In summary, we demonstrated that pulsed-wave ultrasound and low-dose ultrasound hyperthermia could significantly enhance the PLD delivery into the sonicated cancer cells and tumor tissues than conventional continuous-wave ultrasound and ultrasound hyperthermia under the same acoustic power and sonication duration without damaging normal brain tissues. The results indicate that this pulsed-wave ultrasound hyperthermia technology can be very useful in delivering nanodrugs for the treatment of various types of brain cancer tumors.
Furthermore, we proposed a novel treatment strategy by integrating pulsed-wave ultrasound hyperthermia enhanced delivery of PLD with constant chloroquine administration. We proved that this combinatorial strategy could persistently suppress 4T1 tumor growth and postpone its recurrence. These results may pave the way to develop new combinatorial strategy for treatment-refractory cancer. To the best of our knowledge, this is the first study to combine these elements into an integrated strategy to successfully treat cancer and prolong remission.
To push our research forward, we will generalize our treatment strategy of PLD+pUH+CQ to see if it works on different types of cancer. If it does or does not work, then we want to know what causes the distinct therapeutic response. We will also study the role of CQ in cancer therapeutics beyond autophagy inhibition. The multifaceted benefit of CQ, like vascular normalization, cancer stem cell inhibition, and decreasing nanoparticle clearance, will be assessed. With more knowledge about the actual efficacy of CQ, we can step further by combining our treatment strategy with other therapies. We may try the combination of PLD+pUH+CQ with immunotherapy. We anticipate the
immunomodulation from CQ and pUH can synergistically improve the efficacy of immunotherapy, thus cure of cancer can be achieved. Another interesting topic is to incorporate exercise. Exercise is shown to solely suppress tumor growth through mobilization of natural killer cells [83]. The finding indicates that exercise may not just benefit the function and life quality of patients, but actually exerts some direct therapeutic efficacy [84].
On the other hand, we will explore the mechanisms underlying the effects which pulsed-wave ultrasound directly acts on cancer cells, either by interacting with membranous structures or disrupting plasma membrane. We will also see if these mechanisms behave differently between malignant cells and normal cells. If so, these distinctions may provide the specificity required to design an anti-cancer therapy and therefore may lead to a novel therapeutic strategy. Then we will test different sets of ultrasound parameters (acoustic intensity, ultrasound frequency, pulse repetition frequency, etc.) to optimize the treatment efficacy. Furthermore, with knowledge about mechanisms behind bioeffects of pulsed-wave ultrasound, we may expand the applications of pulsed-wave ultrasound, such as immunomodulation and neuromodulation.
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