Table 2.
Formulation strategy using tumor microenvironments for tumor targetability of DOX in preclinical stage.
| Carrier–Type | Formulation & Route of Administration | Experimental Research | Findings | References |
|---|---|---|---|---|
| pH-sensitive PLs | DOX-loaded PL (DOPE: CHEMS: DOPE-PEG2000 = 5.8:3.7:0.5), IV | 4T1 tumor-bearing mice |
Long circulating pH-sensitive liposome. Higher tumor uptake in 4T1 tumor-bearing mice |
[63] |
| Healthy mice | Less QT interval prolongation on an electrocardiogram (reduced cardiotoxicity) | [64] | ||
| pH-sensitive PNPs | DOX and pHPMA conjugates via hydrazone bond (HPMA-NH-DOX), IV |
4T1, MCF-7 cell | A 5-fold faster DOX release in acidic intratumor (pH 6.5) and intratumor cellular (pH 5.5) environments than at pH 7.4 | [65] |
| pH-sensitive PMs | DOX-loaded micelle (DSPE-PEG2000/OA = 10:6), IV |
4T1 tumor-bearing mouse |
pH-sensitive DOX release, 7-fold tumor shrinkage |
[66] |
| ROS-sensitive liposomes | DOPE/Egg PC/DDA = 37.5/60/2.5%, IV | Walker 256 carcinosarcoma-bearing rat | A 3-fold faster DOX release at pH 5.0 than at pH 7.4 A 3-fold higher apoptosis rate |
[68] |
| pH- and ROS-sensitive MSNs | Chitosan-folate conjugated MSN (DOX-MSN-SS-CH-FA), IV | C26-tumor-bearing mice | A 30% burst release in 0.1% H2O2 at pH 6.5 through the diselenide bond cleavage induced by the ROS signal The DOX-loaded liposome showed a 40-fold higher AUC than free DOX, efficient suppression of C26 tumor growth, and improved DOX distribution in tumors |
[69] |
| Rc-targeted PMs | Folate targeted PM co-delivery of DOX and SIS3 (FA/DOX/SIS3), IV | SD rat | EPR and folate Rc-mediated endocytosis P-gp and BCRP inhibition by SIS3 6.1-fold increased AUC and 3.9-fold decreased clearance of DOX compared with free DOX |
[77] |
| FA/DOX/SIS3, unilateral axillary injection | MCF-7/ADR bearing nude mice | EPR and folate Rc-mediated endocytosis P-gp and BCRP inhibition by SIS3 Increased DOX accumulation in tumor tissue Inhibited tumor growth and prolonged the lifetime in DOX resistant tumor mice |
||
| Rc-targeted and pH-sensitive PMs | HOD PM enclosed DOX-NN-VES, IV |
MCF-7/ADR bearing nude mice | EPR and CD44-mediated endocytosis pH-sensitive DOX release at acidic intratumor organelles by hydrazone bond cleavage Increased DOX accumulation in tumor tissue Increased apoptosis and 2.28-fold decreased tumor weight compared with free DOX |
[78] |
| Rc-targeted and pH-sensitive PNPs | Transferrin (Tf)- and poloxamer-integrated pH-sensitive PLGA NPs (Tf–DOX–PLGA), IV |
NCI/ADR ovarian tumor cells | P-gp inhibition in tumor cells Significant decrease in cell viability from 80% to 20% compared with free DOX Arrested cell cycle in the G1 phase and increased apoptotic cell death by 2-fold |
[79] |
PL: PEGylated liposome; PNP: polymeric nanoparticles; PM: Polymeric micelles; MSN: mesoporous silicate nanoparticles; IV: intravenous injection; Rc: Receptor; CHEMS: cholesteryl hemi succinate; DSPE-PEG2000: distearoyl phosphatidyl ethanolamine polyethyleneglycol2000; DOPE: dioleoyl phosphatidyl ethanolamine; pHPMA: Poly N-(2 hydroxypropyl) methacrylamide; OA: oleic acid; ROS: reactive oxygen species; AUC: area under the curve; HOD PM enclosed DOX-NN-VES: HA-2-(octadecyloxy)-1,3-dioxan-5-amine (HOD) PM incorporating a conjugate of DOX and vitamin E succinate using a hydrazone bond (DOX-NN-VES).