Pulmonary targeting microparticulate camptothecin delivery system: anticancer evaluation in a rat orthotopic lung cancer model

Abstract

Large (>6 µm) rigid microparticles (MPs) become passively entrapped within the lungs following intravenous injection making them an attractive and highly efficient alternative to inhalation for pulmonary delivery. In the current studies, PEGylated 6 μm polystyrene MPs with multiple copies of the norvaline (Nva) α-amino acid prodrug of camptothecin (CPT) were prepared. Surface morphology was characterized using a scanning electron microscope (SEM). CPT was released from the CPT-Nva-MPs over 24 hours in rat plasma at 37°C. In vivo CPT plasma concentrations were low (~1 ng/mL or less) and constant over a period of 4 days after a single intravenous injection of CPT-Nva-MPs as compared to high but short-lived systemic exposures after an IV injection of free CPT. This suggests that sustained local CPT concentrations were achieved in the lung after administration of the MP delivery system. Anti-cancer efficacy was evaluated in an orthotopic lung cancer animal model and compared to a bolus injection of CPT. Animals receiving either free CPT (2 mg/kg) or CPT-Nva-MPs (0.22 mg/kg CPT, 100 mg/kg MPs) were found to have statistically significant smaller areas of lung cancer (P<0.05, P<0.01, respectively) than untreated animals. In addition, 40% of the animals receiving CPT-Nva-MPs were found to be free of cancer. The CPT dose using targeted MPs was ten fold lower than after IV injection of free CPT but was more effective in reducing the amount of cancerous areas. In conclusion, CPT-Nva-MPs were able to achieve effective local lung and low systemic CPT concentrations at a dose that was ten times lower than systemically administered CPT resulting in a significant improvement in anticancer efficacy in an orthotopic rat model of lung cancer.

Inhaled chemotherapy in lung cancer: future concept of nanomedicine

“…157 It has been shown previously that a single cancer cell can ingest one or multiple microparticles. The ingested microparticles are arranged in such a way as to reduce the space occupied inside the cell, and the same occurs with macrophages 44,167 (Table 1, Figure 1). …”

“…The macrophages did not recognize the formulation and so did not attack, but cancer cells ingested the molecules due to the cationic charge (PEG technology). 44 However, the polystyrene microparticles used in this study cannot be used in human subjects because they cannot be eliminated from the body. Therefore, an initiative to develop biocompatible aggregated nanogel particles has been started using additional PEG technology.…”

“…Therefore, an initiative to develop biocompatible aggregated nanogel particles has been started using additional PEG technology. 44 In a study by Verschraegen et al 56 aerosol therapy was taken to a level never previously achieved. After effectiveness and safety had been observed, patients were educated to receive their therapy at home.…”

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“…Due to their small size, microspheres can be ingested or injected, can be adjusted to any desired release profile and can also exhibit site-specific as well as organ targeted drug delivery. [62] Intravenous preparation of camptothecin (natural product) loaded microspheres, formulated using oil-in-water evaporation method has been reported to provide prolonged anticancer effect. [63][64][65][66] …”

Polímeros usados como sistemas de transporte de princípios ativos

“…O poliestireno é um polímero não biodegradável, que origina micropartículas de superfície hidrofóbica, pela polimerização do estireno a temperaturas elevadas (80 °C) [81] . Foram desenvolvidas igualmente nanopartículas de poliestireno apresentando superfície hidrofílica, por polimerização através de radicais livres entre monômeros hidrofílicos e monômeros hidrofóbicos de estireno [82] .…”