Chemo-photothermal Tumor Therapy Research Articles

Spherical g-C3N4@PDA nanocarrier for synergistic chemo-photothermal tumor therapy

In this paper, by wrapping the near-infrared (NIR) response polydopamine (PDA) as a nanocoating on the surface of spherical nano graphitic phase carbon nitride (g-C3N4), a multifunctional g-C3N4/PDA (CNP) nanocarrier platform was prepared. The π-conjugation system in PDA and the electronegative hydroxyl groups on the surface of CNP promote the creation of abundant active sites, which had a high drug loading rate of about 98.5 % for the electropositive GA. Due to the strong NIR reaction of CNP, the release of GA from CNP/GA can be greatly accelerated by the rising temperature, bonding disruption and charge transfer. Moreover, the photo-generated electron-hole pairs could be excited by the NIR effect of CNP, which promotes the production of ROS (·OH, ·O2– and 1O2) to induce apoptosis in HepG2 cells. Thus, the present spherical CNP nanocarrier with a combination of enzyme-mimic activity and NIR-responsive properties has a great potential for chemo-photothermal synergistic tumor therapy.

Holmium (III)-doped multifunctional nanotheranostic agent for ultra-high-field magnetic resonance imaging-guided chemo-photothermal tumor therapy

Ultra-high-field (UHF) MRI has shown great advantages over low-field magnetic resonance imaging (MRI). Despite being the most commonly used MRI contrast agents, gadolinium chelates perform poorly in high magnetic fields, which significantly weakens their T1 intensity. In comparison, the rare element Holmium (Ho)-based nanoparticles (NPs) have demonstrated great potential as T2-weighted MRI contrast agents in UHF MRI due to their extremely short electron relaxation times (∼ 10−13s). In this study, a multifunctional nanotherapeutic probe was designed for UHF MRI-guided chemotherapy and photothermal therapy. The Ho (III)-doped mesoporous polydopamine (Ho-MPDA, HM) nanosphere was loaded with the chemotherapeutic drug mitoxantrone (MTO) and then coated with 4T1 cell membranes to enhance active targeting delivery to breast cancer. The prepared nanotherapeutic probe MTO@HMM@4T1 (HMM@T) exhibited good biocompatibility, high drug-loading capability and great potential as Ho (III)-based UHF MRI contrast agents. Moreover, the biodegradation of HMM@T in response to the intratumor pH and glutathione (GSH) promotes MTO release. Near-infrared (NIR) light irradiation of HM induced photothermal therapy and further enhanced drug release. Consequently, HMM@T effectively acted as an MRI-guided tumor-targeting chemo-photothermal therapy against 4T1 breast cancer. Statement of significanceUltra-high-field (UHF) MRI has shown great advantages over low-field magnetic resonance imaging (MRI). Although gadolinium chelates are the most commonly used MRI contrast agents in clinical practice, they exhibit a significantly decreased T1 relaxivity at UHF. Holmium exhibits outstanding UHF magnetic resonance capabilities in comparison with gadolinium chelates currently used in clinic. Herein, a theranostic nanodrug (HMM@T) was designed for UHF MRI-guided chemo-photothermal therapy. The nanodrug possessed remarkable UHF T2 MRI properties (r2 = 152.13 mM−1s−1) and high drug loading capability of 18.4 %. The biodegradation of HMM@T NPs under triple stimulations of pH, GSH, and NIR led to an efficient release of MTO in tumor microenvironment. Our results revealed the potential of a novel UHF MRI-guided multifunctional nanosystem in cancer treatment.

Positive Chemotaxis of CREKA-Modified Ceria@Polydopamine Biomimetic Nanoswimmers for Enhanced Penetration and Chemo-photothermal Tumor Therapy.

Tumor interstitial pressure represents the greatest barrier against drug diffusion into the depth of the tumor. Biometric nanomotors highlight the possibility of enhanced deep penetration and improve cellular uptake. However, control of their directionality remains difficult to achieve. Herein, we report cysteine-arginine-glutamic acid-lysine-alanine (CREKA)-modified ceria@polydopamine nanobowls as tumor microenvironment-fueled nanoscale motors for positive chemotaxis into the tumor depth or toward tumor cells. Upon laser irradiation, this nanoswimmer rapidly depletes the tumor microenvironment-specific hydrogen peroxide (H2O2) in the nanobowl, contributing to a self-generated gradient and subsequently propulsion (9.5 μm/s at 46 °C). Moreover, the asymmetrical modification of CREKA on nanobowls could automatically reconfigure the motion direction toward tumor depth or tumor cells in response to receptor-ligand interaction, leading to a deep penetration (70 μm in multicellular spheroids) and enhanced antitumor effects over conventional nanomedicine-induced chemo-photothermal therapy (tumor growth inhibition rate: 84.2% versus 56.9%). Thus, controlling the direction of nanomotors holds considerable potential for improved antitumor responses, especially in solid tumors with high tumor interstitial pressure.

Light-initiated aggregation of gold nanoparticles for synergistic chemo-photothermal tumor therapy.

The combination of chemotherapy with photothermal therapy (PTT) has attracted extensive attention due to its excellent synergetic effect attributing to the fact that hyperthermia can effectively promote the tumor uptake of chemotherapeutic drugs. Herein, we propose a light-initiated gold nanoparticle (AuNP) aggregation boosting the uptake of chemotherapeutic drugs for enhanced chemo-photothermal tumor therapy. Novel light-responsive AuNPs (tm-AuNPs) were rationally designed and fabricated by conjugating both 2,5-diphenyltetrazole (Tz) and methacrylic acid (Ma) onto the surface of AuNPs with small size (∼20 nm). Upon the irradiation of 405 nm laser, AuNPs could be initiated to form aggregates specifically within tumors through the covalent cycloaddition reaction between Tz and Ma. Taking advantage of the controllable photothermal effect of Au aggregates under NIR excitation, improved enrichment of doxorubicin (DOX) in tumor tissues was realized, combined with PTT, resulting in outstanding synergetic anti-tumor efficacy in living mice. We thus believe that this light-initiated AuNP aggregation approach would offer a valuable and powerful tool for precisely synergistic chemo-photothermal tumor therapy.

Dopamine and DNA functionalized manganese whitlockite nanocrystals for magnetic resonance imaging and chemo-photothermal therapy of tumors

Multifunctional inorganic nanomaterials have opened new avenues for cancer diagnosis and therapy. However, the difficulty to functionalize them has prevented their wider application, owing to the lack of active groups on their surfaces. Here we report a novel method to functionalize manganese whitlockite (Mn-WH) with polydopamine (PDA) and hairpin DNA (hpDNA) to improve the water stability and anti-cancer effects of Mn-WH nanoparticles (Mn-WH NPs). Compared to WH NPs, the Mn-WH@PDA-hpDNA NPs exhibit better water dispersibility, high drug loading capacity, excellent photothermal performance, stable MRI imaging ability, and outstanding chemo-photothermal synergistic therapeutic potential against tumors. After intratumoral injection in nude mice, the Mn-WH@PDA-hpDNA-DOX NPs promote complete tumor ablation upon exposure to 808 laser-irradiation. The nanoparticles showed no major side effects or toxicity. Thus, these results indicate that the Mn-WH@PDA-hpDNA-DOX NPs have excellent potential as anti-cancer agents, along with excellent magnetic resonance imaging (MRI) capabilities and the reported functionalization approach provides a novel and effective strategy for the surface functionalization of inorganic nanomaterials.

Supercritical Fluid-Assisted Fabrication of PDA-Coated Poly (l-lactic Acid)/Curcumin Microparticles for Chemo-Photothermal Therapy of Osteosarcoma

After traditional osteosarcoma resection, recurrence of tumor is still a major clinical challenge. The combination of chemotherapy and photothermal therapy (PTT) has great potential in improving therapeutic effect. However, the studies using polydopamine (PDA) as photothermal transducing agent to improve the anti-cancer activity of curcumin (CM)-loaded poly (l-lactic acid) (PLLA) microparticles (PLLA/CM) have seldom been investigated. In this study, we reported the synthesis of PDA-coated PLLA/CM microparticles (PDA-PLLA/CM) prepared by PDA coating on the surface of the PLLA/CM microparticles fabricated by solution-enhanced dispersion by supercritical CO2 (SEDS) for chemo-photothermal therapy of osteosarcoma. The average particle sizes of PLLA/CM and PDA-PLLA/CM microparticles with a spherical shape were (802.6 ± 8.0) nm and (942.5 ± 39.5) nm, respectively. PDA-PLLA/CM microparticles exhibited pH- and near-infrared (NIR)-responsive release behavior to promote CM release in the drug delivery system. Moreover, PDA-PLLA/CM microparticles displayed good photothermal conversion ability and photothermal stability attributed to PDA coating. Additionally, the results of in vitro anti-cancer experiment showed that 500 μg/mL PDA-PLLA/CM microparticles had good anti-cancer effect on MG-63 cells and no obvious toxicity to MC3T3-E1 cells. After incubation with PDA-PLLA/CM microparticles for 2 days, NIR irradiation treatment improved the anti-cancer activity of PDA-PLLA/CM microparticles obviously and reduced the cell viability of osteosarcoma from 47.4% to 20.6%. These results indicated that PDA-PLLA/CM microparticles possessed a synergetic chemo-photothermal therapy for osteosarcoma. Therefore, this study demonstrated that PDA-PLLA/CM microparticles may be an excellent drug delivery platform for chemo-photothermal therapy of tumors.

A novel medically imageable intelligent cellulose nanofibril-based injectable hydrogel for the chemo-photothermal therapy of tumors

The design of injectable hydrogels with excellent biocompatibility, medical imaging, and antitumor activity to improve the therapeutic efficiency on tumor tissues and to reduce toxic side effects is very important in clinical practice. A novel medically imageable pH-, temperature- and NIR- intelligent cellulose nanofibril (TOCNF)-based injectable hydrogel was designed using pH-, and temperature-responsive TOCNF as the carrier, citric-acid-stabilized Prussian blue nanoparticles (PBNPs) as the contrast agent and photothermal switch, and doxorubicin (DOX) as the chemotherapeutics agent. The hydrogel possessed a nanocage structure and a 3D network structure, which allowed a high loading capacity of PBNPs (2 mg/g) and DOX (415 mg/g). The PBNPs stabilized on TOCNF through electrostatic interactions and hydrogen bond could aid medical magnetic resonance imaging (MRI) and photoacoustic imaging (PAI). Interestingly, the temperature, pH, and NIR tri-stimuli-responsive intelligent switches, inspired by the mimosa leaf, contributed to the controllable sustained DOX release property of the hydrogel. Therefore, in vivo bimodal MRI/PAI and tumor therapy results showed that the previously prepared hydrogel could be ideal for the rapid diagnosis and chemo-photothermal therapy in the clinical treatment of tumors.

A pH-responsive biomimetic drug delivery nanosystem for targeted chemo-photothermal therapy of tumors

A pH-responsive biomimetic drug delivery nanosystem for targeted chemo-photothermal therapy of tumors

Dextran-polylactide micelles loaded with doxorubicin and DiR for image-guided chemo-photothermal tumor therapy

Image-guided chemo-photothermal therapy based on near-infrared (NIR) theranostic agents has found promising applications in treating tumors. In this multimodal treatment, it is of critical importance to image real-time distribution of photothermal agents in vivo and to monitor therapeutic outcomes for implementing personalized treatment. In this study, an optimally synthesized dextran-polylactide (DEX-PLA) copolymer was assembled with doxorubicin (DOX) and DiR, a kind of NIR dye, to construct desirable micelles ((DiR + DOX)/DEX-PLA) for performing image-guided chemo-photothermal therapy. These (DiR + DOX)/DEX-PLA micelles had good physical and photothermal stability in aqueous media and showed high photothermal efficiency in vivo. Based on the H22-tumor-bearing mouse model, (DiR + DOX)/DEX-PLA micelles were found to accumulate inside tumors sustainably and to emit strong fluorescence signals for more than three days. The (DiR + DOX)@DEX-PLA micelles together with NIR laser irradiation were able to highly inhibit tumor growth or even eradicate tumors with one injection and two dose-designated 5-minute laser irradiations at the tumor site during 14 days of treatment. Furthermore, they showed almost no impairment to the body of the treated mice. These (DiR + DOX)@DEX-PLA micelles have confirmative translational potential in clinical tumor therapy on account of their persistent image-guided capacity, high antitumor efficacy and good in vivo safety.

Novel Multifunctional Stimuli-Responsive Nanoparticles for Synergetic Chemo–Photothermal Therapy of Tumors

In this study, a novel class of multifunctional responsive nanoparticles is designed and fabricated as drug nanocarriers for synergetic chemo-photothermal therapy of tumors. The proposed nanoparticles are composed of a thermo-/pH-responsive poly(N-isopropylacrylamide-co-acrylic acid) (PNA) nanogel core, a polydopamine (PDA) layer for photothermal conversion, and an outer folic acid (FA) layer as a targeting agent for the folate receptors on tumor cells. The fabricated nanoparticles show good biocompatibility and outstanding photothermal conversion efficiency. The proposed nanoparticles loaded with doxorubicin (DOX) drug molecules are stable under physiological conditions with low leakage of drugs, while rapidly release drugs in environments with low pH conditions and at high temperature. The experimental results show that the drug release process is mainly governed by Fickian diffusion. In vitro cell experimental results demonstrate that the PNA-DOX@PDA-FA nanoparticles can be phagocytized by 4T1 tumor cells and release drugs in tumor cell acidic environments, and confirm that the combined chemo and photothermal therapeutic efficacy of PNA-DOX@PDA-FA nanoparticles is higher than the photothermal therapeutic efficacy or the chemotherapeutic efficacy alone. The proposed multifunctional responsive nanoparticles in this study provide a novel class of drug nanocarriers as a promising tool for synergetic chemo-photothermal therapy of tumors.

Noncovalent Self-Assembled Smart Gold(III) Porphyrin Nanodrug for Synergistic Chemo-Photothermal Therapy.

Self-assembly is a powerful means to fabricate multifunctional smart nanotheranostics. However, the complicated preparation, toxicity of responsive carriers, and low loading efficiency of drug cargo hinder the outcome. Herein, we developed a responsive carrier-free noncovalent self-assembly strategy of a metallized Au(III) tetra-(4-pyridyl) porphine (AuTPyP) anticancer drug for the preparation of a heat/acid dual-stimulated nanodrug, and it generated a better photothermal effect than monomers under irradiation. The photothermal effect promoted the protonation of the hydrophobic pyridyl group and the following release into tumorous acidic microenvironments. With cRGD modification, the released drug induced the aggravation of intracellular reactive oxygen species (ROS) via the activity inhibition of thioredoxin reductase (TrxR) for synergistic chemo-photothermal therapy of tumors.

Thermosensitive Polymer Dot Nanocomposites for Trimodal Computed Tomography/Photoacoustic/Fluorescence Imaging-Guided Synergistic Chemo-Photothermal Therapy.

Precision delivery of theranostic agents to the tumor site is essential to improve their diagnostic and therapeutic efficacy and concurrently minimize adverse effects during treatment. In this study, a novel concept of near-infrared (NIR) light activation of conjugated polymer dots (Pdots) at thermosensitive hydrogel nanostructures is introduced for multimodal imaging-guided synergistic chemo-photothermal therapy. Interestingly, owing to the attractive photothermal conversion efficiency of Pdots, the Pdots@hydrogel as theranostic agents is able to undergo a controllable softening or melting state under the irradiation of NIR laser, resulting in light-triggered drug release in a controlled way and concurrently hydrogel degradation. Besides, the novel Pdots@hydrogel nanoplatform can serve as the theranostic agent for enhanced trimodal photoacoustic (PA)/computed tomography (CT)/fluorescence (FL) imaging-guided synergistic chemo-photothermal therapy of tumors. More importantly, the constructed intelligent nanocomposite Pdots@hydrogel exhibits excellent biodegradability, strong NIR absorption, bright PA/CT/FL signals, and superior tumor ablation effect. Therefore, the concept of a light-controlled multifunctional Pdots@hydrogel that integrates multiple diagnostic/therapeutic modalities into one nanoplatform can potentially be applied as a smart nanotheranostic agent to various perspectives of personalized nanomedicine.

Fabrication of doxorubicin-gated mesoporous polydopamine nanoplatforms for multimode imaging-guided synergistic chemophotothermal therapy of tumors

A versatile theranostic agent that integrated with therapeutic and diagnostic functions is extremely essential for cancer theranostic. Herein, a multifunctional theranostic nanoplatform (PFP@MPDA-DOX) based on perfluoropentane (PFP) encapsulated mesoporous polydopamine (MPDA) is elaborately designed, followed by gating of drug doxorubicin (DOX) for preventing cargo leaking. The MPDA with pH-responsive biodegradation behavior was served as nanocarrier, which also endows the nanoplatform with a large cavity for PFP filling. The nanoparticles were then gated with DOX molecule by Michael addition and/or Schiff base reaction to shield the leaking of PFP during the blood circulation before the tumor tissue is reached. Also, such nanotheranostic exhibits high photothermal conversion efficiency of 45.6%, which can act as an intelligent nanosystem for photothermal therapy (PTT) and photoacoustic (PA) imaging. Moreover, the liquid-gas phase transition of PFP arising upon exposure to an 808 nm laser and thus produced the bubbles for ultrasound (US) imaging. The subsequent PFP@MPDA-DOX-mediated synergetic chemotherapy (contributed by the DOX gatekeeper) and PTT (contributed by the MPDA) shows excellent anticancer activity, which has been systematically evaluated both in vitro and in vivo. All these positive results certify that the facile incorporation of the antitumor drug gatekeeper and MPDA into one theranostic nanoplatform shows general potential for multimode PA/US imaging and combination chemotherapy/PTT of tumors.

Gas-generating mesoporous silica nanoparticles with rapid localized drug release for enhanced chemophotothermal tumor therapy

Chemophotothermal combination therapy has emerged as a novel and promising strategy to treat cancer. To improve anticancer effectiveness and reduce systemic toxicity, it is essential to trigger drug release at tumor sites or within tumor cells for maximal drug exposure. Herein, we constructed gas-generating mesoporous silica nanoparticles (MSNs) that can load ammonium bicarbonate (ABC) and doxorubicin (DOX) within the pores, encapsulate indocyanine green (ICG) onto the polydopamine (PDA) layer, and modify the RGD peptide on the outer surface [denoted as M(abc)-DOX@PDA-ICG-PEG-RGD] for triggered drug release and targeted chemophotothermal combination therapy. Upon hyperthermia or low pH value, the encapsulated ABC can efficiently generate CO2 gas, thus enhancing the damage to the PDA layer and accelerating DOX release. In vitro experiments showed that the M(abc)-DOX@PDA-ICG-PEG-RGD significantly enhanced cellular uptake and cytotoxicity, and laser irradiation further increased the endocytic and cytotoxic effects. An in vivo study indicated that the nanoparticles can effectively accumulate at the tumor site and significantly inhibited tumor growth with no side-effects to the normal organs. Thus, this gas-generating MSN-based nanocarrier that can trigger drug release in response to laser irradiation or low pH value holds great potential in enhancing cancer chemophotothermal combination therapy.

Photothermally triggered cytosolic drug delivery of glucose functionalized polydopamine nanoparticles in response to tumor microenvironment for the GLUT1-targeting chemo-phototherapy

The success in the application of nanomedicines for tumor therapy is largely dependent on the development of efficient tumor targeting, specific and effective drug delivery systems. Here, through a simple synthetic process, we developed a type of novel glucose transporter 1 (GLUT1)-targeting, tumor microenvironment responsive and near infrared irradiation (NIR) induced cytosolic drug delivery nanoparticles (NPs). Our design was based on polydopamine (PDA) NPs as the photothermal agent and drug delivery carrier, glucosyl functional ligands as the GLUT1 targeting agents, and the conjugation of anticancer drug bortezomib (BTZ) to the catechol groups of PDA NPs in a pH-dependent manner. The in vitro and in vivo studies demonstrated that the functionalized PDA NPs could efficiently accumulate in tumor site and localize in subcellular endo/lysosomes of tumor cells, and they could respond to tumor microenvironment and endo/lysosomal pH as well as NIR to promote the robust release of BTZ. Furthermore, the functionalized PDA NPs were first demonstrated to overcome the endo/lysosomal barrier for the enhanced cytosolic BTZ drug delivery through NIR-triggered endo/lysosomal release, achieving the integration of NIR-triggered photothermal effect and chemotherapy for synergistic tumor ablation. The significant suppression and even complete regression of 4 T1 tumor was observed in mice given only single treatment. Therefore, the GLUT1-targeting, pH and photothermal responsive drug delivery NPs show a great potential for broadly applicable chemo-photothermal tumor therapy.

NIR-laser-triggered drug release from folate decorated albumin nanoparticles for synergistic chemo-photothermal tumor therapy

Photothermal therapy as a physical therapeutic approach for the localized ablation of malignant tissues has greatly attracted research interests due to its negligible systemic effects. Among various photosensitizer, IR-780 iodide as a near-infrared (NIR) fluorescent dye which is limited its further applicability in the clinic due to its low bioavailability. In this work, we developed folic acid (FA) modified bovine serum albumin (BSA) nanoparticles (FA-DINPs) that co-encapsulated chemotherapeutic compound (doxorubicin) and IR-780 for synergistic chemo-photothermal therapy using a modified desolvation method, which would facilitate clinical translation. The achieved FA-DINPs were in the size of 178 ± 5.82 nm and showed excellent photothermal effect. Furthermore, the FA-DINPs could increase drug release by laser irradiation, and enhanced cellular uptake through the FA receptor-mediated endocytosis. Our results also demonstrated that FA-DINPs exhibited remarkable cytotoxicity to cells upon NIR laser irradiation. Moreover, after laser irradiation, FA-DINPs achieved minimal systemic toxicity and high tumor inhibition efficacy without any regrowth in vivo. Therefore, our study provided a promising strategy for cancer synergistic chemo-photothermal therapy.

Molybdenum disulfide-based hyaluronic acid-guided multifunctional theranostic nanoplatform for magnetic resonance imaging and synergetic chemo-photothermal therapy

The construction of multifunctional theranostic nanoplatforms to integrate accurate imaging and enhanced therapy to treat tumors is highly attractive but remains a challenge. Here, we developed a molybdenum disulfide (MoS2)-based hyaluronic acid (HA)-functionalized nanoplatform capable of achieving the targeted co-delivery of the gadolinium (Gd)-based contrast agents (CAs) and the anticancer drug gefitinib (Gef) for magnetic resonance imaging (MRI) and synergetic chemo-photothermal therapy of tumors. Gd3+ ions were coupled to HA-grafted MoS2 nanosheets with diethylenetriaminepentaacetic acid (DTPA) as a linker, followed by the incorporation of Gef. The resulting MoS2-HA-DTPA-Gd/Gef exhibited enhanced relaxivity, 3.3 times greater than that of the commercial CA DTPA-Gd, which facilitated the MRI in vivo. Moreover, the nanoplatform effectively converted the absorbed near-infrared (NIR) light into heat, which not only induced the photothermal ablation of cancer cells but also triggered the release of Gef from MoS2-HA-DTPA-Gd/Gef, enabling the synergetic chemo-photothermal therapy. The results of in vitro and in vivo experiments revealed that MoS2-HA-DTPA-Gd/Gef upon NIR irradiation effectively blocked the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway and activated apoptosis-related proteins to induce cell apoptosis and suppress cell proliferation, thus inhibiting the tumor growth in lung cancer cell-bearing mice. Taken together, this multifunctional theranostic nanoplatform has significant promise for the diagnosis and treatment of cancer.

A tungsten nitride-based degradable nanoplatform for dual-modal image-guided combinatorial chemo-photothermal therapy of tumors.

An innovative tungsten-based multifunctional nanoplatform composed of polyethylene glycol (PEG)-modified tungsten nitride nanoparticles (WN NPs) is constructed for tumor treatment. The PEG-WN NPs not only possess strong near-infrared (NIR) absorbance, high photothermal conversion efficiency, and excellent photothermal stability, but also effectively inhibit tumor cells upon 808 nm laser irradiation. After coating with thiolated (2-hydroxypropyl)-β-cyclodextrin (MUA-CD) on the surface, such a nanoplatform can also be used for drug delivery (such as DOX) and presents a synergistic tumor inhibition effect both in vitro and in vivo. Furthermore, the PEG-WN NPs present good contrasting capability for X-ray computed tomography (CT) and photoacoustic (PA) imaging. With PA/CT imaging, the tumor can be accurately positioned for precise treatment. It is worth mentioning that PEG-WN NPs are biodegradable and could be effectively excreted from the body with no appreciable toxicity in vivo. It is expected that this biocompatible multifunctional nanoplatform can serve as a potential candidate for tumor treatment in future clinical applications.

Bubble-generating polymersomes loaded with both indocyanine green and doxorubicin for effective chemotherapy combined with photothermal therapy

The combination of chemotherapy and photothermaltherapy (PTT) via stimuli-responsive nanovesicles has great potential in tumor treatment. In the present study, bubble-generating polymersomes, which can generate bubbles in response to low pH or hyperthermia, were fabricated to simultaneously encapsulate chemotherapeutic drug and photosensitizing agent for the synergistic chemo-photothermal tumor therapy. Photosensitizer indocyanine green (ICG) was encapsulated into the bilayer of polymersomes formed by amphiphilic triblock copolymer PCL8000-PEG8000-PCL8000 through thin film re-hydration method, while chemotherapeutic doxorubicin (DOX) was loaded into the hydrophilic lumen using a transmembrane ammonium bicarbonate gradient loading procedure. Under acidic condition or laser irradiation, the ammonium bicarbonate (NH4HCO3) encapsulated in the bubble-generating DOX-ICG-co-delivery polymersomes (BG-DIPS) would decompose to produce CO2 bubbles, resulting in destruction of vesicle structure and rapid drug release. In vitro drug release study confirmed that acidic environment and NIR laser irradiation could accelerate DOX release from the BG-DIPS. Cellular uptake study indicated that laser-induced hyperthermia highly enhanced endocytosis of BG-DIPS into 4T1-Luc cancer cells. In vitro cytotoxicity study demonstrated that BG-DIPS exhibited much higher cytotoxicity than free drugs under laser irradiation. In vivo biodistribution study indicated that BG-DIPS could accumulate in the tumor region, prolong drug retention, and increase photothermal conversion efficiency. Furthermore, in vivo antitumor study showed that BG-DIPS with laser irradiation efficiently inhibited 4T1-Luc tumor growth with reduced systemic toxicity. Hence, the formulated bubble-generating polymersomes system was a superior multifunctional nanocarrier for stimuli-response controlled drug delivery and combination chemo-photothermal tumor therapy. Statement of SignificanceThe combination of chemotherapy and photothermaltherapy via stimuli-responsive nanovesicles has great potential in tumor treatment. Herein, bubble-generating polymersomes, which can generate bubbles in response to low pH or hyperthermia, were fabricated to simultaneously encapsulate chemotherapeutic drug (DOX) and photosensitizing agent (ICG) for the synergistic chemo-photothermal tumor therapy. The results in vitro and in vivo demonstrated that bubble-generating DOX-ICG-co-delivery polymersomes (BG-DIPS) would accelerate DOX release from the BG-DIPS and accumulate in the tumor region, prolong drug retention, and increase photothermal conversion efficiency. BG-DIPS with laser irradiation could efficiently inhibited 4T1-Luc tumor growth with reduced systemic toxicity. Hence, the formulated bubble-generating polymersomes system was a superior multifunctional nanocarrier for stimuli-response controlled drug delivery and combination chemo-photothermal tumor therapy.

Dual Chemodrug-Loaded Single-Walled Carbon Nanohorns for Multimodal Imaging-Guided Chemo-Photothermal Therapy of Tumors and Lung Metastases.

Tumor combination therapy using nano formulations with multimodal synergistic therapeutic effects shows great potential for complete ablation of tumors. However, targeting tumor metastases with nano structures is a major obstacle for therapy. Therefore, developing a combination therapy system able to target both primary tumors and their metastases at distant sites with synergistic therapy is desirable for the complete eradication of tumors. To this end, a dual chemodrug-loaded theranostic system based on single walled carbon nanohorns (SWNHs) is developed for targeting both primary breast tumors and their lung metastases.Methods: SWNHs were first modified simultaneously with poly (maleic anhydride-alt-1-octadecene) (C18PMH) and methoxypolyethyleneglycol-b-poly-D, L-lactide (mPEG-PLA) via hydrophobic-hydrophobic interactions and π-π stacking. Then cisplatin and doxorubicin (DOX) (2.9:1 molar ratio) were sequentially loaded onto the modified nanohorns in a noninterfering way. After careful examinations of the release profiles of the loaded drugs and the photothermal performance of the dual chemodrug-loaded SWNHs, termed SWNHs/C18PMH/mPEG-PLA-DOX-Pt, the dual drug chemotherapeutic and chemo-photothermal synergetic therapeutic effects on tumor cells were evaluated. Subsequently, the in vivo behavior and tumor accumulation of the drug-loaded SWNHs were studied by photoacoustic imaging (PAI). For chemo-photothermal therapy of tumors, 4T1 tumor bearing mice were intravenously injected with SWNHs/C18PMH/mPEG-PLA-DOX-Pt at a dose of 10 mg/kg b.w. (in SWNHs) and tumors were illuminated by an 808 nm laser (1W/cm2 for 5 min) 24 h post-injection.Results: DOX and cisplatin were loaded onto the modified SWNHs with high efficiency (44 wt% and 66 wt%, respectively) and released in a pH-sensitive, tandem and sustainable manner. The SWNHs/C18PMH/mPEG-PLA-DOX-Pt had a hydrodynamic diameter of 182 ± 3.2 nm, were highly stable in physiological environment, and had both dual drug chemotherapeutic (CI = 0.439) and chemo-photothermal synergistic antitumor effects (CI = 0.396) in vitro. Moreover, the dual drug-loaded SWNHs had a long blood half-life (10.9 h) and could address both the primary breast tumors and their lung metastases after intravenous administration. Consequently, chemo-photothermal combination therapy ablated the primary tumors and simultaneously eradicated the metastatic lung nodules.Conclusion: Our study demonstrates that SWNHs/C18PMH/mPEG-PLA-DOX-Pt is highly potent for chemo-photothermal combination therapy of primary tumors and cocktail chemotherapy of their metastases at a distant site.