The cell membrane is a highly selective barrier. This limits the cellular uptake of molecules including DNA, oligonucleotides, peptides and proteins used as therapeutic agents. Different approaches have been employed to increase the membrane permeability and intracellular delivery of these therapeutic molecules. One such approach is the use of Cell Penetrating Peptides (CPPs). CPPs represent a new and innovative concept, which bypasses the problem of bioavailability of drugs. The success of CPPs lies in their ability to unlock intracellular and even intranuclear targets for the delivery of agents ranging from peptides to antibodies and drug-loaded nanoparticles. This review highlights the development of cell penetrating peptides for cell-specific delivery strategies involving biomolecules that can be triggered spatially and temporally within a cell transport pathway by change in physiological conditions. The review also discusses conjugations of therapeutic agents to CPPs for enhanced intracellular delivery and bioavailability that are at the clinical stage of development.

Mixed micelles were designed to increase oral bioavailability of Apigenin (Ap). The phospholipid (Ph) complex technology was exploited alongside TPGS' stabilizing effect by PEG chain sterical hindrance of the phase II enzymes. This prevented extensive metabolism of Ap while inhibiting P-glycoprotein's exocytosis. TPGS modified micelles of Ap-Ph complex (TPGS-Ap-Ph) were prepared by thin film hydration method. Ap-Ph complex was confirmed by FTIR and NMR spectroscopy while Ap, Ph and TPGS interactions were studied by surface tensiometry. TPGS-Ap-Ph micelles achieved 87.35% drug encapsulation and 12.6% drug loading showing spherical morphology 137.1 ± 3.4 nm particle size and –12.94 mV surface charge. The negative zeta potential confirmed computer simulation predictions that PEG moieties of TPGS were at micelles surface, while hydrophobic part inserted to the phospholipid hydrophobic core by electrostatic interactions. TPGS-Ap-Ph micelles were found to be stable for more than 90 days after lyophilization. Comparing to free drug, the micelles increased intestinal absorption of Ap 2.4 fold, illustrating apparent permeation (P _app) and absorption constant (K _a) of 7.9 × 10^–4 and 2.05 × 10^–4 (p < 0.001) respectively. Moreover, cell culture studies showed high cellular uptake with sufficient intracellular trafficking in A549 cells. MTT assays revealed a significant cytotoxic effect by TPGS-Ap-Ph micelles. In vivo, an effective inhibition of 72.9% was achieved upon oral administration to S180 carcinoma mice compared to 19.5% by Ap-Ph complex. Altogether reflect that orally administered mixed micelles of TPGS-Ap-Ph could effectively inhibit cancer. The results present the designed micelles as a new way to improve oral bioavailability of sparingly soluble and poorly absorbed drugs.