Targeted Delivery of Cisplatin-Derived Nanoprecursors via a Biomimetic Yeast Microcapsule for Tumor Therapy by the Oral Route

Abstract

Targeted therapy via the patient-friendly oral route remains the holy grail of chemotherapy for cancer. Herein we report a yeast-derived platform for targeted oral delivery of cisplatin (CDDP) that is one of the most effective drugs for chemotherapy of various types of cancers.Methods: The optimal conditions were first established to fabricate yeast microcapsules (YCs) with desirable loading capability. Then, CDDP-derived precursor nanoparticles (PreCDDP) were prepared and packaged into YC to produce orally deliverable PreCDDP/YC. The physiochemical properties, in vitro drug release profiles, in vitro antitumor activity, oral targeting capability, in vivo pharmacokinetics, and in vivo efficacy of the YC-based biomimetic delivery system were examined.Results: YCs obtained under the optimized condition showed desirable loading efficiency for quantum dots that were used as a model nanocargo. In vitro experiments demonstrated rapid endocytosis and prolonged retention of YC in macrophages. By electrostatic force-mediated self-deposition, PreCDDP was efficiently loaded into YC. PreCDDP/YC showed potent cytotoxicity in different tumor cells, indicating that PreCDDP loaded in YC maintained its antitumor activity after intracellular release. As compared to CDDP and PreCDDP, orally administered PreCDDP/YC displayed significantly higher bioavailability. Post oral delivery, YC could accumulate in A549 human lung carcinoma xenografts in mice, achieving by monocyte/macrophage-mediated translocation via the lymphatic system. Through this targeting effect, orally administered PreCDDP/YC showed desirable efficacy in A549 xenograft-bearing mice, which was comparable to that of free CDDP administered by intravenous injection. Orally administered free CDDP, however, did not afford antitumor effects. Furthermore, oral treatment with PreCDDP/YC displayed better safety than free CDDP administered via the oral or intravenous route.Conclusions: This biomimetic approach can serve as an effective strategy to develop targeted oral chemotherapies based on CDDP or its derivatives.

An update on oral drug delivery via intestinal lymphatic transport

“…Based on increasing understanding of involved mechanisms, lymphatic transport has become an important approach in drug discovery. Table 1 39 , 171 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 summarizes examples of application of lymphatic transport in oral drug delivery for reduced first-pass effect, facilitated oral absorption, distant organ targeting and lymphatic associated treatment.…”

“…Orally delivered WGA-conjugated SLNs loading paclitaxel tend to accumulate in the lung, with 6.2-fold higher local drug levels than pure paclitaxel solution 221 . By tracking the signals of the fluorescent dye Cy7.5, orally administered YCW microcapsules could be found migrating from intestinal Peyer's patches to mesenteric lymph nodes and then to MPS organs and tissues and finally reaching human lung carcinoma xenografts in mice 222 . Chitosan-binding peptide-decorated PLGA nanoparticles loading rifampicin/gantrez attained more than 10 times of drug levels in lung tissues and realized effective antifungal treatment 171 , 235 .…”

Bio-Nanocarriers for Lung Cancer Management: Befriending the Barriers

“…Furthermore, bioengineered yeast-derived vacuoles have also been explored for oncological applications [ 69 ]. Fungal bio-nanocarriers that utilize the electrostatic method/chemical modification method for conjugation of nanoparticles to yeast cells or vice versa are other sub-types of bio-nanocarriers that have been formulated for oncological applications in lung cancer [ 70 – 72 ]. The fungal bio-nanocarriers and nano-biocarriers provide an excellent platform for reasons of being an easily modifiable, cost-effective, and safer alternative to the other microbiome-derived counterparts [ 61 , 62 ].…”

“…Due to multiple surface expression of enzymes, proteins like protein G over the bacterial cell wall, the method can be employed for designing various cancer bioassays and imaging [ 34 ] Viral particles encapsulated PEG-self-assembled CdSe/ZnS quantum dots (QDs) The nano-biohybrid, composed of bromoviridae-derived viral capsid encapsulated QDs, provided high biostability with high intracellular cell uptake with minimal leaching of photoreactive products upon irradiation [ 56 ] Nanodevice based on nanoporous glass (NG)-integrated volumetric bar-chart chip (V-Chip) The ELISA-based detection device (NG-V chip) can be surface-modified for the detection of lung cancer biomarkers such as SCCA, CEA, and CYFRA 21–1 with high sensitivity. Rapid diagnosis of the device facilitates economical personalized cum point of care diagnosis in cancer patients and may be used for multiple cancer biomarker detections [ 281 ] Gadolinium (Gd 2 O 3 )-doped carbon-11-choline‑Lenvatinib (GdCo @ Ln) nanoparticles GdCo @ Ln-nanoparticles had clinically significant contrast for imaging and diagnosis, which facilitated PET imaging of lung cancer and significantly improved the survival in patients, thereby helping devise novel strategies for targeting of the malignancy [ 70 ] Bacteriophage T4-fluorescent dye nanoprobe The nanobiohybrids composed of tail-less bacteriophage T4-labelled with Alexa Fluor 546 and Cy3 fluorescent dyes were observed to give fluorescent signal enhancement of ~ 90% as compared to free counterparts. The nano-biohybrid had high intracellular stability and may be applied as a molecular nanoprobe for flow cytometry and cell imaging [ 329 ] Secondary prophylaxis/metastasis prevention Hepatitis B core Ag or the bacteriophage Q β -derived virus-like particles-encapsulated CpG motifs ( CpG-VLPs) A potent CD8 + T cell-mediated immune response against vaccinia virus and solid fibrosarcoma cells was observed on in vivo assessment of the vaccine composed of the CpG-VLPs vaccine [ 251 ] PEGylated liposome-polycation-DNA complex (P-LD) for si-RNA-mediated tumor targeting The nano-bio-hybrid improved the tumor localization and siRNA-mediated gene silencing (threefold higher) through selective survivin downregulation in lung cancer cells.…”

Prevention of Obesity Related Diseases through Laminarin-induced targeted delivery of Bindarit

“…We have previously developed a bioinspired oral targeted delivery system using a yeast-based strategy for the treatment of tumors, atherosclerosis and rheumatoid arthritis based on the recruitment of monocytes in inflammation and tumors 28 , 29 . The present study aimed to develop an oral targeted delivery system based on a natural water-soluble β-1,3 glucan, laminarin (LAM), to deliver BIN to various lesions in obesity and ORDs via monocyte-mediated transportation.…”