The synergistic combination of two or more chemotherapeutics frequently requires packaging in single delivery vehicles for the sequential release of each substance in a predictable manner. Here, we demonstrate for the first time that the rational engineering of a prodrug cocktail into single polymeric nanoparticles (NPs) can enable the sequential release of chemotherapeutics in a controllable manner. Exploiting combretastatin-A4 (CA4, 1) as a model antiangiogenesis agent, two ester derivatives, 2 and 3, tethered with saturated fatty acids (butanoic and heptanoic acid for 2 and 3, respectively) were synthesized. 7-Ethyl-10-hydroxycamptothecin (SN38) derivative 4, esterified with α-linolenic acid, was used as a cytotoxic drug. Because of their augmented lipophilicity and miscibility, all constructed prodrugs readily assembled with clinically approved polymeric matrices. Results showed that altering the aliphatic chains of modifiers for CA4 chemical derivatization enabled the drug retention capacity within particle systems to be adjusted, leading to the identification of the prodrug cocktail of 2 and 4 as an optimal combination for subsequent preclinical studies. Furthermore, in vivo assessements indicated that the resulting NPs simultaneously formulating 2 and 4 exhibited synergistic activities and outperformed NPs loaded with individual prodrugs 2 or 4 in terms of therapeutic efficacy. These findings highlight a novel and versatile strategy for tailoring chemically disparate prodrug cocktails for adaptation within a single nanoplatform as a potential modality for synergistic cancer therapy.Keywords: antiangiogenesis; cancer nanomedicine; combination therapy; prodrug cocktail; self-assembly;

Multifunctional upconversion nanoparticles (UCNPs) that can be implemented in theranostic applications are particularly attractive scaffolds for precise drug delivery. However, most of the current methods for drug formulation are technically complicated, thereby impeding their use in the clinic. Here, we report on the preparation of a lipophilic cytotoxic prodrug-integrated and polyethylene glycol (PEG)-cloaked UCNPs scaffold through a facile one-pot supramolecular approach. By choosing 7-ethyl-10-hydroxycamptothecin (SN38)-derived prodrug 1 as a model chemotherapeutic, we show that this lipophilic prodrug can be feasibly self-assembled onto the surface of UCNPs, which are cooperatively solubilized by PEGylated phospholipids. The resulting SN38 prodrug 1-encapsulated UCNPs (designated 1@pUCNPs) produce a stable colloidal system in aqueous solution, making it suitable for intravenous injection. The SN38 drug loading capacity in pUCNPs is as high as ∼12.3 wt%, and a sustained drug release profile is observed, indicating that the drug payloads can be transported to targeted tumor sites via the enhanced permeability and retention (EPR) effect. Upconversion luminescence (UCL) imaging, including in vivo and ex vivo imaging, suggests that the drug-loaded pUCNPs remain stable in tumors over a long time and preferentially accumulate in tumors presumably via the EPR effect. Furthermore, the 1@pUCNPs show superior therapeutic outcomes compared with the clinically approved SN38 prodrug CPT-11 in the Bcap-37 mouse model of breast cancer. Collectively, our results demonstrate that pUCNPs facilely constructed in a one-pot self-assembly manner may be used as a versatile platform, enabling synchronous in vivo delivery of poorly water-soluble drugs and tumor imaging.

We here provide the first report on the construction of nanoparticles formulating highly potent cytotoxic therapeutics using albumin. Maytansinoid DM1 can be efficiently integrated into albumin nanoparticles, resulting in remarkable alleviation of in vivo drug toxicity and expanding the repertoire of albumin technology available for cancer therapy.

We present a design concept for multifunctional prodrugs that simultaneously induce apoptosis and suppress cancer cell metastasis in vitro and in vivo. These “all-in-one” prodrug constructs possess therapeutic potential as novel “integrative” platforms for metastatic cancer treatment.

Molecularly targeted agents that are designed to target specific lesions have been proven effective as clinical cancer therapies; however, most currently available therapeutic agents are poorly water-soluble and require oral administration, thereby resulting in low bioavailability and a high risk of side effects due to dose intensification. The rational engineering of systemically injectable medicines that encapsulate such therapeutic payloads may revolutionize anticancer therapies and remains an under-explored area of drug development. Here, the injectable delivery of a nanomedicine complexed with an oral multitargeted kinase inhibitor, vandetanib (vanib), was explored using polymeric nanoparticles (NPs) to achieve the selective accumulation of drug payloads within tumor lesions. To demonstrate this concept, we used biodegradable amphiphilic block copolymer poly(ethylene glycol)-block-poly(D, L-lactic acid) (PEG–PLA) to nanoprecipitate this potent agent to form water-soluble NPs that are suitable for intravenous administration. NP-vanib induced cytotoxic activity by inhibiting the angiogenetic events mediated by VEGFR and EGFR kinases in tested cancer cells and inhibited the growth, tube formation and metastasis of HUVECs. The intravenously injection of NP-vanib into mice bearing HCC BEL-7402 xenografts more effectively inhibited the tumor than the oral administration of vanib. In addition, due to the modular design of these NPs, the drug-loaded particles can easily be decorated with iRGD, a tumor-homing and -penetrating peptide motif, which further improved the in vivo performance of these vanib-loaded NPs. Our results demonstrate that reformulating targeted therapeutic agents in NPs permits their systemic administration and thus significantly improves the potency of currently available, orally delivered agents.Keywords: cancer nanomedicine; hepatocellular carcinoma; molecularly targeted agents; self-assembly; targeted delivery

Intramolecular sp3 C–H insertion reaction of α-imino rhodium carbene generated from N-sulfonyl-1,2,3-triazoles has been described. A number of 2,3-dihydrobenzofuran and benzofuran derivatives have been obtained in good to excellent yields.

Rhodium-catalyzed transannulation of 1,2,3-triazoles and ring-opening reactions of epoxides is described. A number of 3,4-dihydro-2H-1,4-oxazines are obtained in moderate yields probably involving generation of α-imino rhodium(II) carbene species.

A small library of water-soluble N-heterocyclic carbene (NHC)-stabilized palladium complexes was prepared and applied for cross-couplings of biomolecules under mild conditions in water. Pd–NHC complexes bearing hydrophilic groups were demonstrated to be efficient catalysts for the Suzuki–Miyaura coupling of various unnatural amino acids and proteins bearing p-iodophenyl functional groups. We further utilized this catalytic system for the rapid bioorthogonal labeling of proteins on the surfaces of mammalian cells. These results demonstrated that NHC-stabilized metal complexes have potential utility in cellular systems.

Intramolecular sp3 C–H insertion reaction of α-imino rhodium carbene generated from N-sulfonyl-1,2,3-triazoles has been described. A number of 2,3-dihydrobenzofuran and benzofuran derivatives have been obtained in good to excellent yields.

We present a design concept for multifunctional prodrugs that simultaneously induce apoptosis and suppress cancer cell metastasis in vitro and in vivo. These “all-in-one” prodrug constructs possess therapeutic potential as novel “integrative” platforms for metastatic cancer treatment.

We here provide the first report on the construction of nanoparticles formulating highly potent cytotoxic therapeutics using albumin. Maytansinoid DM1 can be efficiently integrated into albumin nanoparticles, resulting in remarkable alleviation of in vivo drug toxicity and expanding the repertoire of albumin technology available for cancer therapy.

Multifunctional upconversion nanoparticles (UCNPs) that can be implemented in theranostic applications are particularly attractive scaffolds for precise drug delivery. However, most of the current methods for drug formulation are technically complicated, thereby impeding their use in the clinic. Here, we report on the preparation of a lipophilic cytotoxic prodrug-integrated and polyethylene glycol (PEG)-cloaked UCNPs scaffold through a facile one-pot supramolecular approach. By choosing 7-ethyl-10-hydroxycamptothecin (SN38)-derived prodrug 1 as a model chemotherapeutic, we show that this lipophilic prodrug can be feasibly self-assembled onto the surface of UCNPs, which are cooperatively solubilized by PEGylated phospholipids. The resulting SN38 prodrug 1-encapsulated UCNPs (designated 1@pUCNPs) produce a stable colloidal system in aqueous solution, making it suitable for intravenous injection. The SN38 drug loading capacity in pUCNPs is as high as ∼12.3 wt%, and a sustained drug release profile is observed, indicating that the drug payloads can be transported to targeted tumor sites via the enhanced permeability and retention (EPR) effect. Upconversion luminescence (UCL) imaging, including in vivo and ex vivo imaging, suggests that the drug-loaded pUCNPs remain stable in tumors over a long time and preferentially accumulate in tumors presumably via the EPR effect. Furthermore, the 1@pUCNPs show superior therapeutic outcomes compared with the clinically approved SN38 prodrug CPT-11 in the Bcap-37 mouse model of breast cancer. Collectively, our results demonstrate that pUCNPs facilely constructed in a one-pot self-assembly manner may be used as a versatile platform, enabling synchronous in vivo delivery of poorly water-soluble drugs and tumor imaging.