The present inventions provides drug-drug conjugates, drug-porphyrin conjugates, nanoparticles of the conjugates, as well as modified nanoparticles having PEGylated exteriors or encapsulated by red blood cell vesicles. The conjugates, nanoparticles and nanocarriers are useful for treating cancers and other diseases, as well as for imaging diseased tissue or organs.

Methods of treating tumors by administering compounds to a patient are provided. Compounds such as pro drugs, e.g., 5-aminolevulinic acid (5-ALA), may be administered to the patient orally, by injection, intravenously, or topically, which then accumulate preferentially as compounds such as protoporphyrin IX (PpIX) in tumor cells. After such accumulation, compounds such as PpIX are then activated in various aspects to treat tumors cells, thereby treating cancer. Cancers such as glioblastoma may be treated.

Cancer treatment methods using thermotherapy and/or enhanced immunotherapy are disclosed herein. In one embodiment, the method comprising the steps of: (i) applying controlled thermal energy at 40-43° C. for a first predetermined time period to damage and weaken tumor cells of a tumor in a patient; (ii) administering pulsed high intensity focused ultrasound (pHIFU) in a first ultrasound mode to the tumor cells in the patient so as to damage the tumor cells without increasing the thermal energy; and (iii) administering low intensity focused ultrasound (LIFU) in a second ultrasound mode to further damage the tumor cells at a temperature of 39-43° C. for a second predetermined time period while performing observation of the tumor cells by ultrasonic thermometry.

The present invention relates to a polymer composite for ultrasound-based cancer immunotherapy, which comprises an peroxalate derivatives, and a preparation method thereof. The polymer composite according to the present invention is a structure in which the peroxalate derivatives are encapsulated in an amphipathic polymer compound in which a biocompatible polymer and a sonosensitizer are combined. The peroxalate derivatives produce free electrons and carbon dioxide (CO.sub.2) by reaction with a high concentration of hydrogen peroxide (H.sub.2O.sub.2) in cancer tissue, the generated electrons raise the energy level of the sonosensitizer in the polymer composite to increase the amount of reactive oxygen species (ROS) production, thereby exhibiting an effect of increasing the death rate of cancer cells. In addition, by ultrasound treatment, immunogenic cell death (ICD) is induced due to the cavitation effect of the produced CO.sub.2, so molecules capable of activating immune cells in cancer cells are released without damage to induce an immune response to cancer. Therefore, the polymer composite according to the present invention is expected to be effectively used as an ultrasound-based cancer immunotherapeutic agent.

In alternative embodiments, provided are compositions, including products of manufacture and kits, and methods, for remotely-controlled and non-invasive manipulation of intracellular nucleic acid expression, genetic processes, function and activity in live cells, e.g., adding functions or changing or adding specificities for immune cells, for monitoring physiologic processes, for the correction of pathological processes and for control of therapeutic outcomes. In alternative embodiments, provided are ultrasound-based thermal or mechanical stimulations, and thermo- or mechano-sensitive protein, either synthetically engineered or natively (endogenously) occurring, integrated to control the production of intracellular nucleic acid and gene expression, e.g., for the expression of biological-active proteins, which can be used, in alternative embodiments, for diagnostic or therapeutic purposes. In alternative embodiments, exemplary thermo- and mechanogenetic systems provided herein allow a deep penetration of stimulation and manipulation in vivo at centimeter-level depth with high spatiotemporal precision.

The present invention provides novel compositions and methods for targeted delivery of therapeutics. In particular, the invention provides compositions comprising a plurality of carriers, such as microbubbles, wherein at least one active agent is associated or co-administered with the plurality of carriers for delivery to a target site, e.g., an organ, a tissue, or a tumor site, in a subject. The present invention also provides methods for treating a disease or condition, methods of targeted delivery of an active agent, e.g., to a target site, in a subject, using the carriers based compositions of the invention. The present invention further provides apparatus, devices and methods for preparing the compositions of the present invention.

Disclosed are methods of obtaining zero vergence ultrasound waves for providing sonodynamic therapy with ultrasound waves. The method includes coupling a sonodynamic therapy device with an array of flat piezoelectric transducers to a skin surface. A controller is configured to generate an electrical drive signal at a frequency, modulate the drive signal, and drive the transducer with the modulated drive signal at the frequency to produce a zero vergence ultrasound wave to produce an average acoustic intensity sufficient to activate a sonosensitizer in a treatment region without damaging healthy cells in the treatment region.

The invention provides polymeric particles comprising a matrix of a biocompatible polymer and polyethylene imine, said matrix having incorporated therein an anionic or hydrophobic sonosensitiser and, optionally, an immunomodulatory agent and/or an imaging agent. Such particles find use in methods of sonodynamic therapy, in particular in methods of combined sonodynamic therapy and immunotherapy, for example in the treatment of cancer, metastasis or micrometastasis derived from cancer. The invention is particularly suitable for the treatment of deep-sited, hard to treat tumours such as pancreatic cancer.

A method of inducing cell death in a subject includes administering to the subject a plurality of cell targeted nanobubbles that are internalized by the target cell and insonating nanobubbles internalized into the target cell with ultrasound energy effective to promote inertial cavitation of the internalized nanobubbles and apoptosis and/or necrosis of the target cell.

Methods of treating tumors by administering compounds to a patient are provided. Compounds such as pro drugs, e.g., 5-aminolevulinic acid (5-ALA), may be administered to the patient orally, by injection, intravenously, or topically, which then accumulate preferentially as compounds such as protoporphyrin IX (PpIX) in tumor cells. After such accumulation, compounds such as PpIX are then activated in various aspects to treat tumors cells, thereby treating cancer. Cancers such as glioblastoma may be treated.