting of alendronate-decorated chondroitin sulfate A-graft-poly(lactide-co-glycolide) and doxorubicin (DOX), named PLCSA-AD, which displayed a prolonged retention profile in the tumor microenvironment and augmented therapeutic efficacy via inhibition of the mevalonate pathway. PLCSA-AD exhibited a 1.72-fold lower IC50 value than free DOX and a higher affinity for hydroxyapatite than PLCSA in HOS/MNNG cell-based 2D bone tumor-mimicking models. The inhibition of the mevalonate pathway by PLCSA-AD in tumor cells was verified by investigating the cytosolic fraction of unprenylated proteins, where blank PLCSA-AD significantly increased the expression of cytosolic Ras and RhoA without changing their total cellular amounts. In a bone tumor-mimicking xenografted mouse model, AD-decorated nanotherapeutics significantly increased tumor accumulation (1.73-fold) compared with PLCSA, and higher adsorption to hydroxyapatites was observed in the histological analysis of the tumor. As a result, inhibition of the mevalonate pathway and improvement in tumor accumulation led to markedly enhanced therapeutic efficacy in vivo, suggesting that PLCSA-AD could be promising nanotherapeutics for bone tumor treatment.

Planted Graphene Quantum Dots for Targeted, Enhanced Tumor Imaging and Long-Term Visualization of Local Pharmacokinetics.

While photoluminescent graphene quantum dots (GQDs) have long been considered very suitable for bioimaging owing to their protein-like size, superhigh photostability and in vivo long-term biosafety, their unique and crucial bioimaging applications in vivo remain unreachable. Herein, planted GQDs are presented as an excellent tool for in vivo fluorescent, sustainable and multimodality tumor bioimaging in various scenarios. The GQDs are in situ planted in the poly(ethylene glycol) (PEG) layer of PEGylated nanoparticles via a bottom-up molecular approach to obtain the NPs-GQDs-PEG nanocomposite. The planted GQDs show more than four times prolonged blood circulation and 7-8 times increased tumor accumulation than typical GQDs in vivo. After accessible specificity modification, the multifunctional NPs-GQDs-PEG provides targeted, multimodal molecular imaging for various tumor models in vitro or in vivo. Moreover, the highly photostable GQDs enable long-term, real-time visualization of the local pharmacokinetics of NPs in vivo. Planting GQDs in PEGylated nanomedicine offers a new strategy for broad in vivo biomedical applications of GQDs.

BPA‐Containing Polydopamine Nanoparticles for Boron Neutron Capture Therapy in a U87 Glioma Orthotopic Model

AbstractBoron neutron capture therapy (BNCT) is a promising therapy for refractory cancer based on the cytotoxic reaction of 10B (n, α) 7Li. Although two BNCT agents are clinically available, they are quickly metabolized and show modest enrichment in tumor sites, partially limiting BNCT widespread application. Consequently, novel agents that perform active targeting and show good biocompatibility have to be developed. Herein, boronophenylalanine‐containing polydopamine (B‐PDA) nanoparticles are easily fabricated by encapsulating boronophenylalanine (BPA) in polydopamine via nitrogen‐boronate coordination. In this study, B‐PDA achieves increased tumor accumulation and prolonged retention effects in the tumor site and superior antitumor activity post neutron irradiation in the orthotopic xenograft glioma model. In brief, this study offers a novel strategy for BPA delivery and may broaden the perspective on nanomedicine design for BNCT.

Enhanced Tumor Accumulation of Low-Molecular-Weight Hyaluronic Acid/Chitosan Nanocomplexes for Photothermal Therapy

Targeted phototheranostic nanosystems involving both cancer-specific near-infrared (NIR) fluorescence imaging and NIR light-induced phototherapy have shown great potential to improve cancer detection and treatment. In this study, a bifunctional nanocomplex based on low-molecular-weight hyaluronic acid (LMW-HA) and chitosan oligosaccharide lactate (COL) conjugating a zwitterionic NIR dye (ZW800-1) was rationally designed and prepared, and it was simultaneously used to enhance tumor accumulation and photothermal therapy (PTT). When HA-COL-ZW nanocomplexes were intravenously injected into mice bearing NCI-H460 tumors, HA-COL-ZW revealed increased tumor accumulation with prolonged tumor retention. Moreover, the ZW800-1 incorporated in HA-COL-ZW nanocomplexes showed excellent capability to convert NIR light into heat energy at the tumor site, acting as a PTT agent. Therefore, the targeted phototherapeutic HA-COL-ZW nanocomplex is a biocompatible and effective photothermal nanoagent, which could be a good candidate for future clinical use.

Synthesis of pH-responsive polyzwitterions for activated cellular uptake and tumor accumulation of gold nanoparticles at tumorous acidity

The response sensitivity of surface material plays an important role in adjustable nano-bio interaction in vivo. In this present, a zwitterionic polymer (polyzwitterion) containing quaternary ammonium cation and sulfonamide anion poly(4-((4-(3-(methacryloyloxy)propoxy)phenyl) sulfonamido)-N, N, N-trimethyl-4-oxobutan-1-aminium chloride) (PMPTSA) was synthesized by Reversible Addition-Fragmentation Chain Transfer Polymerization (RAFT) polymerization to explore the pH responsive behavior in tumors. The PMPTSA-coated gold nanoparticles (PMPTSA-@-Au NPs) showed zwitterionic nature such as antifouling ability, low cellular uptake and prolonged circulation time similar with common hydrophilic polymers, including polyethylene glycol (PEG), poly(carboxybetaine methacrylate) and poly(sulfobetaine methacrylate) functional gold nanoparticles in physiological environment (pH 7.4). A high sensitivity and reversible positive charge conversion of P(MPTSA)-@-Au NPs at tumor slight acidic microenvironment (∼pH 6.8) leaded to an enhanced cellular internalization than that at pH 7.4 and increased tumor accumulation compared with PEG, polycarboxybetaines and polymer sulphobetaine (PSB) functional gold nanoparticles. The highly pH responsive PMPTSA will provide the promising application in cancer nanomedicine.

Stiffness-Transformable Nanoplatforms Responsive to the Tumor Microenvironment for Enhanced Tumor Therapeutic Efficacy.

Herein, we report, for the first time, a unique stiffness-transformable manganese oxide hybridized mesoporous organosilica nanoplatform (MMON) for enhancing tumor therapeutic efficacy. The prepared MMONs had a quasi-spherical morphology and were completely transformed into soft bowl-like nanocapsules in the simulated tumor microenvironment through the breakage of Mn-O bonds, which decreased their Young's modulus from 165.7 to 84.5 MPa. Due to their unique stiffness transformation properties, the MMONs had reduced macrophage internalization, improved tumor cell uptake, and enhanced penetration of multicellular spheroids. In addition, in vivo experiments showed that the MMONs displayed a 3.79- and 2.90-fold decrease in non-specific liver distribution and a 2.87- and 1.83-fold increase in tumor accumulation compared to their soft and stiff counterparts, respectively. Furthermore, chlorin e6 (Ce6) modified MMONs had significantly improved photodynamic therapeutic effect.

Stiffness‐Transformable Nanoplatforms Responsive to the Tumor Microenvironment for Enhanced Tumor Therapeutic Efficacy

AbstractHerein, we report, for the first time, a unique stiffness‐transformable manganese oxide hybridized mesoporous organosilica nanoplatform (MMON) for enhancing tumor therapeutic efficacy. The prepared MMONs had a quasi‐spherical morphology and were completely transformed into soft bowl‐like nanocapsules in the simulated tumor microenvironment through the breakage of Mn−O bonds, which decreased their Young's modulus from 165.7 to 84.5 MPa. Due to their unique stiffness transformation properties, the MMONs had reduced macrophage internalization, improved tumor cell uptake, and enhanced penetration of multicellular spheroids. In addition, in vivo experiments showed that the MMONs displayed a 3.79‐ and 2.90‐fold decrease in non‐specific liver distribution and a 2.87‐ and 1.83‐fold increase in tumor accumulation compared to their soft and stiff counterparts, respectively. Furthermore, chlorin e6 (Ce6) modified MMONs had significantly improved photodynamic therapeutic effect.

Enhanced Tumor Uptake and Retention of Cyanine Dye-Albumin Complex for Tumor-Targeted Imaging and Phototherapy.

Heptamethine cyanine dyes are widely used for in vivo near-infrared (NIR) fluorescence imaging and NIR laser-induced cancer phototherapy due to their good optical properties. Since most of heptamethine cyanine dyes available commercially are highly hydrophobic, they can usually be used for in vivo applications after formation of complexes with blood plasma proteins, especially serum albumin, to increase aqueous solubility. The complex formation between cyanine dyes and albumin improves the chemical stability and optical property of the hydrophobic cyanine dyes, which is the bottom of their practical use. In this study, the complexes between three different heptamethine cyanine dyes, namely clinically available indocyanine green (ICG), commercially available IR-786 and zwitterionic ZW800-Cl, and bovine serum albumin (BSA), were prepared to explore the effect of cyanine dyes on their tumor uptake and retention. Among the three complexes, IR-786©BSA exhibited increased tumor accumulation with prolonged tumor retention, compared to other complexes. Moreover, IR-786 bound to BSA played an important role in tumor growth suppression due to its cytotoxicity. To achieve complete tumor ablation, the tumor targeted by IR-786©BSA was further exposed to 808 nm laser irradiation for effective photothermal cancer treatment.

A Leaking-Proof Theranostic Nanoplatform for Tumor-Targeted and Dual-Modality Imaging-Guided Photodynamic Therapy.

Objective: A protein-based leaking-proof theranostic nanoplatform for dual-modality imaging-guided tumor photodynamic therapy (PDT) has been designed. Impact Statement: A site-specific conjugation of chlorin e6 (Ce6) to ferrimagnetic ferritin (MFtn-Ce6) has been constructed to address the challenge of unexpected leakage that often occurs during small-molecule drug delivery. Introduction: PDT is one of the most promising approaches for tumor treatment, while a delivery system is typically required for hydrophobic photosensitizers. However, the nonspecific distribution and leakage of photosensitizers could lead to insufficient drug accumulation in tumor sites. Methods: An engineered ferritin was generated for site-specific conjugation of Ce6 to obtain a leaking-proof delivery system, and a ferrimagnetic core was biomineralized in the cavity of ferritin, resulting in a fluorescent ferrimagnetic ferritin nanoplatform (MFtn-Ce6). The distribution and tumor targeting of MFtn-Ce6 can be detected by magnetic resonance imaging (MRI) and fluorescence imaging (FLI). Results: MFtn-Ce6 showed effective dual-modality MRI and FLI. A prolonged invivo circulation and increased tumor accumulation and retention of photosensitizer was observed. The time-dependent distribution of MFtn-Ce6 can be precisely tracked in real time to find the optimal time window for PDT treatment. The colocalization of ferritin and the iron oxide core confirms the high stability of the nanoplatform invivo. The results showed that mice treated with MFtn-Ce6 exhibited marked tumor-suppressive activity after laser irradiation. Conclusion: The ferritin-based leaking-proof nanoplatform can be used for the efficient delivery of the photosensitizer to achieve an enhanced therapeutic effect. This method established a general approach for the dual-modality imaging-guided tumor delivery of PDT agents.

Deuterated colchicine liposomes based on oligomeric hyaluronic acid modification enhance anti-tumor effect and reduce systemic toxicity

Deuterated drugs are produced by substituting hydrogen atoms with deuterium atoms at specific sites in a drug molecule to prolong its metabolic cycle and reduce the production of toxic metabolites. Deuterated drugs have recently attracted increasing attention from the pharmaceutical industry. Colchicine exhibits a strong anti-tumor activity but has a short half-life, rapid attenuated drug concentration, narrow treatment window, and lack of tumor-specific targeting in vivo, resulting in toxicity and side effects. In this study, we explored whether deuteration could reduce the toxicity of colchicine. We prepared deuterated colchicine liposomes coated with oligo-hyaluronic acid, which can bind to the tumor-specific CD44 receptor and reduce the clearance of immune cells from the blood, resulting in a long blood circulation time and active targeting. We observed that deuteration of the colchicine B ring reduced drug toxicity and improved the anti-tumor response in 4 T1 breast cancer. Liposomes modified with oligo-hyaluronic acid exhibited increased tumor accumulation, further improving the anti-tumor effect of the drugs. Our results provide a basis for the development and application of deuterated drugs in the field of nano-preparations.

Extracellular matrix degrading enzyme with stroma-targeting peptides enhance the penetration of liposomes into tumors.

Various anti-tumor nanomedicines have been developed based on the enhanced permeability and retention effect. However, the dense extracellular matrix (ECM) in tumors remains a major barrier for the delivery and accumulation of nanoparticles into tumors. While ECM-degrading enzymes, such as collagenase, hyaluronidase, and bromelain, have been used to facilitate the accumulation of nanoparticles, serious side effects arising from the current non-tumor-specific delivery methods limit their clinical applications. Here, we report targeted delivery of bromelain into tumor tissues through its covalent attachment to a hyaluronic acid (HA)-peptide conjugate with tumor ECM targeting ability. The ECM targeting peptide, collagen type IV-binding peptide (C4BP), was chosen from six candidate-peptides based on their ability to bind to frozen sections of triple-negative breast cancer, 4T1 tumor ex vivo. The HA- C4BP conjugate showed a significant increase in tumor accumulation in 4T1-bearing mice after intravenous administration compared to unmodified HA. We further demonstrated that the systemic administration of bromelain conjugated C4BP-HA (C4BP-HA-Bro) potentiates the anti-tumor efficacy of liposomal doxorubicin. C4BP-HA-Bro decreased the number and length of collagen fibers and improved the distribution of doxorubicin within the tumor. No infusion reaction was noted after delivery of C4BP-HA-Bro. C4BP-HA thus offers a potential for effective and safe delivery of bromelain for improved intratumoral delivery of therapeutics.

PH-responsive nanoprodrugs combining a Src inhibitor and chemotherapy to potentiate antitumor immunity via pyroptosis in head and neck cancer

As the prominent feature of the development and progression of head and neck squamous cell carcinoma (HNSCC) is immunosuppression, therapeutic strategies to restore antitumor immunity have shown promising prospects. The efficacy of chemotherapy, a mainstay in HNSCC treatment, is exemplified by cytotoxic effects as well as immunostimulation, whereas compensatory activation of prosurvival signals in tumor tissues may compromise its efficacy. Aberrant activation of Src is present in many human malignancies including HNSCC, and is implicated in chemotherapy resistance. In this regard, tumor-microenvironment-responsive prodrug nanomicelles (PDO NPs) are rationally designed to combine chemotherapy (oxaliplatin, OXA) and Src inhibitors (dasatinib, DAS) for HNSCC therapy. PDO NPs are constructed by chemically modifying small-molecule prodrugs (DAS-OXA) loaded in block copolymer iPDPA with pH-triggered transforming capability. PDO NPs can controllably release drugs in response to tumor acidity, thus increasing tumor accumulation and therapeutic efficacy. Moreover, PDO NPs can elicit pyroptosis of tumor cells and induce T-cell-mediated antitumor immunity in murine HNSCC models. In summary, nanoprodrugs integrating Src inhibitors enhance the immunological effects of chemotherapy and provide insight into promising approaches for augmenting immunochemotherapy for HNSCC. Statement of SignificanceIn this study, pH-responsive nanomicelles (PDO NPs) were constructed by loading a small molecular prodrug synthesized by the Src inhibitor dasatinib and the chemotherapy drug oxaliplatin into the amphiphilic block copolymer iPDPA to improve the immunological effects of chemotherapy for HNSCC. These nanomicelles can efficiently accumulate in tumor cells and achieve pH-responsive drug release. The PDO NPs can induce pyroptosis of tumor cells and potentiate antitumor immunity in subcutaneous and syngenetic orthotopic HNSCC mouse models, which may present a promising strategy to enhance immunochemotherapy for HNSCC.

Size-Controllable DNA Origami-Stacked Gold Nanoparticles for Deep Tumor-Penetrating Therapy.

With the rapid development of nanotechnology, researchers have designed a variety of intelligent nanodelivery systems to enhance tumor targeting of anticancer drugs. However, increased tumor accumulation does not indicate deeper penetration in the tumor tissue, without which the tumor cells in the core area cannot be sufficiently killed. Herein, we develop a size-controllable nanoparticle system for deep-penetrating cancer therapy, which will be programmably disassembled with the decrease of the pH from the normal tissue to the tumor microenvironment and to the intracellular area. The integrated nanoparticle is composed of a gold nanoparticle (GNP, ∼30 nm) and a tetrahedral DNA nanostructure (TDN, ∼25 nm) loaded with doxorubicin (DOX). Initially, the nanoparticles maintain a larger size (∼100 nm) to accumulate in the tumor through the enhanced permeability and retention effect. At a pH of about 6.5 at the tumor microenvironment, with the linkage of DNA sequences converting into a triplex structure, the TDNs detach from the GNP and penetrate deeply into the tumor interstitium and then are internalized into the cells. Finally, in acidic lysosomes with pH 5.0, the TDNs release DOX by forming an i-motif structure. This nanosmart delivery system thus shows effective deep penetration into the tumor core with good antitumor efficacy and satisfactory biocompatibility and provides new insights into the development of intelligent nanosystems for anti-cancer treatment.

Tumor-Associated Enzyme-Activatable Spherical Nucleic Acids.

Maximizing the tissue-targeting efficiency of nanomaterials while also protecting them from rapid clearance from the bloodstream and limiting their immunogenicity remains a central problem in the field of systemic-administered nanomedicine. Herein, we introduce a generalizable strategy to simultaneously increase tumor accumulation, prolong blood circulation, and limit nonspecific immune activation of nanomaterials via peptide-based, tumor-responsive, "sheddable" coatings. Spherical nucleic acids (SNAs) were designed and synthesized to contain an exterior coating composed of zwitterionic polypeptides with recognition sequences for tumor-associated proteases. In the presence of matrix metalloproteinases (MMPs), the polypetide coating is rapidly cleaved, leading to increased cellular uptake of these SNAs, relative to SNAs containing nonsheddable shells. Moreover, the zwitterionic nature of the polypeptide shell shields the SNAs from immune system recognition, which extends their blood circulation time and improves tumor accumulation and in vivo cellular uptake relative to control SNAs with no protective coating. Taken together, these results indicate that this strategy is a viable method for increasing nanoparticle tumor accumulation and can have utility for the systemic delivery of oligonucleotides and nanomaterials to target cells in vivo with low immunogenicity.

Liposomal Co-delivery of PD-L1 siRNA/Anemoside B4 for Enhanced Combinational Immunotherapeutic Effect.

Combination therapy has gained a lot of attention thanks to its superior activity against cancer. In the present study, we report a cRGD-targeted liposomal preparation for co-delivery of programmed cell death ligand 1 (PD-L1) small interfering RNA (siRNA) and anemoside B4 (AB4)─AB4/siP-c-L─and evaluate its anticancer efficiency in mouse models of LLC and 4T1 tumors. AB4/siP-c-L showed a particle size of (180.7 ± 7.3) nm and a ζ-potential of (32.8 ± 1.5) mV, with high drug encapsulation, pH-sensitive release properties, and good stability in serum. AB4/siP-c-L demonstrated prolonged blood circulation and increased tumor accumulation. Elevated cellular uptake was dependent on the targeting ligand cRGD. This combination induced significant tumor inhibition in LLC xenograft tumor-bearing mice by downregulating PD-L1 protein expression and modulating the immunosuppressive microenvironment. Liposomes favored the antitumor T-cell response with long-term memory, without obvious toxicity. A similar tumor growth inhibition was also demonstrated in the 4T1 tumor model. In summary, our results indicate that cRGD-modified and AB4- and PD-L1 siRNA-coloaded liposomes have potential as an antitumor preparation, and this approach may lay a foundation for the development of a new targeted drug delivery system.

Improving Tirapazamine (TPZ) to Target and Eradicate Hypoxia Tumors by Gold Nanoparticle Carriers.

Tumor hypoxia is a hallmark of solid tumors and emerged as the therapeutic target for cancer treatments, such as a prodrug Tirapazamine (TPZ) activated in hypoxia. To increase tumor accumulation, gold nanoparticles (GNPs) were selected to conjugate with TPZ. In this study, we successfully formulated and assessed the biochemical and therapeutic roles of the conjugated gold nanoparticles–Tirapazamine (GNPs–TPZ) on therapeutic assessments of MKN45-induced xenograft animal model. The results indicated that GNPs–TPZ was a potential nanomedicine for selectively targeting hypoxia tumors coupled with decreased side effects on healthy tissue or organs. TPZ significantly reduced cell viability of hypoxic gastric cancer MKN45 cells, but not in cells incubated in normoxia condition. For improving tumor targeting efficiency, furthermore, the GNPs drug carrier was conjugated to TPZ via biding mediator bovine serum albumin (BSA), and we demonstrated that this conjugated GNPs–TPZ retained the unique characteristics of hypoxic toxin and possessed the adequate feature of systemic bio-distributions in animals. GNPs–TPZ nanoparticles revealed their superior affinity to hypoxia tumors in the MKN45 xenograft. Moreover, GNPs–TPZ treatments did not significantly alter the biochemical parameters of blood samples acquired from animals. Taken together, TPZ, a prodrug activated by hypoxia, was conjugated with GNPs, whereas BSA severed as an excellent binding agent for preparing the conjugated GNPs–TPZ nanomedicines. We demonstrated that GNPs–TPZ enhanced tumor targeting, resulting in higher therapeutic efficacy compared to TPZ. We suggest that it may sever as an adjuvant treatment or combined therapy with other chemotherapeutics for the treatment of cancer patients in the future.

Single-treatment tumor ablation with photodynamic liposomal irinotecan sucrosulfate

Irinotecan (IRI) loaded actively into PEGylated liposomes via a sucrosulfate gradient has been approved recently to treat advanced pancreatic cancer. In this study, a similar liposomal composition was developed that includes a low mole fraction (1 mol.%) of porphyrin-phospholipid (PoP), a photosensitizer that stably incorporates into liposomes, to confer light-triggered IRI release. IRI-loaded PoP liposomes containing ammonium sucrosulfate (ASOS) as a complexing agent were more stable in serum compared to liposomes employing the more conventional ammonium sulfate. Without irradiation, PoP IRI liposomes released less than 5% IRI during 8 h of incubation in bovine serum at 37 °C, but released over 90% of the drug within minutes of exposure to red light (665 nm) irradiation. A single treatment with IRI-PoP liposomes and light exposure (15 mg/kg IRI with 250 J/cm2) resulted in tumor eradication in mice bearing either MIA PaCa-2 tumors or low-passage patient-derived tumor xenografts that recapitulate characteristics of the clinical disease. Analogous monotherapies of IRI or photodynamic therapy were ineffective in controlling tumor growth. Enhanced drug uptake could be visualized within laser-treated tumors by direct in situ imaging of irinotecan. Biodistribution analysis of IRI, its active metabolite (SN-38), and major metabolite (SN-38 G) showed that laser treatment significantly increased tumor accumulation of all IRI-derived molecular species. A pharmacokinetic model that hypothesized tumor vasculature permeabilization as the primary reason underlying the increased drug deposition accounted for the enhanced drug influx into tumors.

Cooperative coordination-mediated multi-component self-assembly of “all-in-one” nanospike theranostic nano-platform for MRI-guided synergistic therapy against breast cancer

Carrier-free multi-component self-assembled nano-systems have attracted widespread attention owing to their easy preparation, high drug-loading efficiency, and excellent therapeutic efficacy. Herein, MnAs-ICG nanospike was generated by self-assembly of indocyanine green (ICG), manganese ions (Mn2+), and arsenate (AsO43−) based on electrostatic and coordination interactions, effectively integrating the bimodal imaging ability of magnetic resonance imaging (MRI) and fluorescence (FL) imaging-guided synergistic therapy of photothermal/chemo/chemodynamic therapy within an “all-in-one” theranostic nano-platform. The as-prepared MnAs-ICG nanospike had a uniform size, well-defined nanospike morphology, and impressive loading capacities. The MnAs-ICG nanospike exhibited sensitive responsiveness to the acidic tumor microenvironment with morphological transformation and dimensional variability, enabling deep penetration into tumor tissue and on-demand release of functional therapeutic components. In vitro and in vivo results revealed that MnAs-ICG nanospike showed synergistic tumor-killing effect, prolonged blood circulation and increased tumor accumulation compared to their individual components, effectively resulting in synergistic therapy of photothermal/chemo/chemodynamic therapy with excellent anti-tumor effect. Taken together, this new strategy might hold great promise for rationally engineering multifunctional theranostic nano-platforms for breast cancer treatment.

Hydroxyapatite-binding albumin nanoclusters for enhancing bone tumor chemotherapy

Hydroxyapatite-binding albumin nanoclusters (NCs) were developed for improving the anticancer agent accumulation in bone tumors. Human serum albumin (HSA) was decorated with alendronate (AD), and doxorubicin (DOX)-loaded NCs (HSA-AD/DOX) were fabricated via the ball-milling technology, an innovative nano-fabrication method by which more than 90% of the secondary structures of albumin can be preserved. The targeting ability of NCs was confirmed using a novel in vitro bone cancer model, wherein hydroxyapatite and collagen, the major components of the bone matrix representing the highly mineralized bone tumor microenvironment, were co-cultured with HOS/MNNG, a human osteosarcoma cell line. The binding affinity of HSA-AD/DOX to hydroxyapatite was evaluated based on the DOX binding efficiency. HSA-AD/DOX showed a 5.04-fold higher affinity than HSA/DOX. The enhanced distribution of HSA-AD/DOX to bone tumors was verified using a newly developed mouse model bearing HOS/MNNG tumors with hydroxyapatite beads. HSA-AD/DOX led to a 52.0% increase in tumor accumulation compared to that of the unmodified HSA/DOX. This is mainly due to the hydroxyapatite-binding affinity of the AD moiety, which is supported by histological analyses performed on the dissected tumors. Furthermore, HSA-AD/DOX changed the protein expression patterns of the tumors, implying the enhanced apoptotic process. Overall, the targeting ability of HSA-AD/DOX are effectively translated into improved therapeutic efficacy in bone tumor-xenografted mice, suggesting that the developed NCs are a promising delivery system for bone tumor treatment.