RESUMEN
Mesoscopic-sized polyion complex vesicles (PICsomes) with semi-permeable membranes are promising nanoreactors for enzyme prodrug therapy (EPT), mainly due to their ability to accommodate enzymes in their inner cavity. Increased loading efficacy and retained activity of enzymes in PICsomes are crucial for their practical application. Herein, a novel preparation method for enzyme-loaded PICsomes, the stepwise crosslinking (SWCL) method, was developed to achieve both high feed-to-loading enzyme efficiency and high enzymatic activity under in vivo conditions. Cytosine deaminase (CD), which catalyzes the conversion of the 5-fluorocytosine (5-FC) prodrug to cytotoxic 5-fluorouracil (5-FU), was loaded into PICsomes. The SWCL strategy enabled a substantial increase in CD encapsulation efficiency, up to ~44% of the feeding amount. CD-loaded PICsomes (CD@PICsomes) showed prolonged blood circulation to achieve appreciable tumor accumulation via enhanced permeability and retention effect. The combination of CD@PICsomes and 5-FC produced superior antitumor activity in a subcutaneous model of C26 murine colon adenocarcinoma, even at a lower dose than systemic 5-FU treatment, and showed significantly reduced adverse effects. These results reveal the feasibility of PICsome-based EPT as a novel, highly efficient, and safe cancer treatment modality.
RESUMEN
Polyion complex vesicles (PICsomes) are polymeric hollow capsules composed of a unique semipermeable membrane, which may represent a versatile platform for constructing drug-loaded nanoformulation. However, it is difficult to retain water-soluble low-molecular-weight compounds (LMWCs) in the inner space of PICsome because of the high permeability of PIC membrane for LMWCs. Herein, we selected mesoporous silica nanoparticle (MSN) as a drug-retaining nanomatrix, and we demonstrated successful encapsulation of MSN into the PICsome to obtain MSN@PICsome. The efficacy of MSN loading, a ratio of the amount of MSN encapsulated in the PICsome to the amount of feed MSN, was at most 83%, and the diameter of resulting product was approximately 100 nm. The obtained MSN@PICsome was stably dispersed under the physiological condition, and showed considerable longevity in blood circulation of mice. Furthermore, the surface of MSN in MSN@PICsome can be modified without any deterioration of the vesicle structure, obtaining amino-functionalized and sulfonate-functionalized MSN@PICsomes (A-MSN@PICsome and S-MSN@PICsome, respectively). Both surface-modified MSN@PICsomes were successfully loaded with charged water-soluble low-molecular-weight compounds (LMWCs). Particularly, S-MSN@PICsome kept 8 wt % gemcitabine (GEM) per S-MSN, and released it in a sustained manner. GEM-loaded S-MSN@PICsome demonstrated marked cytotoxicity against cultured tumor cells, and achieved significant in vivo efficacy to suppress the growth of subcutaneously implanted lung tumor via intravenous administration.
RESUMEN
We report the cases of 2 patients with clinical T4( cT4) esophageal cancer who achieved pathological complete response on treatment with neoadjuvant chemoradiation therapy. Case 1 involved a 68-year-old woman who was diagnosed as having cT4 advanced esophageal cancer( with involvement of the aorta and left pulmonary vein). Neoadjuvant chemoradiation therapy with 5-fluorouraci(l 5-FU)( 800 mg/m2, days 1-5 and days 29-33), cisplatin( CDDP 80 mg/m2, days 1 and 29), and radiation (39.6 Gy/22 Fr) was administered, and the tumor showed a partial response (PR). Case 2 involved a 69-year-old man who was diagnosed as having cT4 advanced esophageal cancer( with involvement of the main bronchus). Neoadjuvant chemoradiation therapy with 5-FU( 800 mg/m2, days 1-5 and days 29-33), CDDP( 80 mg/m2, days 1 and 29), and radiation( 39.6 Gy/22 Fr) was administered, and the tumor showed a clinical PR. After tumor response was noted, curative esophagectomy was performed in both cases, without any complications, and a pathological complete response was achieved in both patients.