By means of ultrasound, laser, radiofrequency or microwave, minimally invasive intervention therapy could target and clear the tumor lesion through endoscopy, image-guided percutaneous puncture or perforation. This therapeutic strategy attracts increasing attention globally because of its advantages including minimal invasiveness, less complication, fast postoperative recovery and wide application. The malignant tumor is characterized by infiltrative growth and unclear border, which usually necessitate resection of normal tissues in surgery and result in the sequel and dysfunction. Furthermore, ovarian cancer and gastric cancer usually occur obscurely, which have peritoneal or lymph node metastasis at initial diagnosis. The surgery could not eliminate the distant and regional metastasis, which leads to residual tumor cell and high risk of recurrence. Therefore, it is one of the globally challenges to precisely locate the tumor, identify the tumor border and diagnose the metastasis of lymph node in order to accurately diagnose and treat minimal tumor.
1.Microwave ablation of cancer
Translating microwave energy into thermal energy, the microwave ablation therapy could eliminate tumor cells by thermal ablation. This kind of therapy has many advantages like user-friendly, minimal invasiveness, safety and low cost. However, during the treatment, injury of normal tissues cannot be evitable. In order to improve the efficacy and accuracy of treatment, it is imperative to develop microwave-enhancing materials.
Liposome, which has been widely used in clinic, was used as carrier material to load high concentrations of inorganic salts, obtaining a nanocarrier with excellent microwave susceptible property. Long-term clinical application has proved that liposome has good biological safety, therefore, liposomes with good microwave sensitizing effect will have a wide prospect of clinical application in the cancer therapy.
In order to realize microwave-triggered thermochemotherapy, enhance the therapeutic effect and overcome the drug resistance of tumor cells, our group developed temperature-sensitive liposomes simultaneous loading with sodium chloride and doxorubicin. When these liposomes reached the tumor tissue, microwave irradiation was used to induce the rupture of liposome, resulting in rapid drug release, so that the tumor tissue reached a very high concentration of drugs instantaneously. The tumor cell can be killed effectively by the synergistic therapeutic effect of microwave induced hyperthermia and chemotherapy.
2.High intensity focused ultrasound mediated cancer chemothermal therapy
High intensity focused ultrasound (HIFU) can focus the beam into a sharp point within square millimeter at a given distance from the ultrasound source, which allows for long-term irradiation on tumor site, resulting in non-invasively thermal ablation of cancer. Compared with other techniques, HIFU shows unique advantages as a targeting stimulation tool because it can penetrate into deep tissue and focus onto specific locations.
To further enhance the therapeutic effect of HIFU, we developed a HIFU and temperature sensitive cerasome (HTSCs) encapsulating both hydrophilic and amphiphilic anticancer drugs. HTSCs show high blood stability which prevents premature drug release. After ample accumulation of HTSCs in tumor tissue, HIFU irradiation is performed locally, generating inertial cavitation effect and temperature increase. Thus, the enhanced permeability of cerasomes leads to rapid release of the loaded drugs within the target region, which not only enhance the local drug concentration maximizing anticancer ability and therapeutic efficacy, but also minimize systemic side effect. Furthermore, the HIFU induced hyperthermia can play a synergistic effect with chemotherapy and reduce the drug resistance of tumor cells. This non-invasive approach for cancer treatment is a frontier in cancer research, holding great potential for clinical translation.
3.Imaging guided cancer photodynamic therapy
Photodynamic therapy (PDT), which employs singlet oxygen produced by light-activated photosensitizer to kill tumor cells, has many advantages such as small trauma, low toxicity, high selectivity and good applicability. However, the lack of ideal photosensitizer hinders the broader applications of PDT in clinic. The currently used photosensitizers are mostly hydrophobic, which aggregate in the physiological conditions, leading to the fluorescence quenching and a large decrease in PDT efficacy. The water solubility and biocompatibility of photosensitizers can be improved when they are encapsulated into liposomes. However, the treatment efficacy is often reduced due to the poor stability and low drug loading efficacy (usually less than 10%) of liposome, and the premature leakage of photosensitizers can lead to severe toxic and side effects. In order to solve the above problems, instead of using the general physical embedding method, we fabricated porphyrin bilayer cerasomes (PBCs) for the first time by sol–gel reaction and self-assembly process from a conjugate of porphyrin-organoalkoxysilylated lipid (PORSIL) with dual triethoxysilyl heads, a hydrophobic double-chain segment, a porphyrin moiety and a connector unit among them. The covalent linkage of porphyrin to cerasomes may result in the drug loading content of 33% in the PBCs. In the PBCs, each porphyrin molecule is separated by two long carbon chains, preventing the aggregation of porphyrin molecules and fundamentally avoiding the self-quenching of photosensitizers, thus the fluorescence quantum yield is significantly increased. The PBCs can also be used as fluorescent probe due to its unique optical properties. Moreover, a certain proportion of manganese ions can be coordinated into porphyrins to obtain manganese porphyrins, which can enhance T1-weighted magnetic resonance signals.
The PBCs have higher singlet oxygen quantum yield than conventional porphyrin liposomes because the porphyrins are conjugated in the cerasomes bilayer through covalent bond, avoiding the release of photosensitizer and enhancing the PDT effect to cancer cells. In addition, the PBCs can carry other chemo-drugs, realizing the combination of PDT and chemotherapy for cancer treatment. As a result, the PBCs can integrate the fluorescence/magnetic resonance dual imaging and PDT for cancer theranostics. Through the fluorescence/magnetic resonance dual-mode imaging, we can locate the precise position of tumor, leading to the accurate irradiation of laser and fixed-point removal of tumor, which can both improve the treatment efficacy and avoid damage to normal tissue, showing great potential in cancer theranostics.
4.Imaging guided cancer photothermal therapy based on gold nanoshelled microcapsules
Photothermal therapy (PTT) using photothermal agents in combination of near infrared (NIR) light has gained increasing attention in recent years as a minimally invasive approaches for cancer treatment because it involves delivery of high thermal energy to cancer tissue with little collateral damage to the normal tissue. However, for effective, safe and personalized PTT treatment, it is crucial to identify the location and size of the tumors before therapy, to monitor the in vivo distribution of photothermal agents during therapy and evaluate effectiveness after therapy, all these works can be accomplished by medical imaging.
We constructed gold-nanoshelled microcapsules (GNS-MCs) composed of ultrasound responsive polymeric microcapsules and NIR light absorbed gold nanoshells on the surface for contrast-enhanced ultrasound imaging and remote photothermal therapy, respectively. On one hand, GNS-MCs can enhance the ultrasound imaging effect, and combine with CT imaging, the size and location of the tumor can be determined, the process of treatment and recovery after treatment can be monitored. On the other hand, gold nanoshells have strong absorption in the near infrared region, with the irradiation of NIR light, light energy can be efficiently converting into heat, increasing the local temperature and effectively killing the malignant tumor cells. In addition, the therapeutic efficacy can be further enhanced by ultrasonic sonication. Therefore, GNS-MCs can realize the perfect combination of ultrasonic/CT dual modality imaging and photothermal therapy, and provide a new concept and method for the development of advanced technology in cancer diagnosis and therapy.
5.Imaging guided cancer photothermal therapy based on polypyrrole nanocapsules
Polypyrrole nanoparticles conjugating gadolinium chelates (Gd-PEG-PPy) were successfully fabricated for dual-modal magnetic resonance imaging (MRI) and photoacoustic imaging (PA) guided photothermal therapy of cancer. After intravenous injection, the Gd-PEG-PPy nanoparticles could selectively accumulate in the tumor through blood circulation. Owing to the strong absorption in near-infrared region and high photothermal conversion efficiency of Gd-PEG-PPy nanoparticles, it can be used not only for photothermal therapy, but also enhancing photoacoustic imaging. At the same time, Gd-PEG-PPy nanoparticles can significantly enhance the T1 magnetic resonance signal due to the existence of gadolinium chelate. Because of the highly complementary property of magnetic resonance imaging and photoacoustic imaging, combination of these two different imaging modalities provides more comprehensive information. Therefore, dual MR/PA imaging can significantly differentiate the tumor tissue from the normal tissue, thus directing the near-infrared light to irradiate the tumor site accurately. Then the tumor cells can be effectively ablated and the damage to the normal tissue around the tumor will be avoided.