ABSTRACT
To achieve target delivery of anti-tumor drugs with great biocompatibility into tumor tissues, a stimuli-responsive dendronized hyaluronic acid (HA)-docetaxel conjugate (HA-DTX-Dendron, HADD) was designed and prepared. The incorporation of HA in HADD improved the delivery of DTX to tumor cells with rich CD44 receptors. Enhanced biocompatibility and therapeutic outcomes were achieved using glyodendrons-modified HA and tumor microenvironment-responsive linkers in HADD. The glycodendron was connected with HA via GSH-responsive disulfide bonds, and the drug DTX was linked to the carrier via a cathepsin B-responsive tetrapeptide GFLG. This design resulted in self-assembly nanostructures for facilitating uptake of HADD by tumor cells and rapid release of DTX to exert its therapeutic effect. Compared to free DTX, HADD showed much higher tumor growth inhibition in the MDA-MB-231 tumor-bearing mice model (up to 99.71%), and no toxicity was observed. Therefore, HADD could be employed as an efficacious nano-agent for treating triple negative breast cancer (TNBC).
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Docetaxel/analogs & derivatives , Docetaxel/therapeutic use , Drug Carriers/chemistry , Hyaluronic Acid/analogs & derivatives , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Dendrimers/chemical synthesis , Dendrimers/chemistry , Dendrimers/metabolism , Docetaxel/metabolism , Drug Carriers/chemical synthesis , Drug Carriers/metabolism , Female , Humans , Hyaluronan Receptors/metabolism , Hyaluronic Acid/chemical synthesis , Hyaluronic Acid/metabolism , Mice, Inbred BALB C , Mice, Nude , Nanostructures/chemistry , Xenograft Model Antitumor AssaysABSTRACT
PURPOSE: CPC634 is a novel nanoparticle entrapping docetaxel, developed to enhance the intratumoral chemotherapy exposure. This randomized cross-over study compared the intratumoral and plasma pharmacokinetics of CPC634 with conventional docetaxel. PATIENTS AND METHODS: Adult patients with solid tumors were randomized to receive CPC634 (75 mg/m2) in cycle 1, and conventional docetaxel (75 mg/m2) in cycle 2 or vice versa. The study was powered to identify a 25% increase of intratumoral total docetaxel exposure after CPC634 infusion compared with conventional docetaxel. Four patients were allocated per tumor sampling time point, that is, 24, 48, 72, and 96 hours, 7 and 14 days after infusion during both cycles. Total docetaxel and released docetaxel from the nanoparticle were determined in tumor tissue derived from a metastatic lesion and in plasma. Pharmacokinetic data were analyzed using linear mixed modeling. RESULTS: In total, 24 evaluable patients were included. In the tumor, CPC634 exhibited a 461% higher total docetaxel (P < 0.001) and a comparable released docetaxel concentration (P = 0.43). Plasma AUCinf was 27% higher (P = 0.001) and C max was 91% lower (P < 0.001) for CPC634 released docetaxel. The median observed neutrophil count nadir after conventional docetaxel treatment was lower (0.50 × 109/L) compared with CPC634 (4.30 × 109/L; P < 0.001). CONCLUSIONS: Here, we demonstrated that CPC634 enhanced the intratumoral total docetaxel exposure compared with conventional docetaxel. The lower incidence of neutropenia during CPC634 treatment is presumably related to lower plasma C max of released docetaxel. The unique pharmacokinetic profile of CPC634 nanoparticles has the potential to improve docetaxel treatment. A phase II efficacy trial of CPC634 is currently ongoing.
Subject(s)
Docetaxel/pharmacokinetics , Drug Carriers/chemistry , Nanoparticles/chemistry , Neoplasms/drug therapy , Neutropenia/epidemiology , Aged , Aged, 80 and over , Biopsy , Cross-Over Studies , Docetaxel/administration & dosage , Docetaxel/adverse effects , Docetaxel/analogs & derivatives , Drug Liberation , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Neoplasms/pathology , Neutropenia/blood , Neutropenia/chemically induced , Neutropenia/diagnosis , Response Evaluation Criteria in Solid Tumors , Tissue DistributionABSTRACT
The anticancer efficacy of chemotherapy is greatly limited by short blood circulation and poor tumor selectivity. Thus, anticancer prodrugs with prolonged systemic circulation, tumor-specific distribution and bioactivation, could significantly strengthen the chemotherapy efficacy. Herein, we design two novel tumor cell reduction/oxidation-responsive docetaxel (DTX) prodrugs, DTX-maleimide conjugates with disulfide bond (DSSM) or thioether bond (DSM) linkages, to evaluate the roles of different sensitive linkages in drug release, pharmacokinetics and therapeutic efficacy. An ester bond-linkage prodrug (DM) is utilized as a non-sensitive control. DSSM and DSM show reduction- or oxidation-sensitive release behavior, respectively, and exhibit hyperselective bioactivation and cytotoxicities between cancerous and normal cells. They could instantly hitchhike blood circulating albumin after i.v. administration with albumin-binding half-lives as short as 1â¯min, resulting in prolonged systemic circulation, increased tumor accumulation. In response to the upregulated reduction/oxidation environment within tumor cells, DSSM and DSM exhibit selectively release capacity in tumor tissues, their TAITumor/Liver values are over 30-fold greater than DM. Combining the above delivery advantages into one, DSSM and DSM achieve enhanced antitumor efficacy of DTX. Such a uniquely developed strategy, integrating high albumin-binding capability and reduction/oxidation-sensitive drug superselective release in tumors, has great potential to be applied in clinical cancer therapy.
Subject(s)
Breast Neoplasms/drug therapy , Docetaxel/analogs & derivatives , Docetaxel/therapeutic use , Prodrugs/chemistry , Prodrugs/therapeutic use , Serum Albumin/metabolism , Animals , Cell Line, Tumor , Docetaxel/metabolism , Docetaxel/pharmacokinetics , Drug Liberation , Female , Humans , Male , Mice, Inbred BALB C , Oxidation-Reduction , Prodrugs/metabolism , Prodrugs/pharmacokinetics , Protein Binding , Rats, Sprague-Dawley , Tissue DistributionABSTRACT
Chemo-enzymatic synthesis of the ester-linked monosaccharide conjugate of docetaxel, 7-glycolyldocetaxel 2"-O-ß-D-galactopyranoside, was achieved by using lactase as a biocatalyst. The water-solubility and, EE and LE values for the liposome of 7-glycolyldocetaxel 2"-O-ß-D-galactopyranoside were much higher than those of docetaxel. The immunoliposome containing 7-glycolyldocetaxel 2"-O-ß-D-galactopyranoside showed effective suppression of tumor growth.
