Low-power and low-drug-dose photodynamic chemotherapy via the breakdown of tumor-targeted micelles by reactive oxygen species.

Tumor-targeted delivery of anticancer agents using nanocarriers has been explored to increase the therapeutic index of cancer chemotherapy. However, only a few nanocarriers are clinically available because the physiological complexity often compromises their ability to target, penetrate, and control the release of drugs. Here, we report a method which dramatically increases in vivo therapeutic drug efficacy levels through the photodynamic degradation of tumor-targeted nanocarriers. Folate-decorated poly(ethylene glycol)-polythioketal micelles are prepared to encapsulate paclitaxel and porphyrins. Photo-excitation generates reactive oxygen species within the micelles to cleave the polythioketal backbone efficiently and facilitate drug release only at the illuminated tumor site. Intravenous injection of a murine xenograft model with a low dose of paclitaxel within the micelles, one-milligram drug per kg (mouse), corresponding to an amount less than that of Taxol by one order of magnitude, induces dramatic tumor regression without any acute systemic inflammation responses or organ toxicity under low-power irradiation (55 mW cm-2) at 650 nm.

Cancer-targeted reactive oxygen species-degradable polymer nanoparticles for near infrared light-induced drug release.

Nanocarriers can be translocated to the peripheral region of tumor tissues through the well-known enhanced permeability and retention effects. However, a high dose of nanocarriers need to be injected due to the low delivery efficiency of nanocarriers, which can also increase the side effects of off-targeted nanocarriers in normal tissues. It was demonstrated that on-demand drug release from tumor-targeted nanocarriers can reduce the effective dosage of anti-cancer drugs by rapidly increasing the local drug concentration in the tumor tissue. Here we report a near-infrared (NIR) photodynamic method to trigger drug release from tumor-targeted polymer nanoparticles via reactive oxygen species (ROS)-mediated polymer degradation. Paclitaxel and silicon 2,3-naphthalocyanine bis(trihexylsilyloxide) were co-encapsulated as an anti-cancer drug and photosensitizer, respectively, within biotin-decorated poly(ethylene glycol)-polythioketal micelles. Upon NIR light illumination under the maximum permissible exposure level, the photoexcited naphthalocyanine generated ROS cleaved the thioketal groups in the micelles to release the encapsulated paclitaxel. The photodynamically-induced release of paclitaxel dramatically reduced the half maximal inhibitory concentration of paclitaxel by 39.9-fold and eliminated lung adenocarcinoma at a concentration an order of magnitude smaller than its maximum tolerated dosage. Even under a simulated deep tissue condition with a tissue-like phantom, the NIR light-illuminated micelles exhibited a high level of cytotoxicity against the tumor cells and efficiently suppressed tumor growth. Our study demonstrates that photodynamic polymer degradation is an effective means to improve the anticancer drug efficacy of tumor-targeted micelles.

Polyglycerolated nanocarriers with increased ligand multivalency for enhanced in vivo therapeutic efficacy of paclitaxel.

Despite the excellent biocompatibility and antifouling effect of poly(ethylene glycol) (PEG), the high steric hindrance, limited chemical functionality, and low ligand multivalency of PEGylated nanocarriers often lead to inefficient cell targeting and intracellular trafficking. Hence, a new structure of hydrophilic corona allowing a higher ligand density without loss of excellent biocompatibility is highly desirable. Here we introduce tumor-targeted polyglycerolated (PGylated) nanocarriers that dramatically enhance the in vivo therapeutic efficacy of incorporated paclitaxel simply by increasing the surface density of hydrophobic tumor-targeting ligands. Linear polyglycerol-poly (ε-caprolactone) block copolymer (PG-b-PCL) is used to prepare PGylated lipiodol nanoemulsions, where PG serves as a corona conjugated with a large number of folic acid (FA) for efficient tumor targeting. Unlike FA-PEGylated nanoemulsions, FA-PGylated nanoemulsions can display a larger number of FA without structural destabilization. This property enables excellent anti-cancer activities and effective tumor regression in a cervical cancer xenograft murine model at a cumulative drug dose of ∼5 mg kg-1, which is about four fold smaller than that of commercial Taxol formulation. This study highlights the importance of surface chemistry of nanocarriers that enable multivalent ligand functionalization and high tolerance to the conjugation of hydrophobic ligands, which make PG as a very effective hydrophilic corona for in vivo drug delivery.

Genetically Programmed Clusters of Gold Nanoparticles for Cancer Cell-Targeted Photothermal Therapy.

Interpretations of the interactions of nanocarriers with biological cells are often complicated by complex synthesis of materials, broad size distribution, and heterogeneous surface chemistry. Herein, the major capsid proteins of an icosahedral T7 phage (55 nm in diameter) are genetically engineered to display a gold-binding peptide and a prostate cancer cell-binding peptide in a tandem sequence. The genetically modified phage attracts gold nanoparticles (AuNPs) to form a cluster of gold nanoparticles (about 70 nanoparticles per phage). The cluster of AuNPs maintains cell-targeting functionality and exhibits excellent dispersion stability in serum. Under a very low light irradiation (60 mW cm(-2)), only targeted AuNP clusters kill the prostate cancer cells in minutes (not in other cell types), whereas neither nontargeted AuNP clusters nor citrate-stabilized AuNPs cause any significant cell death. The result suggests that the prostate cancer cell-targeted clusters of AuNPs are targeted to only prostate cancer cells and, when illuminated, generate local heating to more efficiently and selectively kill the targeted cancer cells. Our strategy can be generalized to target other types of cells and assemble other kinds of nanoparticles for a broad range of applications.