Nanomedicine-based multimodal therapies: Recent progress and perspectives in colon cancer.

Colon cancer has attracted much attention due to its annually increasing incidence. Conventional chemotherapeutic drugs are unsatisfactory in clinical application because of their lack of targeting and severe toxic side effects. In the past decade, nanomedicines with multimodal therapeutic strategies have shown potential for colon cancer because of their enhanced permeability and retention, high accumulation at tumor sites, co-loading with different drugs, and comb-ination of various therapies. This review summarizes the advances in research on various nanomedicine-based therapeutic strategies including chemotherapy, radiotherapy, phototherapy (photothermal therapy and photodynamic therapy), chemodynamic therapy, gas therapy, and immunotherapy. Additionally, the therapeutic mechanisms, limitations, improvements, and future of the above therapies are discussed.

Decrease in Tumor Interstitial Pressure for Enhanced Drug Intratumoral Delivery and Synergistic Tumor Therapy.

Currently, one of the main reasons for the ineffectiveness of tumor treatment is that the abnormally high tumor interstitial pressure (TIP) hinders the delivery of drugs to the tumor center and promotes intratumoral cell survival and metastasis. Herein, we designed a "nanomotor" by in situ growth of Ag2S nanoparticles on the surface of ultrathin WS2 to fabricate Z-scheme photocatalytic drug AWS@M, which could rapidly enter tumors by splitting water in interstitial liquid to reduce TIP, along with O2 generation. Moreover, the O2 would be further converted to reactive oxygen species (ROS), accompanied by increased local temperature of tumors, and the combination of ROS with thermotherapy could eliminate the deep tumor cells. Therefore, the "nanomotor'' could effectively reduce the TIP levels of cervical cancer and pancreatic cancer (degradation rates of 40.2% and 36.1%, respectively) under 660 nm laser irradiation, further enhance intratumor drug delivery, and inhibit tumor growth (inhibition ratio 95.83% and 87.61%, respectively), and the related mechanism in vivo was explored. This work achieves efficiently photocatalytic water-splitting in tumor interstitial fluid to reduce TIP by the nanomotor, which addresses the bottleneck problem of blocking of intratumor drug delivery, and provides a general strategy for effectively inhibiting tumor growth.

Pyroelectric Catalysis-Based "Nano-Lymphatic" Reduces Tumor Interstitial Pressure for Enhanced Penetration and Hydrodynamic Therapy.

Because of the deficiency of lymphatic reflux in the tumor, the retention of tumor interstitial fluid causes aggravation of the tumor interstitial pressure (TIP), which leads to unsatisfactory tumor penetration of nanomedicine. It is the main inducement of tumor recurrence and metastasis. Herein, we design a pyroelectric catalysis-based "Nano-lymphatic" to decrease the TIP for enhanced tumor penetration and treatments. It realizes photothermal therapy and decomposition of tumor interstitial fluid under NIR-II laser irradiation after reaching the tumor, which reduces the TIP for enhanced tumor penetration. Simultaneously, reactive oxygen species generated during the pyroelectric catalysis can further damage deep tumor stem cells. The results indicate that the "Nano-lymphatic" relieves 52% of TIP, leading to enhanced tumor penetration, which effectively inhibits the tumor proliferation (93.75%) and recurrence. Our finding presents a rational strategy to reduce TIP by pyroelectric catalysis for enhanced tumor penetration and improved treatments, which is of great significance for drug delivery.

Gaseous microenvironmental remodeling of tumors for enhanced photo-gas therapy and real-time tracking.

The gaseous microenvironment (GME) of tumors is rapidly becoming a new concern for nanotechnology-mediated oncotherapy. Here, we constructed a tumor/near-infrared (NIR) light-responsive nanoplatform to generate O2 and NO for remodeling the GME of tumors and phototherapy. The biocompatible and pyrolytic polydopamine was used to load indocyanine green, NONOate, and MnO2 NPs as a nanoenzyme (PINM). Then, HA was modified on the PINM to form the final nanoplatform (PINMH). PINMH can target tumors favorably due to the modification of HA. Under the NIR light irradiation, PINM converts the light and O2 to hyperpyrexia (58.5 °C) and cytotoxic 1O2. MnO2 NPs catalyze the H2O2 overexpressed in tumors to O2, which increases the amount of 1O2. Moreover, NONOate decomposes to NO (100 µM) under hyperpyrexia, thus leading to the gas therapy. The results verified that the responsive nanoplatform with precise gaseous regulation and phototherapy exhibited a superior anti-tumor effect (V/V0 = 1.2) and biosafety. In addition, PINMH can be tracked in real-time via magnetic resonance imaging. In this study, an intelligent nano-platform integrated with diagnosis and treatment was developed, which used the phototherapy technology to reshape GME and achieve good anti-tumor effects, aiming to provide an innovative and reasonable strategy for the development of tumor treatment.

Nanomagnetic liposome-encapsulated parthenolide and indocyanine green for targeting and chemo-photothermal antitumor therapy.

Aim: To synthesize a drug-delivery system with chemo-photothermal function and magnetic targeting, to validate its antitumor effect. Materials & methods: Parthenolide (PTL), employing chemotherapy and indocyanine green (ICG) providing phototherapy, were encased separately in the lipid and aqueous phases of liposomes (Lips). The Fe3O4 nanoparticles (MNPs), endowing magnetic targeting, were modified on the surface of Lips. The antitumor effects were investigated in vitro and in vivo. Results: ICG-PTL-Lips@MNPs showed outstanding synergistic antitumor efficacy in vitro and in vivo. Especially, after 14-day treatment, the tumor volumes decreased significantly and the biotoxicity was very low. Conclusion: The designed ICG-PTL-Lips@MNPs possess synergistic effects of chemotherapy, photothermal and targeting therapy, which are expected to provide an alternative way to further improve antitumor efficacy.

Nano-drug System Based on Hierarchical Drug Release for Deep Localized/Systematic Cascade Tumor Therapy Stimulating Antitumor Immune Responses.

Inaccessibility of deep-seated malignant cells in the central region of tumors and uncontrollable tumor recurrence represent a significant challenge for conventional synergistic cancer therapy. Herein, we designed a novel nanoplatform based on hierarchical drug release for deep cascade cancer therapy including localized photothermal therapy, systematic chemotherapy, and elicited immune responses. Methods: The first-step chemotherapy could be carried out by polydopamine (PDA) releasing doxorubicin (DOX) in the specific microenvironment of lysosomes (pH 5.5). The branched gold nanoshells and PDA converted the light to heat efficiently to accomplish the second-step photothermal therapy and collapsed biomimetic vesicles (BVs) to release paclitaxel (PTX), which promoted the third-step of chemotherapy and triggered immune responses. Results: After 10 days of treatment, there were no obvious residual tumors in tumor-bearing mice. Significantly, 10 days after stopping treatment, mice in the drug immune-therapeutic group showed little tumor recurrence (1.5 times) compared to substantial recurrence (20 times) in the conventional treatment group. Conclusion: The hierarchical drug release and cascade therapeutic modality enhance the penetration of drugs deep into the tumor tissue and effectively inhibit recurrence. This cascade therapeutic modality provides a novel approach for more effective cancer therapy.

Dual-template cascade synthesis of highly multi-branched Au nanoshells with ultrastrong NIR absorption and efficient photothermal therapeutic intervention.

With the rapid development of photothermal therapy (PTT) in cancer treatment, it is necessary to obtain effective plasma-responsive tunable photothermal transducing agents. Inspired by the peptide-directed hierarchical mineralized Ag nanocages (Ag NCs), scientists designed a new duel-template cascade preparation method, and novel unique multi-branched gold nanoshells (BGSs) were successfully prepared under mild conditions using green strategy. The length, density and diameter of the branches were tuned, which led to the adjustment of the surface plasma response of the nanostructure. Because of the hierarchical structure and anisotropic surface, an obvious red shift of the local surface plasmon resonance spectrum was observed for the branched Au nanoshells. The excellent photothermal conversion efficiency (70.9%) and photo-induced heating responsive curves proved the superior photothermal conversion performance and photothermal stability of BGSs. The in vitro and in vivo results indicated that the heat generated by the intense NIR absorption of BGSs can selectively destroy cancer cells under laser irradiation. The nanostructures with ultrastrong absorption have promising prospects in tumor therapy.

Gold-nanobranched-shell based drug vehicles with ultrahigh photothermal efficiency for chemo-photothermal therapy.

Development of combined chemo-photothermal nanoplatform is of great interest for enhancing antitumor efficacy. Herein, a multifunctional drug delivery system was synthesized based on gold-nanobranched coated betulinic acid liposomes (GNBS-BA-Lips) for chemo-photothermal synergistic therapy. In this system, GNBS-BA-Lips exhibited broad near-infrared (NIR) absorption, preferable photothermal response and good photostability under NIR irradiation. Importantly, the gold-nanobranched nanostructure possessed high photothermal conversion efficiency (η = 55.7%), and the temperature change (ΔT) reached 43.2 °C after laser irradiation for 5 min. Upon NIR irradiation, the nanocarriers apparently endowed higher cell uptake, resulting in an enhanced intracellular drug accumulation. Furthermore, the tumor growth inhibition ratio achieved from chemo-photothermal therapy of GNBS-BA-Lips was 86.9 ±â€¯1.1%, which was higher than that of the chemotherapy or photothermal therapy alone, showing an outstanding synergistic anticancer effect. Our data suggested that the nanoplatform should be considered as a critical platform in the development of cancer multi-mode therapies.

Trimodal synergistic antitumor drug delivery system based on graphene oxide.

A multifunctional antitumor drug delivery system was synthesized based on graphene oxide (GO) for near-infrared (NIR) light controlling chemotherapeutic/photothermal (PTT) /photodynamic (PDT) trimodal synergistic therapy. The system named ICG-Wed-GO was formed by co-loading wedelolactone (Wed) and indocyanine green (ICG) on the surface of GO through π-π stacking interaction. Under NIR laser irradiation, ICG-Wed-GO could effectively absorb and transform optical energy to heat, generate reactive oxygen species (ROS) to ablating and damage tumor cells. The temperature of ICG-Wed-GO solution reached up to 79.4 °C in 10 min with NIR irradiation. In in vitro and in vivo study, ICG-Wed-GO showed excellent antitumor effect. After 14-day treatment of ICG-Wed-GO with NIR laser irradiation, the tumor disappeared completely on tumor-bearing mice. The low biotoxicity of ICG-Wed-GO was also proved. The system achieved the synergistic trimodal chemotherapeutic/photothermal/photodynamic treatment and demonstrated excellent antitumor effect, which is expected to have a greater potential for cancer therapy.

Doxorubicin/gold nanoparticles coated with liposomes for chemo-photothermal synergetic antitumor therapy.

Hybrid liposome/metal nanoparticles are promising candidate drug-carriers for therapy of various diseases due to their unique photothermal effect. In this study, self-crystallized gold nanoparticles (Au NPs) and doxorubicin (DOX) were co-encapsulated within liposomes (Au/DOX-Lips) by thin film hydration and gel separation technology. The surface plasmon resonance bands of drug-carriers were controllable in the near-infrared (NIR) zone. When the complex liposome/metallic hybrids were irradiated by NIR light, they displayed higher endocytosis efficiency following the fracture of liposomal membranes and the release of Au NPs. Then, the Au NPs penetrated further into deeper tumor tissue to accomplish photothermal treatment. The Au/DOX-Lips showed an excellent antitumor effect, whose inhibition rate for tumor cells was up to 78.28%. In experiments on mice bearing tumors, the Au/DOX-Lips treated mice exhibited superior tumor suppression. This novel drug system provides huge potential for biomedical application.