Successful in vivo hyperthermal therapy toward breast cancer by Chinese medicine shikonin-loaded thermosensitive micelle

Abstract

The Chinese traditional medicine Shikonin is an ideal drug due to its multiple targets to tumor cells. But in clinics, improving its aqueous solubility and tumor accumulation is still a challenge. Herein, a copolymer with tunable poly(N-isopropylacrymaide) and polylactic acid block lengths is designed, synthesized, and characterized in nuclear magnetic resonance. The corresponding thermosensitive nanomicelle (TN) with well-defined core-shell structure is then assembled in an aqueous solution. For promoting the therapeutic index, the physical-chemistry properties of TNs including narrow size, low critical micellar concentration, high serum stability, tunable volume phase transition temperature (VPTT), high drug-loading capacity, and temperature-controlled drug release are systematically investigated and regulated through the fine self-assembly. The shikonin is then entrapped in a degradable inner core resulting in a shikonin-loaded thermosensitive nanomicelle (STN) with a VPTT of ~40°C. Compared with small-molecular shikonin, the in vitro cellular internalization and cytotoxicity of STN against breast cancer cells (Michigan Cancer Foundation-7) are obviously enhanced. In addition, the therapeutic effect is further enhanced by the programmed cell death (PCD) specifically evoked by shikonin. Interestingly, both the proliferation inhibition and PCD are synergistically promoted as T > VPTT, namely the temperature-regulated passive targeting. Consequently, as intravenous injection is administered to the BALB/c nude mice bearing breast cancer, the intratumor accumulation of STNs is significantly increased as T > VPTT, which is regulated by the in-house developed heating device. The in vivo antitumor assays against breast cancer further confirm the synergistically enhanced therapeutic efficiency. The findings of this study indicate that STN is a potential effective nanoformulation in clinical cancer therapy.

<p>Novel Drug Delivery Systems for Loading of Natural Plant Extracts and Their Biomedical Applications</p>

“…134,135 More examples of herbal loaded NE are presented in Table 1. [136][137][138][139][140] Nanosphere (NS) Nanosphere is a colloidal aqueous solution with amorphous or crystalline nature having a size range between 10 and 200 nm (Figure 8) that composed of a polymeric core encapsulating active ingredients and/or adsorbing them onto the nanoparticles. 141,142 The main virtue of this system includes delayed drug release, regular plasma drug concentrations, more stability in biological fluids, high protection from enzymatic and chemical degradation, improved bioavailability, potential antitumor efficiency, enhance complete entrapment of the drug, and reduced toxicity.…”

Design of DOX-GNRs-PNIPAM@PEG-PLA Micelle With Temperature and Light Dual-Function for Potent Melanoma Therapy

“…Subsequently, 4 mg/mL PEG-PLA amphiphilic block copolymer solution (DMAC) was mixed with the PNIPAM/DOX/GNRs powder and stirred at room temperature to form the nanoparticles (Gong et al, 2019). After a 6-h reaction time, the solution was dialyzed with a dialysis bag (MW cut off 3500) against phosphate belanced solution (PBS) for 12 h in order to obtain the DAPP solution and to remove any unreacted polymer (Su et al, 2017).…”

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“…When dissolved in water, such polymer molecules assemble to form flower-like micellar structure. These flower-like micelles can dissolve the drug in the hydrophobic core and sustain drug release for long periods of time 23 . Sustained, the zero-order release has been reported using PLA-PEO-PLA (Mw of PEO = 8900 Da; Mw of PLA= 4100-6500 Da) triblock flower-like micelles (mean diameter of approximately 7-13 nm) for sulindac (20 days) and tetracaine (10 days).…”