Method and apparatus for drug delivery to surgical margins

Abstract

A method and apparatus for the targeted delivery- of chemotherapy to a surgical cavity, including a triggered nanoparticle encapsulating a therapeutic agent and an energy delivery device that applied trigger energy- to the surgical cavity-. Following surgical removal of a cancerous tumor, the nanoparticle is administered, and the energy- delivery- device is configured to apply trigger energy to the surgical cavity and proximal tissue. Delivery of a therapeutic drug dose to cancerous and precancerous cells remaining after surgery may prevent local tumor recurrence.

Description

METHOD AND APPARATUS FOR DRUG DELIVERY TO SURGICAL MARGINSTECHNICAL FIELD

[0001] The present disclosure describes methods and apparatuses for delivery of chemotherapy.BACKGROUND

[0002] Cancer, a group of diseases characterized by the uncontrolled growth and spread of abnormal cells, is one of the leading causes of death worldwide. Surgery is a mainstay in the treatment of many cancers. As a primary treatment approach, surgery aims to remove the tumor or cancerous tissue, along with a margin of normal healthy tissue, in order to prevent the spread or recurrence of the disease. The specific surgical approach depends on the type, location, and stage of cancer, as w ell as the patient's overall health and preferences.

[0003] Local tumor recurrence after surgical resection refers to the return of cancer in the same region where the original tumor was removed. Despite advancements in surgical techniques and adjuvant therapies, local recurrence remains a significant challenge in cancer treatment. Local recurrence most often results from the presence of individual precancerous cells that will later develop into cancer, or of individual cancer cells in the remaining normal tissue surrounding the original tumor that was removed. To minimize the risk of local recurrence, surgeons aim to remove the tumor with a clear margin of normal healthy tissue (i.e. normal tissue that may contain individual cancerous cells). In some cases surgeons are not able to remove the desired margin of normal tissue due to adjacent sensitive tissues that should not be removed but that likely contain cancer cells. In other cases the margin did not extend sufficiently far and cancer cells beyond the margin remain. Adjuvant treatments such as radiation, chemotherapy, or immunotherapy are often employed in combination with surgery to target such residual cancer cells and reduce the likelihood of recurrence.SUMMARY

[0004] The present disclosure describes methods and apparatuses for delivery of chemotherapy to normal tissue surrounding a cancerous tumor immediately after surgical removal of that tumor. Specifically, the purpose is treatment of any precancerous cells and cancer cells located in normal tissue remaining after tumor surgery that were not part of the removed tissue, to avoid cancer regrowth.

[0005] In some cancers such as soft tissue sarcoma and oral cavity cancer, local tumor recurrence rates are particularly high. For soft tissue sarcoma, local recurrence rate depends on width of the surgical margin (i.e. , normal tissue removed during surgery), but varies between ~12 to 38 % during 5-year follow-up, and is up to 44% within 10 years. In the most common form of oral cavity7cancer - oral squamous cell carcinoma - local recurrence occurs in 20-45% of patients following surgery, and is assumed to result from remaining precancerous cells following surgery7. Precancerous cells are genetically altered cells that can become cancer cells at a later point. Local radiation at the area of the surgically removed tumor is commonly used after surgery7to reduce the risk of tumor recurrence. While chemotherapy is known to be effective against cancer cells, there is currently no effective method for the targeted delivery of a large dose of chemotherapy to normal tissue surrounding the surgically removed tumor (i.e., the surgical cavity), to reduce the risk of local recurrence. While direct application of chemotherapy to the surgical cavity7is possible, the chemotherapy then only penetrates 1-2 mm deep into the surrounding tissue, which is inadequate. For example, diffusion-driven drug delivery techniques may only penetrate approximately 1-2 mm from the infusion site before dropping off exponentially. In implantation of drug-impregnated polymer into the brain tumor resection cavity, penetration using such implantation technique may be similarly limited to 1-2 mm.

[0006] Certain techniques may be used to achieve or enhance delivery of chemotherapy agents to the surgical margin. For example, electroporation may be used to enhance cell uptake of chemotherapy injected into the margin tissue, or administered intravenously. Another approach may include high intensity focused ultrasound to either ablate tissue in the margin, or enhance cellular uptake of drugs directly injected into the margin tissue. Further approaches may use various biomaterials that can be placed in the surgical cavity, that then slowly release therapeutic agents. Such approaches usually rely on diffusion of chemotherapy agents within tissue. As stated above, such diffusion is very ineffective, and limited to 1-2 mm from the site of drug administration. Methods, systems, and apparatuses according to the present disclosure may circumvent this limitation by releasing drug within the vasculature of the margin tissue, for example, at depths in a range from 0.5 to 3 cm from the surgical cavity surface.

[0007] Nanoparticle drug delivery systems (DDS) may be used for targeted delivery7of chemotherapy agents to tumors, and include liposomes, micelles, and polymer-based nanoparticles, among others. A specific category of DDS are so-called triggered DDS, where release of the encapsulated chemotherapy is initiated by a trigger signal. The trigger thatfacilitates release depends on the ty pe of triggered DDS, and can include for example temperature, light, ultrasound, electromagnetic fields, or X-rays. Typically, the intended delivery strategy includes extravasation of the nanoparticle DDS, followed by triggered drug release. Many DDS techniques for cancer therapy are based on the enhanced permeability and retention (EPR) effect, that enables preferential extravasation of nanoparticle DDS in tumors. The EPR effect is based on the property that tumor vessels are more leaky than normal vessels, combined with a lack of lymphatic drainage present in tumors. This allows for the slow accumulation of nanoparticles in tumors, typically over 24-48 hours.

[0008] In contrast, the DDS of the present disclosure may be based on rapid drug release (for example, within seconds) from DDS within the vessels of the targeted tissue. Recently, such DDS based on so-called intravascular triggered release have been studied more widely, where release occurs primarily within the capillary vessels of the targeted tissue region. Large quantities of drug can be delivered to a locally targeted tissue regions with triggered nanoparticles based on intravascular triggered release, such as thermosensitive liposomes. Delivery kinetics of intravascular triggered nanoparticles based on computational models indicate that triggered nanoparticles for intravascular triggered release require rapid release within seconds to be effective, since blood only remains for a few seconds within the vessels of the targeted tissue. Only certain nanoparticles were used for intravascular triggered release. Certain techniques are based on slow accumulation of DDS within the tumor, and computer models indicate that the use of nanoparticles such as thermosensitive liposomes that release the contained drug within minutes to hours are inadequate for intravascular triggered delivery.

[0009] Certain techniques may be used for exposing cancerous tumors to trigger energy (e.g., hyperthermia) adequate for drug release from triggered nanoparticles. Devices based on radiofrequency fields, ultrasound, or other energy generating means may be used. In some examples, methods and systems according to the present disclosure differ in the exposure of the surgical cavity after surgical tumor removal to trigger energy, rather than direct trigger energy application to a deep-seated tumor as described in these prior art. For example, systems and methods according to the present disclosure may be used, in some examples, to expose a surgical cavity surface and surrounding tissue in a range from 0.5 to 3 cm deep.

[0010] In some examples, the present disclosure describes application of triggered nanoparticles, preferably based on intravascular triggered release, to deliver a large chemotherapy dose to the surgical cavity (i.e. , the normal tissue surrounding the removed tumor) following surgical tumor resection. The nanoparticles may be combined with atrigger energy delivery device specifically designed for exposing the surgical cavity in a range from 0.5 to 3 cm deep to trigger energy sufficient to release drug from the nanoparticles. In some examples, systems and techniques may be used to kill at least some, a majority of, or substantially all precancerous or cancerous cells remaining in the normal tissue surrounding the surgically removed tumor. In some examples, systems and techniques may be used for targeting residual cancerous or precancerous cells following tumor surgery. In some examples, systems and techniques may be used for combined hyperthermia and chemotherapy. For example, systems and techniques may be used for treatment of residual cancer cells after surgical tumor removal from a patient, while the patient is still in an operating room and a surgical cavity surface is accessible. In some examples, systems and techniques may be used after surgically extracting a tumor, e.g., to release the anti-cancer agent from the nanoparticles in tissue surrounding the surgically extracted tumor. In some examples, systems and techniques may be used for drug delivery to remnant cancer cells after surgical tumor removal.

[0011] In some examples, an example system for drug delivery’ to a surgical cavity may include a source of nanoparticles configured to encapsulate a therapeutic agent and being responsive to a predetermined trigger energy. The system may further include an energy’ delivery’ apparatus configured to deliver the trigger energy' to facilitate the release of the therapeutic agent at specific regions within or proximate to the surgical cavity.

[0012] In some examples, an example method includes administering nanoparticles loaded with at least one anti-cancer agent. The nanoparticles are configured for delivery to a surgical cavity. The method may further include applying a release-triggering energy to specified regions within or adjacent to the surgical cavity. The release-triggering energy may be applied before, during, or after nanoparticle administration.

[0013] In some examples, a method includes introducing thermosensitive liposomes encapsulating doxorubicin into a bloodstream. The liposomes may be configured for triggered intravascular release at temperatures above 40 °C. The method may further include targeting near-infrared radiation onto a surgical cavity surface with the radiation penetrating below the surface. The near-infrared radiation may be configured to release doxorubicin from the liposomes inside tissue capillaries. The released doxorubicin may be configured for killing the residual cancer cells remnant in tissue in a vicinity’ of the surgical cavity surface. The method may further include monitoring tissue temperature and adjusting near-infrared radiation intensity based on the monitored tissue temperature. The method may furtherinclude monitoring of doxorubicin delivery' during near-infrared radiation exposure of the surgical cavity surface by fluorescence imaging.

[0014] In some examples, a method includes administering thermally triggered nanoparticles configured for intravascular triggered release, loaded with at least one anticancer agent, into a bloodstream. The method may further include applying near-infrared energy to a tissue surrounding a surgically extracted tumor. The near-infrared energy may be configured to release the anti-cancer agent from the nanoparticles in the tissue surrounding the surgically extracted tumor.

[0015] In some examples, a method includes infusing thermally triggered nanoparticles incorporating at least one anti-cancer drug into systemic blood circulation. The nanoparticles may be configured for intravascular triggered release. The method may’ further include releasing drug from thermally triggered nanoparticles in a tissue surrounding the surgically extracted tumor by7applying a drug-releasing energy. The released drug is configured to kill remnant cancer cells.

[0016] The details of one or more examples of the techniques of this disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the techniques will be apparent from the description and drawings, and from the claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The summary, as well as the following detailed description, is further understood when read in conjunction with the appended drawings. For the purpose of illustrating the disclosure, examples are shown in the drawings; however, the disclosure is not limited to the specific techniques, compositions, and devices disclosed. In addition, the drawings are not necessarily drawn to scale.

[0018] FIG. 1 is a flowchart illustrating an example technique for delivering nanoparticles to a surgical cavity'.

[0019] FIG. 2A is a schematic diagram illustrating a tumor that will be surgically removed together with surrounding individual cancer ous / precancerous cells and cell islets of cancerous and / or precancerous cells. The dotted line indicates the plane where tissue may be cut and removed.

[0020] FIG. 2B is a schematic diagram illustrating the surgical cavity with remaining precancerous and / or cancerous cells, or islets of such cells.

[0021] FIG. 2C is a schematic diagram illustrating an example trigger energy delivery device that exposes the surgical cavity surface up to a certain depth to trigger energy, to release drug from triggered nanoparticles.

[0022] FIG. 3 is a schematic diagram illustrating an example delivery mechanism of intravascular triggered release, where release of the encapsulated chemotherapy occurs within the vasculature (typically, the capillaries) of the targeted tissue adjacent to the surgical cavity surface. Following chemotherapy release, the drug passes through the vascular wall into tissue and is then taken up by normal, cancerous, and precancerous cells (depending on which cell t pe is present) with the goal of killing remaining cancerous and / or precancerous cells.

[0023] FIG. 4A shows a microscope image of a mouse tissue segment (800 x 800 um), 1 second after injection of a fluorescent contrast agent.

[0024] FIG. 4B shows a microscope image of the mouse tissue segment (800 x 800 um) of FIG. 4A, 2 seconds after injection of the fluorescent contrast agent.

[0025] FIG. 4C shows a microscope image of the mouse tissue segment (800 x 800 um) of FIG. 4A, 3 seconds after injection of the fluorescent contrast agent.

[0026] FIG. 4D shows a microscope image of the mouse tissue segment (800 x 800 um) of FIG. 4A, 4 seconds after injection of the fluorescent contrast agent. FIGS. 4A to 4D demonstrate that blood only remains for a few seconds within a particular tissue segment.

[0027] FIG. 5A is a chart depicting the release kinetics of DDS appropriate for intravascular triggered release, with majority of drug released within 10 seconds of exposure to trigger energy.

[0028] FIG. 5B is a chart showing a specific type of thermosensitive liposomes where release was measured by the applicants at body temperature (37 °C), and at hyperthermic temperatures (41 and 43 °C).

[0029] FIG. 6 is a schematic diagram illustrating an example hyperthermia device including an infrared laser, and an actuated mirror.

[0030] FIG. 7 is a flowchart illustrating an example method including deploying heatsensitive nanoparticles.

[0031] FIG. 8 is a chart depicting how convective cooling of the surgical cavity surface can be employed to enhance penetration depth of temperatures required for drug release (here, assumed above 40 °C), and thus increase the tissue depth where drug release occurs.

[0032] FIG. 9A is a fluorescence image representing drug uptake surrounding a hyperthermia probe visualized by increasing fluorescence, before hyperthermia application.

[0033] FIG. 9B is a fluorescence image representing drug uptake surrounding a hyperthermia probe visualized by increasing fluorescence, at 5 minutes after hyperthermia application.

[0034] FIG. 9C is a fluorescence image representing drug uptake surrounding a hyperthermia probe visualized by increasing fluorescence, at 10 minutes after hyperthermia application.

[0035] FIG. 9D is a fluorescence image representing drug uptake surrounding a hyperthermia probe visualized by increasing fluorescence, at 30 minutes after hyperthermia application.DETAILED DESCRIPTIONA. Overview

[0036] The present disclosure provides methods and apparatus for the targeted chemotherapy delivery' to treat precancerous (cells that may later become cancerous), and cancerous cells remaining in the normal tissue margin, i.e. adjacent to a tumor that has been removed by surgery. Either immediately after surgery, or at a later point, one or more chemotherapy agents encapsulated in triggered nanoparticles are administered to a patient by conventional methods such as intravenous infusion. These nanoparticles with encapsulated chemotherapy agent(s) will circulate for extended duration in the patient's blood, preferably for at least 30 minutes. Starting either before, during, or following this triggered nanoparticle administration, the surgical cavity is exposed to the trigger signal to induce localized release of the chemotherapy agent (as described with reference to FIGS. 1 and 2A to 2C), ideally within 0.5-3 cm of the surgical cavity7surface. In some examples, nanoparticles based on intravascular triggered release are employed (FIG. 3) - i.e., nanoparticles that release substantial drug amounts while passing through the microvasculature of the target tissue, which means typically within a few seconds (FIG. 4). In some examples, heat-triggered nanoparticles such as thermosensitive liposomes will be used; thus, hyperthermia in the range ideal for chemotherapy release from those heat-triggered nanoparticles (e.g., in a range from about 40 to about 45 °C for thermosensitive liposomes) will be applied to the surgical cavity and deeper surrounding tissue, up to 3 cm deep. The trigger energy7magnitude (e.g., hyperthermia) may be adequate to trigger drug release from nanoparticles in a range from a 0.5 to 3 cm wide rim of tissue adjacent to the surgical cavity7. E.g., if thermosensitive liposomes are used, a 0.5 to 3 cm wide rim of tissue to temperatures may be heated to promote release (e.g., in a range from about 40 to about 45 °C).B. Triggered Nanoparticles

[0037] Triggered nanoparticles, also known as stimuli-responsive nanoparticles, are a more recent technology in the field of DDS. These nanoparticles can change their properties (e.g., size or porosity ) in response to specific stimuli, allowing for controlled and targeted delivery of therapeutic agents. This approach can significantly enhance the efficacy of treatments and minimize side effects, particularly in applications such as cancer therapy. Different types of triggered nanoparticles may respond to different triggers. Nanoparticles that respond to externally applied stimuli may be used. Such external stimuli include, for example, one or more of light, temperature (thermosensitive), electromagnetic fields, or ultrasound. Triggered nanoparticles may allow for high precision in drug delivery, as the release of the therapeutic agent can be controlled spatially (only at the disease site) and temporally (at a specific time) (as discussed with reference to FIGS. 9A to 9D).

[0038] Intra-vascular triggered nanoparticles may be used for intravascular-triggered release from nanoparticles, such that the release of the encapsulated drug occurs predominantly within the vasculature (typically the capillary vessels) of the targeted tissue region (as discussed with reference to FIG. 3). In some examples, the systemic circulation sen es as reservoir of encapsulated (non-bioavailable) drug, and drug is released (becomes bioavailable) in the vessels of the targeted tissue region where the trigger is applied. Intravascular-triggered nanoparticles require very rapid release of the encapsulated therapeutic agent (e.g., chemotherapy) within a few seconds (as discussed with reference to FIG. 5), since blood only remains for a few seconds within a particular tissue segment (as discussed with reference to FIG. 4). Only certain triggered nanoparticles can achieve such rapid release, and certain techniques thus do not use nanoparticles intended for intravascular triggered release. Such rapid release may be used because the nanoparticles circulate through tissue via the blood stream. Blood with nanoparticles remains within any targeted tissue region only for a few seconds (FIG. 4), and this time has been measured in many human tumors and other tissues. This time is for example ~2 s for primary liver cancer, ~3 s for head and neck and prostate tumors, and ~I I s for kidney cancer. Certain intra-vascular triggered nanoparticles may include thermosensitive liposomes. Only certain liposome formulations may be useful for intravascular-triggered release (i.e., that release most of the contained drug within less than 10 s). Even release within minutes may not be adequate, as then only a tiny fraction of drug is released while the nanoparticles pass through the vasculature during a few seconds (as discussed with reference to FIG. 4).

[0039] Intravascular-triggered nanoparticles may provide: (1) ability to deliver a large drug dose compared to other nanoparticles; and (2) control of the delivered dose by adjusting the duration of the trigger signal: as long as the trigger is applied, nanoparticle-encapsulated drug enters the target region where drug is then released. For thermosensitive liposomes, there may be a correlation between hyperthermia duration and drug amount delivered to tumors.

[0040] In some examples, intra-vascular triggered nanoparticles may be combined with drugs that are rapidly taken up by tissue, once released; any released drug not taken up within the tissue region of release will return to systemic circulation and will then be delivered throughout the body. The fraction of drug that is taken up by targeted tissue while passing through tissue vasculature once is often termed "extraction fraction' or ‘extraction ratio'. In some examples, chemotherapy drugs with extraction ratios above 0.3 (i.e. , >30% of the drug are taken up by targeted tissue), for example, such as doxorubicin, idarubicin, or gemcitabine, may be used.

[0041] In some examples, thermosensitive liposomes are used for intravascular triggered release. In some examples, thermosensitive liposomes may encapsulate chemotherapy agents with a relatively high extraction ratio (i.e., above 0.3). While the majority of triggered particles are -100 nm in size and thus termed ‘nanoparticles’, larger particles (e.g., microparticles that are >1 um in diameter) that are appropriate for intra-vascular triggered release (e.g., ultrasound-triggered microbubbles) may also be used.

[0042] To promote intravascular triggered release, the nanoparticles may be administered directly or indirectly to the systemic blood circulation, e.g. by intravenous injection or infusion.C. Devices for Triggering Release

[0043] An appropriate device for applying the release trigger energy to the targeted tissue may be used depending on the type of the triggered nanoparticle. Examples of devices include focused ultrasound transducers for ultrasound triggered nano- and micro-particles; laser for light-triggered nanoparticles; electromagnetic field generators (e.g., coils) for nanoparticles triggered by electromagnetic fields; and various hyperthermia devices for nanoparticles triggered by heat / temperature. Certain devices may not be specifically configured for applying trigger energy to a surgical cavity and surrounding tissue.

[0044] For application of the trigger signal to a surgical cavity and with suitable tissue penetration (e.g., 0.5 to 3 cm), an infrared light source is used as device for applying therelease trigger in a preferred embodiment. Advantageously, light can be applied without contact to the surgical cavity and can achieve tissue penetration of 1-2 cm at infrared wavelengths (temperature penetration may be even higher, due to thermal diffusion). Thus, either light-triggered nanoparticles or temperature sensitive nanoparticles may be used in some examples using infrared-based devices to trigger drug release.

[0045] In some examples, infrared laser or other infrared sources may be employ ed to target infrared radiation to the surgical cavity and deeper tissues without contact. If infrared lasers are employed, electronically, mechanically, or electro-mechanically actuated mirrors may be used to scan the targeted tissue surface without exposing surrounding tissue outside the cavity (for example, as described with reference to FIG. 6). Alternatively, non-targeted tissue may be covered by adequate material to avoid heating.

[0046] When thermosensitive nanoparticles are employed, monitoring of tissue temperature may promote ensuring that ideal temperature for drug release is achieved throughout the surgical cavity7. Such temperature monitoring can be facilitated either by infrared cameras, or by temperature sensors (e.g., thermocouples, thermistors) placed in contact with the tissue, or below the tissue surface. In some examples, temperature feedback from such temperature sensing methods will be employed to modulate power or use pulse width modulation of the infrared device to employ feedback control of tissue heating, and to keep tissue surface temperature within a targeted temperature range. This enables a system where the user selects the target region on an image obtained of the surgical cavity of a patient, and the system automatically exposes the selected target region uniformly to the desired temperature range that facilitates localized drug release (as described with reference to FIG. 7).

[0047] In some heating scenarios, for example, when heating occurs from the surface, tissue temperature is typically highest at the tissue surface and drops off towards body temperature with increasing tissue depth (as described with reference to FIG. 8). Since release from triggered nanoparticles such as thermosensitive liposomes ty pically occurs above a certain threshold temperature (e.g., about 40 °C), drug release is limited to a certain tissue depth (for example, dl in FIG. 8). If desirable, the depth penetration of temperature, and of drug release can be increased by convective cooling of the tissue surface (d2 in FIG. 8), to promote penetration of tissue heating for interstitial probes.D. Monitoring of Drug Delivery by Intraoperative Fluorescence Imaging

[0048] Intraoperative fluorescence may enhance the visibility' of tissues during surgery, providing surgeons with real-time guidance and improving the accuracy of procedures. The technique may use fluorescent probes or dyes, which are administered prior to or during surgery', and a special imaging system that can detect the emitted fluorescence. In the context of cancer surgery, such techniques can help distinguish cancerous tissues from healthy ones. Certain fluorescent agents are preferentially taken up by cancer cells or are activated only in the presence of cancer, illuminating the tumor when viewed under the imaging system.

[0049] In methods and systems according to the present disclosure, intraoperative fluorescence imaging may be employed to monitor location and amount of drug delivered to the surgical cavity, as an optional additional component. Such fluorescence imaging may use either naturally fluorescent drugs (e.g., doxorubicin, idarubicin, methotrexate), or drugs that have been labeled by fluorophores. Certain techniques may use fluorescence imaging to visualize fluorescent probes, drugs and nanoparticles following delivery'. Fluorescence imaging may be used to monitor drug delivery of intravascular triggered thermosensitive liposomes in real-time, during triggered release - i.e., during drug delivery (as described with reference to FIG. 9). In this context, real-time means, that location and amount of drug release can be monitored while the trigger (i.e., hyperthermia) is applied. This may enable visualization of the continuous uptake of drug by the target tissue during delivery (i.e., during heating), in contrast to techniques where release is visualized after delivery is complete. Real-time monitoring may enable a clinician (e.g. physician, medical physicist or nurse) to monitor drug delivery during the procedure, and for example keep applying the trigger until a desired (therapeutically effective) amount of drug has been delivered. With intravascular triggered nanoparticles, drug delivery continues to take place as long as the trigger is applied. In addition, fluorescence monitoring can ensure that chemotherapy drug is delivered to all desired regions of the surgical cavity. If necessary, trigger energy intensity' and / or location can be adjusted to achieve delivery' to all desired tissue regions.Targeted Chemotherapy’ Delivery

[0050] FIG. 1 is a flowchart illustrating an example technique for delivering nanoparticles to a surgical cavity'. Following surgical removal (resection) of a cancerous tumor by any suitable method (100), triggered drug delivery' particles may be administered into the systemic blood circulation, e.g., by intravenous infusion (102). The triggered nanoparticles can include any of those described in the prior art as indicated earlier, includinglarger microparticles that may also be employed instead of common nanoparticles. Particles may include one or more of various light-triggered nanoparticles, polymer-based nanoparticles that release drugs triggered by hyperthermia, nanoparticles that can be activated by magnetic or electric fields, or liposomes triggered by X-ray radiation. For purposes of the described embodiments, the nanoparticles are configured for intravascular triggered release. In some examples, most of the drug is released within less than 10 seconds from the particles once the particles are exposed to the trigger energy. FIG. 5A is a chart depicting the release kinetics of DDS appropriate for intravascular triggered release, with majority of drug released within 10 seconds of exposure to trigger energy. FIG. 5B is a chart showing a specific type of thermosensitive liposomes where release was measured by the applicants at body temperature (37 °C), and at hyperthermic temperatures (41 and 43 °C). These thermosensitive liposomes included dipalmitoylphosphatidylcholine (DPPC); monostearoylphosphatidylcholine (MSPC); 1 ,2-Distearoyl-sn-Glycero-3- Phosphoethanolamine-N-Poly(ethyleneglycol)20) (DSPE-PEG2000) with a molar ratio of DPPC:MSPC:DSPE-PEG2000 of 86: 10:4. Certain nanoparticles may not be suited or configured for intravascular triggered delivery as these nanoparticles release much more slowly, within minutes to hours rather than seconds. This is because certain nanoparticles are based on the enhanced permeability and retention (EPR) mechanism, which take place over many hours. The surgical cavity may be exposed to trigger energy to trigger rapid release of drug from the triggered nanoparticles (104).

[0051] FIG. 2A is a schematic diagram illustrating a tumor that will be surgically removed together with surrounding individual cancer ous / precancerous cells and cell islets of cancerous and / or precancerous cells. The dotted line indicates the plane where tissue may be cut and removed. Referring now to FIG. 2A, a cancerous tumor 1 - such as for example soft tissue sarcoma or oral cavity tumors - is embedded in normal tissue. Tumors amenable to surgical removal may be targeted. The tumor 1 is surrounded by individual precancerous or cancer cells and / or small clusters of cancer cells 3. The tissue that is intended to be surgically removed (‘resected’) is indicated by a dotted line 2. The dotted line includes normal tissue surrounding the tumor 1, with the intent of removing all precancerous and cancerous cancer cells, and cluster of precancerous and cancer cells 3.

[0052] FIG. 2B is a schematic diagram illustrating the surgical cavity with remaining precancerous and / or cancerous cells, or islets of such cells. FIG. 2B shows the tissue remaining immediately after surgical tumor removal. Several precancerous or cancerous cells or clusters of such cells 4 are unintentionally remaining after surgery. These remainingprecancerous or cancer cells will likely result in local tumor regrowth, or local tumor recurrence. The surgical cavity 5 indicates the normal tissue surface remaining after surgery. As indicated in FIG. 1, triggered nanoparticles may be administered after surgical tumor removal is completed. While the nanoparticles may also be administered before beginning of the surgery' or during surgery', such administration may result in many nanoparticles slowly leaking the drug after administration, reducing the drug available for triggered release.

[0053] FIG. 2C is a schematic diagram illustrating an example trigger energy delivery device that exposes the surgical cavity surface up to a certain depth to trigger energy, to release drug from triggered nanoparticles. An energy' delivery device 6 is employed to deliver the specific ty pe of energy (‘trigger energy ’) 7 required by the triggered nanoparticles for release, to the surgical cavity 5. The trigger energy may either directly induce triggered release, or induce release indirectly. For example, for heat-triggered nanoparticles, the energy delivery' device 6 may emit a form of energy that induces tissue heating - for example microwaves, ultrasound, or infrared radiation. Drug release is then induced indirectly due to tissue being heated by this energy. In some examples, the energy penetrates into the normal tissue such that the remaining precancerous or cancerous cells and precancer / cancer cell clusters 4 are exposed to the trigger energy. Typically, a penetration depth in a range from about 0.5 to 3 cm is most desirable since the cancer cells 4 are usually located within less than 0.5-3 cm from the surgical cavity surface 5. The purpose of the trigger energy 7 is not the direct exposure of the cancer cells 4 to this energy, but the purpose is triggering drug release from the nanoparticles.

[0054] FIG. 3 is a schematic diagram illustrating an example delivery mechanism of intravascular triggered release, w here release of the encapsulated chemotherapy occurs w ithin the vasculature (typically, the capillaries) of the targeted tissue adjacent to the surgical cavity’ surface. A microscopic (-100 um wide) tissue section adjacent to the surgical cavity 5 is shown magnified. Two individual precancer or cancer cells 4 are shown near the surgical cavity' surface 5. In addition, a small blood vessel (e.g., capillary ) is represented by vessel walls 8. The blood direction in the vessel is indicated by arrow 9. Triggered nanoparticles 10 filled with chemotherapeutic drug 11 are carried by blood through the vessel. The stars 11 indicate individual drug molecules. Once the nanoparticles 10 are exposed to trigger energy 7 of adequate magnitude, the nanoparticles start releasing the contained drug 11 within the vessel. The arrows 12 indicate this triggered release of the drug 11. As the nanoparticles 10 are carried by blood flow along the vessel 8 (from left to right), progressively more and more drug 11 is released. Once drug 11 has been released, the drug crosses the vessel wall asindicated by arrows 13. Finally, the drug 11 is taken up by precancer or cancer cells 4 to induce the intended cell killing. One purpose is to release adequate amounts of drug 11 inside the vessels adjacent to precancer / cancer cells 4 near the surgical cavity surface 5, to kill most or all cancer cells 4 and prevent tumor regrowlh. Since blood only remains for a few seconds within vessels of a particular tissue segment, nanoparticles require rapid release.

[0055] FIGS. 4A to 4D demonstrate that blood only remains for a few seconds within a particular tissue segment. In particular, an image sequence is shown at various intervals, visualizing the distribution of a contrast agent throughout the capillaries of a small tissue segment; these data demonstrate that blood only remains for a few seconds within the capillaries of a particular tissue segment. The delivery mechanism indicated in FIG. 3 is termed ‘intravascular triggered release'.

[0056] The time for which the trigger energy 7 is applied affects the release. In some examples, the systemic circulation serves as large reservoir of non-bioavailable drug that becomes bioavailable once the nanoparticles enter the tissue where the release energy is applied to. As long as the release energy’ is applied, new nanoparticles 10 with drug 11 enter the targeted tissue region and release the drug 11. I.e., the longer the trigger energy 7 is applied, the more drug 11 is released near the surgical cavity 5, and more drug is taken up by cancer cells 4. Thus, in some examples, the duration of trigger energy’ 7 is selected to achieve delivery’ of drug amounts required for complete cell kill of cancer cells 4.

[0057] The type of drug 11 encapsulated in nanoparticles 10 also affects drug delivery. Drugs that rapidly cross the vessel wall 8, and that are furthermore rapidly taken up by cancer cells 4 may promote treatment. A parameter that describes how fast a drug is taken up by tissue is the ‘extraction fraction’ or ‘extraction ratio’. This extraction fraction describes the fraction of the drug that passes through the vessel wall while carried by blood through the capillary vessel of a particular tissue segment. In some examples, the drugs employed have an extraction fraction of 0.3 or higher; i.e., >=30% of drug 11 passes / diffuses across the wall of 8, during a single pass through the vessel. Such drugs with extraction ratio >0.3 include the chemotherapy agents doxorubicin, idarubicin, and gemcitabine, among others.

[0058] For a triggered nanoparticle to be suitable for intravascular triggered release, substantial amounts of drug need to be released within seconds as discussed earlier (FIG. 5A). Suitable triggered nanoparticles for intravascular triggered delivery’ include some formulations of thermosensitive liposomes, which are available with sufficiently rapid release. Here, hyperthermia serves as trigger energy’ to induce drug release. For example, in the release of a formulation of thermosensitive liposomes encapsulating doxorubicin at above-41 °C, these liposomes release most of the contained drug within -2 seconds (FIG. 5B), and are therefore suitable for intravascular triggered release applications. Thus, in another example, thermosensitive liposomes with rapid release such that the majority of the drug is released within less than 10 seconds are employed as triggered nanoparticles.

[0059] Referring now again to FIG. 2, when thermosensitive liposomes are employed, the energy device 6 needs to emit a type of energy 7 that induces hyperthermia in the normal tissue adjacent to the surgical cavity 5. Suitable forms of energy include those that can be applied without contact, for example infrared radiation. In some example, the radiation is applied to the surgical cavity and not to surrounding tissue surfaces, radially distant from the cavity’ 5.

[0060] FIG. 6 is a schematic diagram illustrating an example hyperthermia device including an infrared laser, and an actuated mirror. Tissue temperature is measured either by an infrared camera, by temperature sensors, or by both. If desired, tissue regions where drug delivery' is not intended can be protected by adequate material. If infrared radiation is used, material with limited absorption in the infrared radiation range is preferred. In the system of FIG. 6, a hyperthermia system includes an infrared laser 16 combined with an actuated mirror 18. The mirror is configured to be controlled by any suitable electromechanical means. A computer-controlled system controls laser activation (e.g., power or on-off timing, i.e., pulse width modulation) and mirror position to expose the whole surgical cavity to infrared radiation. An infrared camera 19 is used to monitor temperature distribution at the tissue surface of the surgical cavity75, and this temperature information is used as feedback for the computer-controlled system, to achieve uniform temperature throughout the surgical cavity7surface. Alternatively or in addition, one or more temperature sensors 20 such as thermistors or thermocouples may be placed at, or adjacent to the cavity’ surface 5 to monitor temperature and serve for feedback control. During infrared laser application, a temperature gradient wi 11 develop such that temperature will drop off with increasing tissue depth from surface of surgical cavity 5, towards body temperature (~37 °C). In some examples, tissue within up to -0.5-3 cm from the cavity surface will be exposed to temperatures adequate for drug release (e.g., above -40 °C for typical thermosensitive liposomes).

[0061] FIG. 8 is a chart depicting how convective cooling of the surgical cavity surface can be employed to enhance penetration depth of temperatures required for drug release (here, assumed above 40 °C), and thus increase the tissue depth where drug release occurs. FIG. 8 shows a typical tissue temperature profile, when the surgical cavity tissue surface isexposed to heat. Thus, the target temperature measured by infrared camera 19 at the tissue surface of surgical cavity 5 will ideally be selected such that the threshold temperature where substantial release triggered nanoparticles occurs is within -0.5-3 cm from the cavity surface 5. The tissue surface of surgical cavity 5 may optionally be cooled by convection with air or other gases to enhance penetration depth of tissue heating (FIG. 8). Sheets 21 made of material opaque to infrared radiation may be employed to shield tissue regions where no exposure and no drug release are desired. Such protection is particularly desirable in other embodiments that provide less accurate spatial control than lasers.

[0062] FIG. 7 is a flowchart illustrating an example method including deploying heatsensitive nanoparticles. In some examples, operation of a computer-controlled hyperthermia system shown in FIG. 6 may be implemented by the flowchart of FIG. 7. First, a photographic image is obtained of the surgical cavity and surrounding tissue - either by the infrared camera 19 (if the camera has the ability to take conventional photographic images), or optionally by a separate photographic camera (200). In the latter case, image registration methods known to a person skilled in the art may be employed to register images of the two cameras to each other. Next, the user selects the region where drug delivery is intended - for example, by outlining the surgical cavity on the image with a mouse, touch screen, or other appropriate input methods (202). In addition, the user may indicate the desired target temperature at the tissue surface, as well as heating duration (204). Based on these user inputs, the computer-controlled system may control laser and mirror to expose the region selected by the user to the desired target temperature, for the indicated duration (206). Realtime infrared image data obtained by infrared camera 19 and / or temperature sensors 20 will be used to achieve the desired temperature throughout the user-selected region.

[0063] FIG. 9A is a fluorescence image representing drug uptake surrounding a hyperthermia probe visualized by increasing fluorescence, immediately before hyperthermia application. FIG. 9B is a fluorescence image representing drug uptake surrounding a hyperthermia probe visualized by increasing fluorescence, at 5 minutes after hyperthermia application. FIG. 9C is a fluorescence image representing drug uptake surrounding a hyperthermia probe visualized by increasing fluorescence, at 10 minutes after hyperthermia application. FIG. 9D is a fluorescence image representing drug uptake surrounding a hyperthermia probe visualized by increasing fluorescence, at 30 minutes after hyperthermia application. As shown in FIGS. 9A to 9D, longer heating duration will result in larger amount of drug delivery.

[0064] In some examples, any suitable fluorescence imaging system may be employed in combination with the system components described above. In some examples, fluorescent drugs (e.g., doxorubicin or idarubicin) or fluorescently -tagged drugs will be used to enable fluorescence imaging of drug uptake. Real-time fluorescence imaging may be used to visualize and monitor drug delivery during heating of tissue, when fluorescent drugs such as doxorubicin are encapsulated in thermosensitive liposomes (FIGS. 9A and 9B). I.e., the location and amount of drug delivery can be monitored and potentially adjusted in real-time, by adjusting tissue heating via control of the hyperthermia device. The fluorescence imaging system may thus be used to visualize drug delivery in real-time, during heating - for example by overlay of the fluorescence image on a photographic image of the surgical cavity. Alternatively, the fluorescence image data may be used to control the hyperthermia device and adjust heating duration and location such that adequate drug amounts are delivered throughout the surgical cavity.

[0065] In particular, it is intended that the present disclosure not be limited to the embodiments and figures contained herein, but include modifications of those embodiments including portions of the embodiments and combinations of elements of different embodiments as come within the scope of the claims listed below. For example, focused or unfocused infrared radiation may be provided by other methods than lasers known to persons skilled in the art, such as heat lamps combined with appropriate optical lenses and / or mirrors. A surgical cavity may exhibit various geometries, and may for example be more spherical in case of brain tumors or be very shallow (i.e., not represent a ‘cavity’ in the literal sense) in case of oral cavity cancers.

[0066] The following enumerated clauses describe examples according to the present disclosure.

[0067] Clause 1 : A system for drug delivery to a surgical cavity, the system including: a source of nanoparticles configured to encapsulate a therapeutic agent and being responsive to a predetermined trigger energy; and an energy' delivery' apparatus configured to deliver the trigger energy' to facilitate the release of the therapeutic agent at specific regions within or proximate to the surgical cavity.

[0068] Clause 2: The system of clause 1, where the nanoparticles are configured for triggered release by hyperthermia.

[0069] Clause 3: The system of clauses 1 or 2, where the nanoparticles are configured for triggered release by ultrasound.

[0070] Clause 4: The system of any of clauses 1 to 3. where the nanoparticles are configured for triggered release by light.

[0071] Clause 5: The system of any of clauses 1 to 4, where the nanoparticles are configured for triggered release by electromagnetic fields.

[0072] Clause 6: The system of any of clauses 1 to 5, where the nanoparticles are thermosensitive liposomes.

[0073] Clause 7: The system of any of clauses 1 to 6, where the nanoparticles are configured for an intravascular release, facilitating a release of greater than 50% of the encapsulated therapeutic agent within a duration of less than 10 seconds upon exposure to the trigger energy'.

[0074] Clause 8: The system of any of clauses 1 to 7, where the encapsulated chemotherapy agent has an extraction ratio of more than 0.3 (30%).

[0075] Clause 9: The system of any of clauses 1 to 8, where the energy' delivery' device is an infrared source.

[0076] Clause 10: The system of clause 9, where the infrared source is a laser.

[0077] Clause 11: The system of any of clauses 1 to 10, where the surgical cavity surface is cooled by convective gas flow.

[0078] Clause 12: The system of any of clauses 1 to 11, where temperature of the surgical cavity surface is monitored by either an infrared camera, by one or more temperature probes placed at or near the surgical cavity’ surface, or by both an infrared camera and one or more temperature probes.

[0079] Clause 13: The system of any of clauses 9 to 12, where the infrared source is combined with actuated mirrors to steer the heating location across all or parts of the surgical cavity’ surface.

[0080] Clause 14: The system of any of clauses 1 to 13, where trigger magnitude and trigger duration are controlled to achieve a desired drug delivery amount at or near the surgical cavity.

[0081] Clause 15: The system of any of clauses 1 to 14, where the trigger energy induces drug release from nanoparticles within a depth in a range from 0.5 to 3 cm from the surgical cavity surface.

[0082] Clause 16: The system of any of clauses 12 to 15, where the monitored temperature is used for feedback control, to adjust either infrared source power, employ pulse width modulation, actuate the mirror, or combine adjusting power, pulse width modulationand mirror actuation to heat either the surgical cavity, or a tissue region selected by the user to a user-defined target temperature in the range from 40 to 50 °C.

[0083] Clause 17: The system of any of clauses 1 to 16 where the encapsulated chemotherapy agent is fluorescent or fluorescently tagged.

[0084] Clause 18: The system of clause 17, where a fluorescence imaging system is used to visualize and / or report the amount and location of the therapeutic agent delivered to the user.

[0085] Clause 19: The system of clauses 17 or 18, where fluorescence imaging data from a fluorescence imaging system is used to control the energy delivery7device, to achieve a desired fluorescence within a user defined target tissue region.

[0086] Clause 20: The system of clause 19, where background fluorescence image data obtained before applying trigger energy is subtracted from subsequent imaging data sets obtained during or after trigger application.

[0087] Clause 21 : A method including: administering nanoparticles loaded with at least one anti-cancer agent, the nanoparticles being configured for delivery to a surgical cavity, and applying a release-triggering energy to specified regions within or adjacent to the surgical cavity, where the release-triggering energy is applied before, during, or after nanoparticle administration.

[0088] Clause 22: The method of clause 21, where the nanoparticles include triggered nanoparticles that are configured for triggered release by hyperthermia.

[0089] Clause 23: The method of clause 22, where the triggered nanoparticles are configured for triggered release by light.

[0090] Clause 24: The method of clauses 22 or 23, where the triggered nanoparticles are configured for triggered release by electromagnetic fields.

[0091] Clause 25: The method of any of clauses 22 to 24, where the triggered nanoparticles are thermosensitive liposomes.

[0092] Clause 26: The method of any of clauses 22 to 25, where the triggered nanoparticles release more than 50% of the contained drug within 10 seconds.

[0093] Clause 27: The method of any of clauses 21 to 26, where the encapsulated drug has an extraction ratio of more than 0.3 (30%).

[0094] Clause 28: The method of any of clauses 21 to 27, where trigger energy7is applied either of a predetermined duration, at a predetermined magnitude, or both predetermined magnitude and duration.

[0095] Clause 29: The method of any of clauses 21 to 28, where tissue up to a depth of from 0.5 to 3 cm of the surgical cavity surface is exposed to hyperthermia.

[0096] Clause 30: The method of clause 29, where hyperthermia is in the range from 40 to 50 °C.

[0097] Clause 31 : The method of clauses 29 or 30, where tissue surface temperature is monitored by either an infrared camera, by one or more temperature probes placed at or near the surgical cavity surface, or by both an infrared camera and temperature probes.

[0098] Clause 32: The method of any of clauses 21 to 31, where the encapsulated anticancer agent is fluorescent or tagged with a fluorescent marker. Further, fluorescence imaging is utilized to visualize the location and quantity of the delivered agent intermittently during and / or after the application of the triggering energy.

[0099] Clause 33: The method of clause 32, where fluorescence intensity is employed to control one or more of the following: the magnitude of the trigger energy, the location where trigger energy' is applied, and the duration of trigger energy application.

[0100] Clause 34: The method of any of clauses 21 to 34, where the user selects the region including all or parts of the surgical cavity where drug delivery is intended based on an image acquired of the surgical cavity7and surrounding tissue.

[0101] Clause 35: The method of clause 34, where the user selected region is exposed to a defined hyperthermic target temperature in the range from 40 to 50 °C.

[0102] Clause 36: A method including: introducing thermosensitive liposomes encapsulating doxorubicin into a bloodstream, where the liposomes are configured for triggered intravascular release at temperatures above 40 °C; targeting near-infrared radiation onto a surgical cavity surface with the radiation penetrating below the surface, where the near-infrared radiation is configured to release doxorubicin from the liposomes inside tissue capillaries, and where the released doxorubicin is configured for killing residual cancer cells remnant in tissue in a vicinity7of the surgical cavity7surface; monitoring tissue temperature and adjusting near-infrared radiation intensity based on the monitored tissue temperature; and monitoring doxorubicin delivery during near-infrared radiation exposure of the surgical cavity surface by fluorescence imaging.

[0103] Clause 37: The method of clause 36, where the thermosensitive liposomes include dipalmitoylphosphatidylcholine (DPPC); monostearoylphosphatidy lcholine (MSPC); l,2-Distearoyl-sn-Glycero-3-Phosphoethanolamine-N-Poly(ethyleneglycol)20) (DSPE- PEG2000), where the molar ratio of DPPC:MSPC:DSPE-PEG2000 is 86: 10:4, where themolar ratio of each component (DPPC, MSPC, or DSPE-PEG2000) can vary by up to 10% from the specified ratio.

[0104] Clause 38: The method of clauses 36 or 37, where tissue within about from 0.5 to 2 cm of the surgical cavity surface is heated by the near-infrared radiation to temperatures in a range from 40 to 45 °C, for a duration of 30-60 minutes.

[0105] Clause 39: The method of any of clauses 36 to 38, where cancerous tumors are either soft tissue sarcoma or oral cavity squamous cell carcinoma.

[0106] Clause 40: The method of any of clauses 36 to 39, where near-infrared radiation is emitted by a laser with a wavelength in a range from 700 to 850 nm, and where tissue temperature is monitored by either an infrared camera, or by one or more temperature probes placed at or near the surgical cavity surface.

[0107] Clause 41 : The method of clauses 39 or 40, where the temperature measurements are used to modify the intensity or duty cycle of the infrared laser as to keep the measured temperature within a defined range, preferably in a range from 40 to 45 °C.

[0108] Clause 42: The method of any of clauses 36 to 41, where a physician selects a tissue region encompassing the whole or part of the surgical cavity on a photographic image obtained before applying near-infrared radiation, and the near-infrared radiation is then applied to the selected tissue region as to heat this tissue and induce drug release from the thermosensitive liposomes, to treat remnant cancer cells present in the selected tissue region.

[0109] Clause 43: The method of any of clauses 36 to 42, where infrared radiation is applied either before, during, or after the introduction of thermosensitive liposomes encapsulating doxorubicin into a patient’s blood stream, and where the duration of the liposome infusion is in a range from 10 to 40 minutes.

[0110] Clause 44: The method of any of clauses 36 to 43, where convective air cooling with air temperature between 0 and 25 °C is applied to the tissue surface where near-infrared radiation is applied to, and where the cooling is configured to enable the exposure of deeper tissue regions to hyperthermia adequate for inducing drug release from liposomes.[OHl] Clause 45: A method including: administering thermally triggered nanoparticles configured for intravascular triggered release, loaded with at least one anti -cancer agent, into a bloodstream; and applying near-infrared energy to a tissue surrounding a surgically extracted tumor, where the near-infrared energy is configured to release the anti-cancer agent from the nanoparticles in the tissue surrounding the surgically extracted tumor.

[0112] Clause 46: The method of clause 45, where the thermally triggered nanoparticles are thermosensitive liposomes.

[0113] Clause 47: The method of clauses 45 or 46, where the thermally triggered nanoparticles are configured for intravascular release, and release more than 50% of the at least one anti-cancer agent within 10 seconds when exposed to temperatures in a range from 40 to 45 °C.

[0114] Clause 48: The method of any of clauses 45 to 47, where the near-infrared radiation is produced by a halogen lamp combined with water-filtering.

[0115] Clause 49: The method of any of clauses 45 to 48, where the at least one anticancer agent is configured for use with intravascular triggered nanoparticles, and has an extraction ratio of more than 0.3 (30%).

[0116] Clause 50: The method of any of clauses 45 to 49, where the at least one anticancer agent is either doxorubicin or idarubicin.

[0117] Clause 51 : The method of any of clauses 45 to 50, where near-infrared energy is applied either of a predetermined duration, at a predetermined intensity, or both predetermined intensity and duration.

[0118] Clause 52: The method of any of clauses 45 to 51, where tissue up to a depth in a range from 0.5 to 3 cm of the surgical cavity surface is exposed to hyperthermia in a range from 40 to 50 °C.

[0119] Clause 53: The method of any of clauses 45 to 52, where tissue surface temperature is monitored by either an infrared camera, by one or more temperature probes placed at or near the surgical cavity surface, or by both an infrared camera and temperature probes.

[0120] Clause 54: The method of any of clauses 45 to 53, where the user selects the region including all or parts of the surgical cavity where drug delivery is intended based on an image acquired of the surgical cavity and surrounding tissue before the application of near-infrared radiation.

[0121] Clause 55: The method of any of clauses 45 to 54, where the encapsulated anticancer agent is fluorescent or tagged with a fluorescent marker and where fluorescence imaging is utilized to visualize the location and quantity of the delivered fluorescent agent intermittently during and / or after the application of the near-infrared energy.

[0122] Clause 56: The method of clause 55, where a fluorescence image obtained before the infusion of encapsulated chemotherapy is subtracted from subsequent fluorescence images, and where motion correction is applied during the image subtraction.

[0123] Clause 57: The method of clause 56, where either the intensity, the location, or the duration of applied near-infrared radiation, or a combination thereof are modified based on the fluorescence images, to ensure adequate drug delivery to all targeted tissue.

[0124] Clause 58: The method of clauses 56 or 57, where near-infrared radiation is applied via a near-infrared laser, preferably in the range from 800 to 1100 nm.

[0125] Clause 59: A method including: infusing thermally triggered nanoparticles incorporating at least one anti-cancer drug, where the nanoparticles are configured for intravascular triggered release, into systemic blood circulation; and releasing drug from thermally triggered nanoparticles in a tissue surrounding a surgically extracted tumor by applying a drug-releasing energy, where the released drug is configured to kill remnant cancer cells.

[0126] Clause 60: The method of clause 59, where drug-releasing energy is applied by a near-infrared laser.

[0127] Clause 61 : The method of clauses 59 or 60, where the thermally triggered nanoparticles are thermosensitive liposomes configured for intravascular triggered release, that release more than 50% of the contained chemotherapy agent within less than 5 seconds when exposed to temperatures above 40 °C.

[0128] Clause 62: The method of any of clauses 59 to 61, where the chemotherapy agent is doxorubicin.

[0129] Clause 63: The method of any of clauses 59 to 62, where the patient is a dog or a cat with soft tissue sarcoma.

[0130] Clause 64: The method of any of clauses 59 to 63, where drug-releasing energy is applied for a predetermined duration in a range from 15 to 60 minutes, and where the intensity of the drug-releasing energy is controlled to achieve a predetermined surface tissue temperature in a range from 40 to 45 °C.

[0131] Clause 65: The method of any of clauses 59 to 64, where the chemotherapy agent is fluorescent, and fluorescence imaging is used to monitor drug delivery in real-time during the application of drug -releasing energy, and fluorescence images are visualized for observation by the treating physician.

[0132] Various examples have been described. Those skilled in the art will appreciate that numerous changes and modifications can be made to the examples described in this disclosure and that such changes and modifications can be made without departing from the spirit of the disclosure. These and other examples are within the scope of the following claims.

Claims

CLAIMSWhat is claimed is:

1. A system for drug delivery' to a surgical cavity7, the system comprising: a source of nanoparticles configured to encapsulate a therapeutic agent and being responsive to a predetermined trigger energy; and an energy delivery apparatus configured to deliver the trigger energy to facilitate the release of the therapeutic agent at specific regions within or proximate to the surgical cavity7.

2. The system of claim 1, wherein the nanoparticles are configured for triggered release by one or more of hyperthermia, ultrasound, light, or electromagnetic fields.

3. The system of claim 2, wherein the nanoparticles are thermosensitive liposomes.

4. The system of any one of claims 1 to 3, wherein the nanoparticles are configured for an intravascular release, facilitating a release of greater than 50% of the encapsulated therapeutic agent within a duration of less than 10 seconds upon exposure to the trigger energy.

5. The system of claim 1, wherein the energy delivery apparatus is an infrared source.

6. The system of claim 1, wherein the trigger energy is configured to induce drug release from nanoparticles within a depth in a range from 0.5 to 3 cm from the surgical cavity surface.

7. The system of claim 1 wherein the therapeutic agent is fluorescent or fluorescently tagged.

8. The system of claim 7, further comprising a fluorescence imaging system configured to visualize and / or report the amount and location of the therapeutic agent delivered to the user.

9. A method comprising: administering nanoparticles loaded with at least one anti-cancer agent, the nanoparticles being configured for delivery to a surgical cavity; and applying a release-triggering energy to specified regions within or adjacent to the surgical cavity, wherein the release-triggering energy is applied before, during, or after nanoparticle administration.

10. The method of claim 9, wherein the nanoparticles comprise triggered nanoparticles configured for triggered release by one or more of hyperthermia, light, or electromagnetic fields.

11. A method comprising: introducing thermosensitive liposomes encapsulating doxorubicin into a bloodstream, wherein the liposomes are configured for triggered intravascular release at temperatures above 40 °C; targeting near-infrared radiation onto a surgical cavity surface with the radiation penetrating below the surface, wherein the near-infrared radiation is configured to release doxorubicin from the liposomes inside tissue capillaries, and wherein the released doxorubicin is configured for killing residual cancer cells remnant in tissue in a vicinity of the surgical cavity surface; monitoring tissue temperature and adjusting near-infrared radiation intensity based on the monitored tissue temperature; and monitoring doxorubicin delivery during near-infrared radiation exposure of the surgical cavity surface by fluorescence imaging.

12. The method of claim 11, wherein tissue within about from 0.5 to 2 cm of the surgical cavity surface is heated by the near-infrared radiation to temperatures in a range from 40 to 45 °C, for a duration in a range from 30 to 60 minutes.

13. A method comprising: administering thermally triggered nanoparticles configured for intravascular triggered release, loaded with at least one anti-cancer agent, into a bloodstream; and applying near-infrared energy to a tissue surrounding a surgically extracted tumor, wherein the near-infrared energy' is configured to release the anti-cancer agent from the nanoparticles in the tissue surrounding the surgically extracted tumor.

14. The method of claim 13, wherein the thermally triggered nanoparticles are thermosensitive liposomes.

15. A method comprising: infusing thermally triggered nanoparticles incorporating at least one anti-cancer drug, wherein the nanoparticles are configured for intravascular triggered release, into systemic blood circulation; and releasing drug from thermally triggered nanoparticles in a tissue surrounding a surgically extracted tumor by applying a drug-releasing energy, wherein the released drug is configured to kill remnant cancer cells.

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