Efficient ultrasound-mediated drug delivery to orthotopic liver tumors - Direct comparison of doxorubicin-loaded nanobubbles and microbubbles.

Liver metastasis is a major obstacle in treating aggressive cancers, and current therapeutic options often prove insufficient. To overcome these challenges, there has been growing interest in ultrasound-mediated drug delivery using lipid-shelled microbubbles (MBs) and nanobubbles (NBs) as promising strategies for enhancing drug delivery to tumors. Our previous work demonstrated the potential of Doxorubicin-loaded C3F8 NBs (hDox-NB, 280 ± 123 nm) in improving cancer treatment in vitro using low-frequency unfocused therapeutic ultrasound (TUS). In this study, we investigated the pharmacokinetics and biodistribution of sonicated hDox-NBs in orthotopic rat liver tumors. We compared their delivery and therapeutic efficiency with size-isolated MBs (hDox-MB, 1104 ± 373 nm) made from identical shell material and core gas. Results showed a similar accumulation of hDox in tumors treated with hDox-MBs and unfocused therapeutic ultrasound (hDox-MB + TUS) and hDox-NB + TUS. However, significantly increased apoptotic cell death in the tumor and fewer off-target apoptotic cells in the normal liver were found upon the treatment with hDox-NB + TUS. The tumor-to-liver apoptotic ratio was elevated 9.4-fold following treatment with hDox-NB + TUS compared to hDox-MB + TUS, suggesting that the therapeutic efficacy and specificity are significantly increased when using hDox-NB + TUS. These findings highlight the potential of this approach as a viable treatment modality for liver tumors. By elucidating the behavior of drug-loaded bubbles in vivo, we aim to contribute to developing more effective liver cancer treatments that could ultimately improve patient outcomes and decrease off-target side effects.

Efficient ultrasound-mediated drug delivery to orthotopic liver tumors - Direct comparison of doxorubicin-loaded nanobubbles and microbubbles.

Liver metastasis is a major obstacle in treating aggressive cancers, and current therapeutic options often prove insufficient. To overcome these challenges, there has been growing interest in ultrasound-mediated drug delivery using lipid-shelled microbubbles (MBs) and nanobubbles (NBs) as promising strategies for enhancing drug delivery to tumors. Our previous work demonstrated the potential of Doxorubicin-loaded C3F8 NBs (hDox-NB, 280 ± 123 nm) in improving cancer treatment in vitro using low-frequency ultrasound. In this study, we investigated the pharmacokinetics and biodistribution of sonicated hDox-NBs in orthotopic rat liver tumors. We compared their delivery and therapeutic efficiency with size-isolated MBs (hDox-MB, 1104 ± 373 nm). Results showed a similar accumulation of hDox in tumors treated with hDox-MBs and unfocused therapeutic ultrasound (hDox-MB+TUS) and hDox-NB+TUS. However, significantly increased apoptotic cell death in the tumor and fewer off-target apoptotic cells in the normal liver were found upon the treatment with hDox-NB+TUS. The tumor-to-liver apoptotic ratio was elevated 9.4-fold following treatment with hDox-NB+TUS compared to hDox-MB+TUS, suggesting that the therapeutic efficacy and specificity are significantly increased when using hDox-NB+TUS. These findings highlight the potential of this approach as a viable treatment modality for liver tumors. By elucidating the behavior of drug-loaded bubbles in vivo, we aim to contribute to developing more effective liver cancer treatments that could ultimately improve patient outcomes and decrease off-target side effects.

Lipid-based colloidal nanoparticles for applications in targeted vaccine delivery.

Bioactive molecules and their effects have been influenced by their solubility and administration route. In many therapeutic reagents, the performance of therapeutics is dependent on physiological barriers in the human body and delivery efficacy. Therefore, an effective and stable therapeutic delivery promotes pharmaceutical advancement and suitable biological usage of drugs. In the biological and pharmacological industries, lipid nanoparticles (LNPs) have emerged as a potential carrier to deliver therapeutics. Since studies reported doxorubicin-loaded liposomes (Doxil®), LNPs have been applied to numerous clinical trials. Lipid-based nanoparticles, including liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid nanoparticles, have also been developed to deliver active ingredients in vaccines. In this review, we present the type of LNPs used to develop vaccines with attractive advantages. We then discuss messenger RNA (mRNA) delivery for the clinical application of mRNA therapeutic-loaded LNPs and recent research trend of LNP-based vaccine development.

Noninvasive calibrated tissue temperature estimation using backscattered energy of acoustic harmonics.

PURPOSE: A real-time and non-invasive thermometry technique is essential in thermal therapies to monitor and control the treatment. Ultrasound is an attractive thermometry modality due to its relatively high sensitivity to change in temperature and fast data acquisition and processing capabilities. A temperature-sensitive acoustic parameter is required for ultrasound thermometry in order to track the changes in that parameter during the treatment. Currently, the main ultrasound thermometry methods are based on variation in the attenuation coefficient, the change in backscattered energy of the signal (CBE), the backscattered radio-frequency (RF) echo-shift due to change in the speed of sound and thermal expansion of the medium, and change in the amplitudes of the acoustic harmonics. In this work, an ultrasound thermometry method based on second harmonic CBE (CBEh2) and combined fundamental and second harmonic CBE (CBEcomb) is used to produce 2D temperature maps, detect localized heated region generated by low intensity focused ultrasound (LIFU), and control temperature in the heated region. MATERIALS AND METHODS: Ex vivo pork muscle tissue samples were exposed to localized LIFU heating source and 2D temperature maps were produced from the RF data acquired by a 4.2 MHz linear array probe using a Verasonics Vantage™ ultrasound scanner (Verasonics Inc., Redmond, WA) after the exposure. Calibrated needle thermocouples were also placed in the ex vivo tissue sample close to the LIFU focal zone for temperature calibration purposes. The estimated temperature maps were the established echo-shift technique. A tissue motion compensation algorithm was also used to reduce the susceptibility to motion artifacts. RESULTS: 2D temperature maps were generated using CBE of acoustic harmonic and echo-shift techniques. The results show a direct correlation between the CBE of acoustic harmonics and focal tissue temperature for a range of temperatures from 37 °C (baseline) to 47 °C. CONCLUSIONS: The findings of this study show that the CBE of acoustic harmonics technique can be used to noninvasively estimate temperature change in tissue in the hyperthermia temperature range.

Real-Time Control of Nanoparticle-Mediated Thermal Therapy Using Photoacoustic Imaging.

OBJECTIVE: This work aims to determine whether photoacoustic (PA) thermometry from a commercially available PA imaging system can be used to control the temperature in nanoparticle-mediated thermal therapies. METHODS: The PA imaging system was interfaced to obtain PA images while scanning ex-vivo tissue. These images were then used to obtain temperature maps in real-time during heating. Validation and calibration of the PA thermometry were done using a fluoroptic thermometer. This thermometer was also used to develop and tune a software-based proportional integral derivative (PID) controller. Finally, a PA-based PID closed-loop controller was used to control gold nanorod (GNR) mediated laser therapy. RESULTS: The use of GNRs substantially enhanced laser heating; the temperature rise increased 7-fold by injecting a GNR solution with a concentration of 0.029 mg/mL. The control experiments showed that the desired temperature could be achieved and maintained at a targeted location in the ex-vivo tissue. The steady-state mean absolute deviations (MAD) from the targeted temperature during control were between 0.16 [Formula: see text] and 0.5 [Formula: see text], depending on the experiment. CONCLUSION: It was possible to control hyperthermia treatments using a software-based PID controller and a commercial PA imaging system. SIGNIFICANCE: The monitoring and control of the temperature in thermal-based therapies are important for assuring a prescribed temperature to the target tissue while minimizing the temperature of the surrounding healthy tissue. This easily implemented non-invasive control system will facilitate the realization of a broad range of hyperthermia treatments.

Determining the Radiation Enhancement Effects of Gold Nanoparticles in Cells in a Combined Treatment with Cisplatin and Radiation at Therapeutic Megavoltage Energies.

Combined use of chemotherapy and radiation therapy is commonly used in cancer treatment, but the toxic effects on normal tissue are a major limitation. This study assesses the potential to improve radiation therapy when combining gold nanoparticle (GNP) mediated radiation sensitization with chemoradiation compared to chemoradiation alone. Incorporation of GNPs with 2 Gy, 6 MV (megavoltage) radiation resulted in a 19 ± 6% decrease in survival of MDA-MB-231 cells. Monte-Carlo simulations were performed to assess dosimetric differences in the presence of GNPs in radiation. The results show that physics dosimetry represents a small fraction of the observed effect. The survival fraction of the cells exposed to GNPs, cisplatin, and radiation was 0.16 ± 0.007, while cells treated with cisplatin and radiation only was 0.23 ± 0.011. The presence of GNPs resulted in a 30 ± 6% decrease in the survival, having an additive effect. The concentration of the GNPs and free drug used for this study was 0.3 and 435 nM, respectively. These concentrations are relatively lower and achievable in an in vivo setting. Hence, the results of our study would accelerate the incorporation of GNP-mediated chemoradiation into current cancer therapeutic protocols in the near future.

Peptide Mediated In Vivo Tumor Targeting of Nanoparticles through Optimization in Single and Multilayer In Vitro Cell Models.

Optimizing the interface between nanoparticles (NPs) and the biological environment at various levels should be considered for improving delivery of NPs to the target tumor area. For NPs to be successfully delivered to cancer cells, NPs needs to be functionalized for circulation through the blood vessels. In this study, accumulation of Polyethylene Glycol (PEG) functionalized gold nanoparticles (GNPs) was first tested using in vitro monolayer cells and multilayer cell models prior to in vivo models. A diameter of 10 nm sized GNP was selected for this study for sufficient penetration through tumor tissue. The surfaces of the GNPs were modified with PEG molecules, to improve circulation time by reducing non-specific uptake by the reticuloendothelial system (RES) in animal models, and with a peptide containing integrin binding domain, RGD (arginyl-glycyl-aspartic acid), to improve internalization at the cellular level. A 10-12% accumulation of the injected GNP dose within the tumor was observed in vivo and the GNPs remained within the tumor tissue up to 72 h. This study suggests an in vitro platform for optimizing the accumulation of NP complexes in cells and tissue structures before testing them in animal models. Higher accumulation within the tumor in vivo upon surface modification is a promising outcome for future applications where GNPs can be used for drug delivery and radiation therapy.

Nuclear Targeting of Gold Nanoparticles for Improved Therapeutics.

Nanomedicine is an exponentially growing field, and gold nanoparticles (GNPs) in particular are extensively used in research due to their abilities as anti-cancer drug carriers for chemotherapy and as dose enhancers in radiotherapy. Most GNP research in the past involved a system where GNP localization was in the cytoplasm of the cell. However, it is predicted that therapy response can be enhanced if GNPs can be effectively targeted into the nucleus. With nuclear targeting, there is a possibility in producing additional free radicals in response to irradiation within the nucleus. This can cause more damage to the DNA of cancer cells. In this review article, we discuss the successful NP-based platforms available for nuclear targeting. In addition, we also present the possible mechanisms of nuclear targeting in detail followed by its applications in cancer therapy.

Colloidal Gold-Mediated Delivery of Bleomycin for Improved Outcome in Chemotherapy.

Nanoparticles (NPs) can be used to overcome the side effects of poor distribution of anticancer drugs. Among other NPs, colloidal gold nanoparticles (GNPs) offer the possibility of transporting major quantities of drugs due to their large surface-to-volume ratio. This is while confining these anticancer drugs as closely as possible to their biological targets through passive and active targeting, thus ensuring limited harmful systemic distribution. In this study, we chose to use bleomycin (BLM) as the anticancer drug due to its limited therapeutic efficiency (harmful side effects). BLM was conjugated onto GNPs through a thiol bond. The effectiveness of the chemotherapeutic drug, BLM, is observed by visualizing DNA double strand breaks and by calculating the survival fraction. The action of the drug (where the drug takes effect) is known to be in the nucleus, and our experiments have shown that some of the GNPs carrying BLM were present in the nucleus. The use of GNPs to deliver BLM increased the delivery and therapeutic efficacy of the drug. Having a better control over delivery of anticancer drugs using GNPs will establish a more successful NP-based platform for a combined therapeutic approach. This is due to the fact that GNPs can also be used as radiation dose enhancers in cancer research.

Uptake of Gold Nanoparticles in Breathless (Hypoxic) Cancer Cells.

Gold nanoparticles (GNPs) are emerging as promising novel agents for cancer therapy. However, the oxygen concentration in human tumors is highly heterogeneous, and there are many regions with very low levels of oxygen (hypoxia). A majority of solid tumors contain regions with oxygen pressure values of less than 0.7% in the gas phase. The purpose of this study was to investigate NP stability, toxicity, and cellular uptake under hypoxic conditions. GNPs 50 nm in diameter were used, and the experiment was performed under 0.2% (hypoxic) and 21% (normoxic) oxygen levels using MCF-7 and HeLa cells. Hypoxic cells with prolonged exposure (eighteen hours) to hypoxia had a higher NP uptake at both 6- and 24-hour NP incubation time points. No significant toxicity was introduced by NPs under hypoxic and normoxic conditions. These findings will play a vital role in the optimization of GNP-based therapeutics in cancer treatment.

Cancer nanotechnology: enhanced therapeutic response using peptide-modified gold nanoparticles.

The applications of nanoparticles (NPs) for improved therapeutics are at the forefront of cancer nanotechnology. Gold nanoparticles (GNPs) have been extensively used due to their ability to act as both an anticancer drug carrier in chemotherapy and as a dose enhancer in radiotherapy. GNPs used in the studies were predominantly localized in the cell cytoplasm. However, the therapeutic response can be further enhanced if NPs can be effectively targeted into the nucleus. Here, we present an effective strategy for designing a GNP-peptide complex for nuclear targeting. Two peptides were conjugated onto a NP: One peptide enhanced the uptake while the other peptide enhanced the nuclear delivery. The nuclear targeted cells displayed a four-fold increase in the therapeutic response when treated with radiation as compared to untargeted ones. There was a modest increase in the DNA damage for radiated cells with nuclear targeted GNPs. This research will establish a more successful NP-based platform for combining more than one treatment modality, such as chemotherapy and radiotherapy, and creates a more aggressive approach in eradicating cancer.